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e997b67c95b401a71e5936a501c3ee9a9d958154	wikidoc	Lone pair	Lone pair A lone pair is a (valence) electron pair without bonding or sharing with other atoms. They are found in the outermost electron shell of an atom, so lone pairs are a subset of a molecule's valence electrons. They can be identified by examining the outermost energy level of an atom — lone electron pairs consist of paired electrons as opposed to single electrons, which may appear if the atomic orbital is not full. Electron pairs are therefore considered lone pairs if two electrons are paired but are not used in bonding. Thus, the number of lone electrons plus the number of bonding electrons equal the total number of valence electrons from a compound. A single lone pair can be found with atoms in the nitrogen group such as nitrogen in ammonia, two lone pairs can be found with atoms in the chalcogen group such as oxygen in water and the halogens can carry three lone pairs such as in hydrochloric acid. # Angle Changes The pairs often exhibit a negative polar character with their high charge density and are located closer to the atomic nucleus on average compared to the bonding pair of electrons. The presence of a lone pair decreases the bond angle between the bonding pair of electrons, due to their high electric charge which causes great repulsion between the electrons. They are also used in the formation of a dative bond. For example, the creation of the hydronium (H3O+) ion occurs when acids are dissolved in water and is due to the oxygen atom donating a lone pair to the hydrogen ion. This can be seen more clearly when looked at in two more common molecules. For example methane (CH4) has an angle between the hydrogens of 109.5o, whereas in water (H2O) the angle between the hydrogens is just 104.5 o. As you can clearly see, if lone pairs are present (in water there are two) then the other hydrogens are pushed further away to a point where there is the least repulsion from the lone pair but also from the other electrons. That's an illustration of the VSEPR theory. # Unusual lone pairs A stereochemically active lone pair is also expected for divalent lead and tin ions due to their formal electronic configuration of ns2. In the solid state this results in the distorted metal coordination observed in the litharge structure adopted by both PbO and SnO. The formation of these heavy metal ns2 lone pairs which was previously attributed to intra-atomic hybridization of the metal s and p states has recently been shown to have a strong anion dependence. This dependence on the electronic states of the anion can explain why some divalent lead and tin materials such as PbS and SnTe show no stereochemical evidence of the lone pair and adopt the symmetric rocksalt crystal structure,. In molecular systems the lone pair can also result in a distortion in the coordination of ligands around the metal ion. The lead lone pair effect can be observed in supramolecular complexes of Lead(II) nitrate and in 2007 a study linked the lone pair to lead poisoning. Lead ions in the human metabolism replace native metallic ions in several key proteins, for example: zinc cations in the ALAD protein, which is also known as Porphobilinogen synthase. This seems to be the molecular basis of "lead poisoning", or "saturnism" ("plumbism"). Computational experiments reveal that although the coordination number does not change upon substitution in calcium-binding proteins, the introduction of lead distorts the way the ligands organize themselves to accommodate such an emerging lone pair: consequently, these proteins are perturbed. This lone-pair effect becomes dramatic for zinc-binding proteins, such as the above-mentionned porphobilinogen synthase, as the natural substrate cannot bind anymore: in those cases the protein is inhibited. Group 14 lone pairs manifest themselves in triple bonds as well. The familiar alkynes have bond order 3 with 180° bond angles (A) but going down the row germanium to germanium formal triple bonds have an effective bond order 2 with one lone pair (B) and trans-bent geometries. In lead the bond order is even 1 with lone pairs for each lead atom (C). In the organogermanium compound D, the bond order is also 1 with complexation of the acidic isonitrile groups based on interaction with germaniums empty 4p orbital	Lone pair A lone pair is a (valence) electron pair without bonding or sharing with other atoms. They are found in the outermost electron shell of an atom, so lone pairs are a subset of a molecule's valence electrons. They can be identified by examining the outermost energy level of an atom — lone electron pairs consist of paired electrons as opposed to single electrons, which may appear if the atomic orbital is not full. Electron pairs are therefore considered lone pairs if two electrons are paired but are not used in bonding. Thus, the number of lone electrons plus the number of bonding electrons equal the total number of valence electrons from a compound. A single lone pair can be found with atoms in the nitrogen group such as nitrogen in ammonia, two lone pairs can be found with atoms in the chalcogen group such as oxygen in water and the halogens can carry three lone pairs such as in hydrochloric acid. # Angle Changes The pairs often exhibit a negative polar character with their high charge density and are located closer to the atomic nucleus on average compared to the bonding pair of electrons. The presence of a lone pair decreases the bond angle between the bonding pair of electrons, due to their high electric charge which causes great repulsion between the electrons. They are also used in the formation of a dative bond. For example, the creation of the hydronium (H3O+) ion occurs when acids are dissolved in water and is due to the oxygen atom donating a lone pair to the hydrogen ion. This can be seen more clearly when looked at in two more common molecules. For example methane (CH4) has an angle between the hydrogens of 109.5o, whereas in water (H2O) the angle between the hydrogens is just 104.5 o. As you can clearly see, if lone pairs are present (in water there are two) then the other hydrogens are pushed further away to a point where there is the least repulsion from the lone pair but also from the other electrons. That's an illustration of the VSEPR theory. # Unusual lone pairs A stereochemically active lone pair is also expected for divalent lead and tin ions due to their formal electronic configuration of ns2. In the solid state this results in the distorted metal coordination observed in the litharge structure adopted by both PbO and SnO. The formation of these heavy metal ns2 lone pairs which was previously attributed to intra-atomic hybridization of the metal s and p states[1] has recently been shown to have a strong anion dependence[2]. This dependence on the electronic states of the anion can explain why some divalent lead and tin materials such as PbS and SnTe show no stereochemical evidence of the lone pair and adopt the symmetric rocksalt crystal structure[3],[4]. In molecular systems the lone pair can also result in a distortion in the coordination of ligands around the metal ion. The lead lone pair effect can be observed in supramolecular complexes of Lead(II) nitrate and in 2007 a study [5] linked the lone pair to lead poisoning. Lead ions in the human metabolism replace native metallic ions in several key proteins, for example: zinc cations in the ALAD protein, which is also known as Porphobilinogen synthase. This seems to be the molecular basis of "lead poisoning", or "saturnism" ("plumbism"). Computational experiments reveal that although the coordination number does not change upon substitution in calcium-binding proteins, the introduction of lead distorts the way the ligands organize themselves to accommodate such an emerging lone pair: consequently, these proteins are perturbed. This lone-pair effect becomes dramatic for zinc-binding proteins, such as the above-mentionned porphobilinogen synthase, as the natural substrate cannot bind anymore: in those cases the protein is inhibited. Group 14 lone pairs manifest themselves in triple bonds as well. The familiar alkynes have bond order 3 with 180° bond angles (A) but going down the row germanium to germanium formal triple bonds have an effective bond order 2 with one lone pair (B) and trans-bent geometries. In lead the bond order is even 1 with lone pairs for each lead atom (C). In the organogermanium compound D, the bond order is also 1 with complexation of the acidic isonitrile groups based on interaction with germaniums empty 4p orbital [6]	https://www.wikidoc.org/index.php/Electron_pair
b20e980a69fd6bc43866ce273400842d75eefb0c	wikidoc	Eledoisin	Eledoisin Eledoisin is an undecapeptide of mollusk origin, belonging to the tachykinin family of neuropeptides. It was first isolated from the posterior salivary glands of two mollusk species Eledone muschata and Eledone aldovandi, which belong to the octopod order of Cephalopoda. Other tachykinins from nonmammalian sources include kassinin and physalaemin. The mammalian tachykinins substance P, NKA, and NKB have similar effects as tachykinins of nonmammals and have been more widely studied and characterized. These peptides exhibit a wide and complex spectrum of pharmacological and physiological activities such as vasodilation, hypertension, and stimulation of extravascular smooth muscle. Eledoisin has the amino acid sequence pGlu-Pro-Ser-Lys-Asp-Ala-Phe-Ile-Gly-Leu-Met-NH. Like all tachykinin peptides, Eledoisin shares the same consensus C-terminal sequence, that is, Phe-Xxx-Gly-Leu-Met-NH. The invariant "Phe7" residue is probably required for receptor binding. "Xxx" is either an aromatic (phenylalanine, tyrosine) or a branched aliphatic (valine, isoleucine) side chain and is thought to be important in receptor selectivity. This common region, often referred to as the "message domain," is believed to be responsible for activating the receptor. The divergent N-terminal region or the "address domain" varies in amino-acid sequence and length and is believed to play a role in determining the receptor subtype specificity.	Eledoisin Eledoisin is an undecapeptide of mollusk origin, belonging to the tachykinin family of neuropeptides. It was first isolated from the posterior salivary glands of two mollusk species Eledone muschata and Eledone aldovandi, which belong to the octopod order of Cephalopoda. [1] Other tachykinins from nonmammalian sources include kassinin and physalaemin. The mammalian tachykinins substance P, NKA, and NKB have similar effects as tachykinins of nonmammals and have been more widely studied and characterized. These peptides exhibit a wide and complex spectrum of pharmacological and physiological activities such as vasodilation, hypertension, and stimulation of extravascular smooth muscle.[2] Eledoisin has the amino acid sequence pGlu-Pro-Ser-Lys-Asp-Ala-Phe-Ile-Gly-Leu-Met-NH. Like all tachykinin peptides, Eledoisin shares the same consensus C-terminal sequence, that is, Phe-Xxx-Gly-Leu-Met-NH. The invariant "Phe7" residue is probably required for receptor binding. "Xxx" is either an aromatic (phenylalanine, tyrosine) or a branched aliphatic (valine, isoleucine) side chain and is thought to be important in receptor selectivity. This common region, often referred to as the "message domain," is believed to be responsible for activating the receptor. The divergent N-terminal region or the "address domain" varies in amino-acid sequence and length and is believed to play a role in determining the receptor subtype specificity. [3]	https://www.wikidoc.org/index.php/Eledoisin
5c9eae626e3c321f9fb608269cf7833ce88290b6	wikidoc	Elettaria	Elettaria Elettaria is a genus of one or two species of cardamoms, native to southeastern Asia from India south to Sri Lanka and east to Malaysia and western Indonesia, where it grows in tropical rainforests. Some authorities treat the genus as containing only one species Elettaria cardamomum, while others separate Sri Lankan plants out as a separate species Elettaria repens Sonner. Common names include Green Cardamom, True Cardamom, and (E. repens) Ceylon Cardamom; in Hindi it is Elachi or Elaichi in malayalam Ellaykka. It is a pungent aromatic herbaceous perennial plant growing to 2–4 m in height. The leaves are alternate in two ranks, linear-lanceolate, 40-60 cm long, with a long pointed tip. The flowers are white to lilac or pale violet, produced in a loose spike 30-60 cm long. The fruit is a three-sided yellow-green pod 1-2 cm long, containing several black seeds. # Uses The green seed pods of the plant are dried and the seeds inside the pod are used in Indian and other Asian cuisines either whole or in a ground form. It is the most widely cultivated species of cardamom; for other types and uses, see cardamom. Ground cardamom is an ingredient in many Indian curries, and is a primary contributor to the flavour of masala chai. In the Middle East and Iran, cardamom is used to flavour coffee and tea. In Turkey, it is used to flavor the black Turkish tea (Kakakule in Turkish). As well as in its native range, it is also grown in Nepal, Vietnam, Thailand, and Central America. In India, the states of Sikkim and Kerala are the main producers of cardamom; they rank highest both in cultivated area and in production. It was first imported into Europe c.1200 CE.	Elettaria Elettaria is a genus of one or two species of cardamoms, native to southeastern Asia from India south to Sri Lanka and east to Malaysia and western Indonesia, where it grows in tropical rainforests. Some authorities treat the genus as containing only one species Elettaria cardamomum, while others separate Sri Lankan plants out as a separate species Elettaria repens Sonner. Common names include Green Cardamom, True Cardamom, and (E. repens) Ceylon Cardamom; in Hindi it is Elachi or Elaichi in malayalam Ellaykka. It is a pungent aromatic herbaceous perennial plant growing to 2–4 m in height. The leaves are alternate in two ranks, linear-lanceolate, 40-60 cm long, with a long pointed tip. The flowers are white to lilac or pale violet, produced in a loose spike 30-60 cm long. The fruit is a three-sided yellow-green pod 1-2 cm long, containing several black seeds. ## Uses The green seed pods of the plant are dried and the seeds inside the pod are used in Indian and other Asian cuisines either whole or in a ground form. It is the most widely cultivated species of cardamom; for other types and uses, see cardamom. Ground cardamom is an ingredient in many Indian curries, and is a primary contributor to the flavour of masala chai. In the Middle East and Iran, cardamom is used to flavour coffee and tea. In Turkey, it is used to flavor the black Turkish tea (Kakakule in Turkish). As well as in its native range, it is also grown in Nepal, Vietnam, Thailand, and Central America. In India, the states of Sikkim and Kerala are the main producers of cardamom; they rank highest both in cultivated area and in production. It was first imported into Europe c.1200 CE.	https://www.wikidoc.org/index.php/Elettaria
ebc1ee72d656660fa45a8d0fbb541894c042b8ec	wikidoc	Half-life	Half-life # Overview The half-life of a quantity, subject to exponential decay, is the time required for the quantity to decay to half of its initial value. The concept originated in the study of radioactive decay, but applies to many other fields as well, including phenomena which are described by non-exponential decays. The term half-life was coined in 1907, but it was always referred to as half-life period. It was not until the early 1950s that the word period was dropped from the name. The table at right shows the reduction of the quantity in terms of the number of half-lives elapsed. It can be shown that, for exponential decay, the half-life t_{1/2} obeys this relation: t_{1/2} = \frac{\ln (2)}{\lambda} where - \ln (2) is the natural logarithm of 2 (approximately 0.693), and - λ is the decay constant, a positive constant used to describe the rate of exponential decay. The half-life is related to the mean lifetime τ by the following relation: # Examples The constant \lambda can represent many different specific physical quantities, depending on what process is being described. - In an RC circuit or RL circuit, \lambda is the reciprocal of the circuit's time constant. For simple RC and RL circuits, \lambda equals 1/RC or R/L, respectively. - In first-order chemical reactions, \lambda is the reaction rate constant. - In radioactive decay, it describes the probability of decay per unit time: dN = \lambda N dt, where dN is the number of nuclei decayed during the time dt, and N is the quantity of radioactive nuclei. - In biology (specifically pharmacokinetics), from MeSH: Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Year introduced: 1974 (1971). # Decay by two or more processes Some quantities decay by two processes simultaneously (see Decay by two or more processes). In a fashion similar to the previous section, we can calculate the new total half-life T_{1/2} and we'll find it to be: -r, in terms of the two half-lives t_1 and t_2 i.e., half their harmonic mean. # Derivation Quantities that are subject to exponential decay are commonly denoted by the symbol N. (This convention suggests a decaying number of discrete items. This interpretation is valid in many, but not all, cases of exponential decay.) If the quantity is denoted by the symbol N, the value of N at a time t is given by the formula: where N_0 is the initial value of N (at t = 0) When t = 0, the exponential is equal to 1, and N(t) is equal to N_0. As t approaches infinity, the exponential approaches zero. In particular, there is a time t_{1/2} \, such that Substituting into the formula above, we have # Experimental determination The half-life of a process can be determined easily by experiment. In fact, some methods do not require advance knowledge of the law governing the decay rate, be it exponential decay or another pattern. Most appropriate to validate the concept of half-life for radioactive decay, in particular when dealing with a small number of atoms, is to perform experiments and correct computer simulations. See in how to test the behavior of the last atoms. Validation of physics-math models consists in comparing the model's behavior with experimental observations of real physical systems or valid simulations (physical and/or computer). The references given here describe how to test the validity of the exponential formula for small number of atoms with simple simulations, experiments, and computer code. In radioactive decay, the exponential model does not apply for a small number of atoms (or a small number of atoms is not within the domain of validity of the formula or equation or table). The DIY experiments use pennies or M&M's candies. , . A similar experiment is performed with isotopes of a very short half-life, for example, see Fig 5 in . See how to write a computer program that simulates radioactive decay including the required randomness in and experience the behavior of the last atoms. Of particular note, atoms undergo radioactive decay in whole units, and so after enough half-lives the remaining original quantity becomes an actual zero rather than asymptotically approaching zero as with continuous systems.	Half-life Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The half-life of a quantity, subject to exponential decay, is the time required for the quantity to decay to half of its initial value. The concept originated in the study of radioactive decay, but applies to many other fields as well, including phenomena which are described by non-exponential decays. The term half-life was coined in 1907, but it was always referred to as half-life period. It was not until the early 1950s that the word period was dropped from the name. [1] The table at right shows the reduction of the quantity in terms of the number of half-lives elapsed. It can be shown that, for exponential decay, the half-life <math>t_{1/2}</math> obeys this relation: t_{1/2} = \frac{\ln (2)}{\lambda} </math> where - <math>\ln (2)</math> is the natural logarithm of 2 (approximately 0.693), and - λ is the decay constant, a positive constant used to describe the rate of exponential decay. The half-life is related to the mean lifetime τ by the following relation: # Examples The constant <math>\lambda</math> can represent many different specific physical quantities, depending on what process is being described. - In an RC circuit or RL circuit, <math>\lambda</math> is the reciprocal of the circuit's time constant. For simple RC and RL circuits, <math>\lambda</math> equals <math>1/RC</math> or <math>R/L</math>, respectively. - In first-order chemical reactions, <math>\lambda</math> is the reaction rate constant. - In radioactive decay, it describes the probability of decay per unit time: <math>dN = \lambda N dt</math>, where dN is the number of nuclei decayed during the time dt, and N is the quantity of radioactive nuclei. - In biology (specifically pharmacokinetics), from MeSH: Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Year introduced: 1974 (1971). # Decay by two or more processes Some quantities decay by two processes simultaneously (see Decay by two or more processes). In a fashion similar to the previous section, we can calculate the new total half-life <math>T_{1/2}</math> and we'll find it to be: or, in terms of the two half-lives <math>t_1</math> and <math>t_2</math> i.e., half their harmonic mean. # Derivation Quantities that are subject to exponential decay are commonly denoted by the symbol <math>N</math>. (This convention suggests a decaying number of discrete items. This interpretation is valid in many, but not all, cases of exponential decay.) If the quantity is denoted by the symbol <math>N</math>, the value of <math>N</math> at a time <math>t</math> is given by the formula: where <math>N_0</math> is the initial value of <math>N</math> (at <math>t = 0</math>) When <math>t = 0</math>, the exponential is equal to 1, and <math>N(t)</math> is equal to <math>N_0</math>. As <math>t</math> approaches infinity, the exponential approaches zero. In particular, there is a time <math>t_{1/2} \,</math> such that Substituting into the formula above, we have # Experimental determination The half-life of a process can be determined easily by experiment. In fact, some methods do not require advance knowledge of the law governing the decay rate, be it exponential decay or another pattern. Most appropriate to validate the concept of half-life for radioactive decay, in particular when dealing with a small number of atoms, is to perform experiments and correct computer simulations. See in [2] how to test the behavior of the last atoms. Validation of physics-math models consists in comparing the model's behavior with experimental observations of real physical systems or valid simulations (physical and/or computer). The references given here describe how to test the validity of the exponential formula for small number of atoms with simple simulations, experiments, and computer code. In radioactive decay, the exponential model does not apply for a small number of atoms (or a small number of atoms is not within the domain of validity of the formula or equation or table). The DIY experiments use pennies or M&M's candies. [3], [4]. A similar experiment is performed with isotopes of a very short half-life, for example, see Fig 5 in [5]. See how to write a computer program that simulates radioactive decay including the required randomness in [6] and experience the behavior of the last atoms. Of particular note, atoms undergo radioactive decay in whole units, and so after enough half-lives the remaining original quantity becomes an actual zero rather than asymptotically approaching zero as with continuous systems.	https://www.wikidoc.org/index.php/Elimination_half-life
8275dd319df52a1f71a183d7d7e75ee61e8e10a0	wikidoc	Elinogrel	Elinogrel Elinogrel (previously known as PRT060128) is a novel, potent and selective P2Y12 inhibitor that is available in both intravenous (IV) and oral formulation. Elinogrel is a direct-acting drug (unlike thienopyridines that are pro-drugs) and does not require metabolic activation. Also, another difference from thienopyridines is that the inhibition of P2Y12 platelet receptor is reversible. Specifically, elinogrel has been shown to compete directly with ADP for binding at the P2Y12 receptor, being the first among the novel, non-thienopyridine P2Y12 inhibitors with this peculiarity. Elinogrel’s half-life is approximately 12 hours and the compound is cleared to a similar extent through the kidney and the liver. Elinogrel has recently concluded the phase II program and is currently in early phase III experimental phase. The drug is currently not commercially available. # Phase II of Elinogrel Elinogrel has been tested in 2 phase II studies, one in patients with STEMI and another in patients with stable CAD undergoing PCI. The ERASE-MI trial was a phase IIa, dose-escalation study were 70 patients with STEMI undergoing primary PCI were randomized to elinogrel or placebo. The trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and similar between all tested doses of elinogrel and placebo and also no differences in serious adverse events, laboratory values, or ST resolution were demonstrated between elinogrel and placebo. The INNOVATE-PCI was a larger phase IIb trial, in which 652 patients with stable CAD undergoing PCI were randomized in a double-blind fashion to elinogrel or matching placebo with a triple dummy design. Patients were assigned to receive either clopidogrel 300/600 mg followed by 75mg once daily or elinogrel 80 or 120 mg IV followed by 100 mg or 150 mg of orally twice daily before PCI. Compared with clopidogrel, elinogrel achieved a more rapid and potent platelet inhibition with similar rate of bleeding (which were primarily observed at the PCI access site) and also similar rate of clinical and biological efficacy end-points. Elinogrel was well tolerated but an increased incidence of dyspnea and transaminase elevation was reported. - Berger JS, Roe MT, Gibson CM, Kilaru R, Green CL, Melton L, Blankenship JD, Metzger DC, Granger CB, Gretler DD, Grines CL, Huber K, Zeymer U, Buszman P, Harrington RA, Armstrong PW (2009). "Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial". Am Heart J. 158 (6): 998–1004. PMID 19958867.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} - Leonardi S, Rao SV, Harrington RA, Bhatt DL, Gibson CM, Roe MT, Kochman J, Huber K, Zeymer U, Madan M, Gretler DD, McClure MW, Paynter GE, Thompson V, Welsh RC (2010). "Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI)". Am Heart J. 160 (1): 65–72. PMID 20598974.CS1 maint: Multiple names: authors list (link)	Elinogrel Elinogrel (previously known as PRT060128) is a novel, potent and selective P2Y12 inhibitor that is available in both intravenous (IV) and oral formulation. Elinogrel is a direct-acting drug (unlike thienopyridines that are pro-drugs) and does not require metabolic activation. Also, another difference from thienopyridines is that the inhibition of P2Y12 platelet receptor is reversible. Specifically, elinogrel has been shown to compete directly with ADP for binding at the P2Y12 receptor, being the first among the novel, non-thienopyridine P2Y12 inhibitors with this peculiarity. Elinogrel’s half-life is approximately 12 hours and the compound is cleared to a similar extent through the kidney and the liver. Elinogrel has recently concluded the phase II program and is currently in early phase III experimental phase. The drug is currently not commercially available. # Phase II of Elinogrel Elinogrel has been tested in 2 phase II studies, one in patients with STEMI and another in patients with stable CAD undergoing PCI. The ERASE-MI trial was a phase IIa, dose-escalation study were 70 patients with STEMI undergoing primary PCI were randomized to elinogrel or placebo. The trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and similar between all tested doses of elinogrel and placebo and also no differences in serious adverse events, laboratory values, or ST resolution were demonstrated between elinogrel and placebo. The INNOVATE-PCI was a larger phase IIb trial, in which 652 patients with stable CAD undergoing PCI were randomized in a double-blind fashion to elinogrel or matching placebo with a triple dummy design. Patients were assigned to receive either clopidogrel 300/600 mg followed by 75mg once daily or elinogrel 80 or 120 mg IV followed by 100 mg or 150 mg of orally twice daily before PCI. Compared with clopidogrel, elinogrel achieved a more rapid and potent platelet inhibition with similar rate of bleeding (which were primarily observed at the PCI access site) and also similar rate of clinical and biological efficacy end-points. Elinogrel was well tolerated but an increased incidence of dyspnea and transaminase elevation was reported. - Berger JS, Roe MT, Gibson CM, Kilaru R, Green CL, Melton L, Blankenship JD, Metzger DC, Granger CB, Gretler DD, Grines CL, Huber K, Zeymer U, Buszman P, Harrington RA, Armstrong PW (2009). "Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial". Am Heart J. 158 (6): 998–1004. PMID 19958867.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} - Leonardi S, Rao SV, Harrington RA, Bhatt DL, Gibson CM, Roe MT, Kochman J, Huber K, Zeymer U, Madan M, Gretler DD, McClure MW, Paynter GE, Thompson V, Welsh RC (2010). "Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI)". Am Heart J. 160 (1): 65–72. PMID 20598974.CS1 maint: Multiple names: authors list (link)	https://www.wikidoc.org/index.php/Elinogrel
c1d727d5c5594cce09cd7db20bc2fee6dce74ed1	wikidoc	Emollient	Emollient Emollients are substances which soften and soothe the skin. They are used to correct dryness and scaling of the skin. They are a key component in the manufacture of lipstick, lotions and other cosmetic products. The terms "moisturizer" (something that adds moisture) and "emollient" (something that softens) are sometimes used interchangeably, as they describe different effects of these agents on the skin. However, the term emollient is most often used to describe single ingredients, whereas "moisturizer" describes finished products. # Mechanism of action Emollients have three basic properties: - Occlusion - providing a layer of oil on the surface of the skin to slow water loss and thus increase the moisture content of the stratum corneum. - Humectant - increasing the water-holding capacity of the stratum corneum. - Lubrication - adding slip or glide across the skin.	Emollient Emollients are substances which soften and soothe the skin. They are used to correct dryness and scaling of the skin. They are a key component in the manufacture of lipstick, lotions and other cosmetic products. The terms "moisturizer" (something that adds moisture) and "emollient" (something that softens) are sometimes used interchangeably, as they describe different effects of these agents on the skin. However, the term emollient is most often used to describe single ingredients, whereas "moisturizer" describes finished products. # Mechanism of action Emollients have three basic properties: - Occlusion - providing a layer of oil on the surface of the skin to slow water loss and thus increase the moisture content of the stratum corneum. - Humectant - increasing the water-holding capacity of the stratum corneum. - Lubrication - adding slip or glide across the skin.	https://www.wikidoc.org/index.php/Emollient
07841190d01153177c5fe11636cd0233fc3c9592	wikidoc	Enadoline	Enadoline Enadoline is a drug which acts as a highly selective κ-opioid agonist. In human studies, it produced visual distortions and feelings of dissociation, reminiscent of the effects of Salvinorin-A. It was looked at as a potential analgesic, but abandoned because of the dose-limiting effects of dysphoria, which could be expected from a κ-opioid agonist. There was mention of its potential in treating comatose head injury or stroke victims, where that type of side effect would be immaterial.	Enadoline Enadoline is a drug which acts as a highly selective κ-opioid agonist. In human studies, it produced visual distortions and feelings of dissociation, reminiscent of the effects of Salvinorin-A.[1] It was looked at as a potential analgesic, but abandoned because of the dose-limiting effects of dysphoria, which could be expected from a κ-opioid agonist. There was mention of its potential in treating comatose head injury or stroke victims, where that type of side effect would be immaterial.[2] Template:Pharma-stub	https://www.wikidoc.org/index.php/Enadoline
0c5ced2c9b255684c50922b6b08c20cab5055e4b	wikidoc	Endorphin	Endorphin Endorphins ("endogenous morphine") are endogenous opioid peptides that function as neurotransmitters. They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce analgesia and a feeling of well-being. The term "endorphin" implies a pharmacological activity (analogous to the activity of the corticosteroid category of biochemicals) as opposed to a specific chemical formulation. It consists of two parts: endo- and -orphin; these are short forms of the words endogenous and morphine, intended to mean "a morphine-like substance originating from within the body." The term endorphin rush has been adopted in popular speech to refer to feelings of exhilaration brought on by pain, danger, or other forms of stress, supposedly due to the influence of endorphins. When a nerve impulse reaches the spinal cord, endorphins are released which prevent nerve cells from releasing more pain signals. Immediately after injury, endorphins allow animals to feel a sense of power and control over themselves that allows them to persist with activity for an extended time. # History Opioid neuropeptides were first discovered in 1974 by two independent groups of investigators. - John Hughes and Hans Kosterlitz of Scotland isolated — from the brain of a pig — what they called enkephalins (from the Greek εγκέφαλος, cerebrum). - Around the same time in the calf brain, Rabi Simantov and Solomon H. Snyder of the United States found what Eric Simon (who independently discovered opioid receptors in the brain) later termed "endorphin" by an abbreviation of "endogenous morphine", which literally means "morphine produced naturally in the body". Importantly, recent studies have demonstrated that diverse animal and human tissues are in fact capable of producing morphine itself, which is not a peptide. # Mechanism of action β-endorphin is released into blood from the pituitary gland and into the spinal cord and brain from hypothalamic neurons. The β-endorphin that is released into the blood cannot enter the brain in large quantities because of the blood-brain barrier so the physiological importance of the β-endorphin that can be measured in the blood is far from clear. β-endorphin is a cleavage product of pro-opiomelanocortin (POMC) which is also the precursor hormone for adrenocorticotrophic hormone (ACTH). The behavioural effects of β-endorphin are exerted by its actions in the brain and spinal cord, and probably the hypothalamic neurons are the major source of β-endorphin at these sites. In situations where the level of ACTH is increased (e.g. Cushing’s Syndrome), the level of endorphins also increases slightly. β-endorphin has the highest affinity for the μ1 opioid receptor, slightly lower affinity for the μ2 and δ opioid receptors and low affinity for the κ1 opioid receptors. μ opioid receptors are the main receptor through which morphine acts. Classically, μ opioid receptors are presynaptic, and inhibit neurotransmitter release; though through this mechanism, they inhibit the release of the inhibitory neurotransmitter GABA, and disinhibit the dopamine pathways, causing more dopamine to be released. By hijacking this process, exogenous opioids cause inappropriate dopamine release, and lead to aberrant synaptic plasticity, which causes addiction. Opioid receptors have many other and more important roles in the brain and periphery however, modulating pain, cardiac, gastric and vascular function as well as possibly panic and satiation, and receptors are often found at postsynaptic locations as well as presynaptically. # Activity Scientists debate whether specific activities release measurable levels of endorphins. Much of the current data comes from animal models which may not be relevant to humans. The studies that do involve humans often measure endorphin plasma levels, which do not necessarily correlate with levels in the central nervous system. Other studies use a blanket opioid antagonist (usually naloxone) to indirectly measure the release of endorphins by observing the changes that occur when any endorphin activity that might be present is blocked. Capsaicin (the active chemical in red chili peppers) also has been shown to stimulate endorphin release. Topical capsaicin has been used as a treatment for certain types of chronic pain. ## Runner's high Another widely publicized effect of endorphin production is the so-called "runner's high", which is said to occur when strenuous exercise takes a person over a threshold that activates endorphin production. Endorphins are released during long, continuous workouts, when the level of intensity is between moderate and high, and breathing is difficult. This also corresponds with the time that muscles use up their stored glycogen. During a release of endorphins the person may be exposed to bodily harm from strenuous bodily functions after going past his or her body's physical limit. This means that runners can keep running despite pain, continuously surpassing what they once considered to be their limit. In 2008, researchers in Germany reported on the mechanisms that cause the runner's high. Using PET scans combined with recently available chemicals that reveal endorphins in the brain, they were able to compare runners’ brains before and after a run. The runners the researchers recruited were told that the opioid receptors in their brains were being studied, and did not realize that their endorphin levels were being studied in regard to the runner's high. The participants were scanned and received psychological tests before and after a two-hour run. Data received from the study showed endorphins were produced during the exercise and were attaching themselves to areas of the brain associated with emotions (limbic and prefrontal areas). It is also suggested by many that endorphins are some of the many chemicals that contribute to runner's high; other candidates include epinephrine, serotonin, dopamine and more. Previous research on the role of endorphins in producing runner's high questioned the mechanisms at work, their data possibly demonstrated that the "high" comes from completing a challenge rather than as a result of exertion. Studies in the early 1980s cast doubt on the relationship between endorphins and the runner's high for several reasons: - The first was that when an antagonist (pharmacological agent that blocks the action for the substance under study) was infused (e.g. naloxone) or ingested (naltrexone) the same changes in mood state occurred as when the person exercised with no blocker. - A study in 2003 by Georgia Tech found that runner's high might be caused by the release of another naturally produced chemical, anandamide. The authors suggest that the body produces this chemical to deal with prolonged stress and pain from strenuous exercise, similar to the original theory involving endorphins. However, the release of anandamide was not reported with the cognitive effects of the runner's high; this suggests that anandamide release may not be significantly related to runner's high. ## Relaxation In 2003, clinical researchers reported that profound relaxation in a float tank triggers the production of endorphins. This explains the pain relief experienced during float sessions. ## Acupuncture In 1999, clinical researchers reported that inserting acupuncture needles into specific body points triggers the production of endorphins. In another study, higher levels of endorphins were found in cerebrospinal fluid after patients underwent acupuncture. In addition, naloxone appeared to block acupuncture’s pain-relieving effects. ## Pregnancy A placental tissue of foetal origin — i.e. the syncytiotrophoblast — excretes beta-endorphins into the maternal blood system from the 3rd month of pregnancy. A recent study proposes an adaptive background for this phenomenon. The authors argue that foetuses make their mothers endorphin-dependent then manipulate them to increase nutrient allocation to the placenta. Their hypothesis predicts that: (1) anatomic position of endorphin production should mirror its presumed role in foetal-maternal conflict; (2) endorphin levels should co-vary positively with nutrient carrying capacity of maternal blood system; (3) postpartum psychological symptoms (such as postpartum blues, depression and psychosis) in humans are side-effects of this mechanism that can be interpreted as endorphin-deprivation symptoms; (4) shortly after parturition, placentophagy could play an adaptive role in decreasing the negative side-effects of foetal manipulation; (5) later, breast-feeding induced endorphin excretion of the maternal pituitary saves mother from further deprivation symptoms. These predictions appear to be supported by empirical data. # Etymology From French endorphine, from (endo)gène ‘endogenous’ + mo(rphine) ‘morphine’.	Endorphin Endorphins ("endogenous morphine") are endogenous opioid peptides that function as neurotransmitters.[1] They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise,[2] excitement, pain, consumption of spicy food, love and orgasm,[3][4] and they resemble the opiates in their abilities to produce analgesia and a feeling of well-being. The term "endorphin" implies a pharmacological activity (analogous to the activity of the corticosteroid category of biochemicals) as opposed to a specific chemical formulation. It consists of two parts: endo- and -orphin; these are short forms of the words endogenous and morphine, intended to mean "a morphine-like substance originating from within the body."[5] The term endorphin rush has been adopted in popular speech to refer to feelings of exhilaration brought on by pain, danger, or other forms of stress,[2] supposedly due to the influence of endorphins. When a nerve impulse reaches the spinal cord, endorphins are released which prevent nerve cells from releasing more pain signals. Immediately after injury, endorphins allow animals to feel a sense of power and control over themselves that allows them to persist with activity for an extended time.[citation needed] # History Opioid neuropeptides were first discovered in 1974 by two independent groups of investigators. - John Hughes and Hans Kosterlitz of Scotland isolated — from the brain of a pig — what they called enkephalins (from the Greek εγκέφαλος, cerebrum).[6][7] - Around the same time in the calf brain, Rabi Simantov and Solomon H. Snyder of the United States found[8] what Eric Simon (who independently discovered opioid receptors in the brain) later termed "endorphin" by an abbreviation of "endogenous morphine", which literally means "morphine produced naturally in the body".[5] Importantly, recent studies have demonstrated that diverse animal and human tissues are in fact capable of producing morphine itself, which is not a peptide.[9][10] # Mechanism of action β-endorphin is released into blood from the pituitary gland and into the spinal cord and brain from hypothalamic neurons. The β-endorphin that is released into the blood cannot enter the brain in large quantities because of the blood-brain barrier so the physiological importance of the β-endorphin that can be measured in the blood is far from clear. β-endorphin is a cleavage product of pro-opiomelanocortin (POMC) which is also the precursor hormone for adrenocorticotrophic hormone (ACTH). The behavioural effects of β-endorphin are exerted by its actions in the brain and spinal cord, and probably the hypothalamic neurons are the major source of β-endorphin at these sites. In situations where the level of ACTH is increased (e.g. Cushing’s Syndrome), the level of endorphins also increases slightly. β-endorphin has the highest affinity for the μ1 opioid receptor, slightly lower affinity for the μ2 and δ opioid receptors and low affinity for the κ1 opioid receptors. μ opioid receptors are the main receptor through which morphine acts. Classically, μ opioid receptors are presynaptic, and inhibit neurotransmitter release; though through this mechanism, they inhibit the release of the inhibitory neurotransmitter GABA, and disinhibit the dopamine pathways, causing more dopamine to be released. By hijacking this process, exogenous opioids cause inappropriate dopamine release, and lead to aberrant synaptic plasticity, which causes addiction. Opioid receptors have many other and more important roles in the brain and periphery however, modulating pain, cardiac, gastric and vascular function as well as possibly panic and satiation, and receptors are often found at postsynaptic locations as well as presynaptically. # Activity Scientists debate whether specific activities release measurable levels of endorphins. Much of the current data comes from animal models which may not be relevant to humans. The studies that do involve humans often measure endorphin plasma levels, which do not necessarily correlate with levels in the central nervous system. Other studies use a blanket opioid antagonist (usually naloxone) to indirectly measure the release of endorphins by observing the changes that occur when any endorphin activity that might be present is blocked. Capsaicin (the active chemical in red chili peppers) also has been shown to stimulate endorphin release.[11] Topical capsaicin has been used as a treatment for certain types of chronic pain. ## Runner's high Another widely publicized effect of endorphin production is the so-called "runner's high", which is said to occur when strenuous exercise takes a person over a threshold that activates endorphin production. Endorphins are released during long, continuous workouts, when the level of intensity is between moderate and high, and breathing is difficult. This also corresponds with the time that muscles use up their stored glycogen. During a release of endorphins the person may be exposed to bodily harm from strenuous bodily functions after going past his or her body's physical limit. This means that runners can keep running despite pain, continuously surpassing what they once considered to be their limit.[citation needed] In 2008, researchers in Germany reported on the mechanisms that cause the runner's high. Using PET scans combined with recently available chemicals that reveal endorphins in the brain, they were able to compare runners’ brains before and after a run.[12] The runners the researchers recruited were told that the opioid receptors in their brains were being studied, and did not realize that their endorphin levels were being studied in regard to the runner's high. The participants were scanned and received psychological tests before and after a two-hour run. Data received from the study showed endorphins were produced during the exercise and were attaching themselves to areas of the brain associated with emotions (limbic and prefrontal areas).[13] It is also suggested by many that endorphins are some of the many chemicals that contribute to runner's high; other candidates include epinephrine, serotonin, dopamine and more. Previous research on the role of endorphins in producing runner's high questioned the mechanisms at work, their data possibly demonstrated that the "high" comes from completing a challenge rather than as a result of exertion.[14] Studies in the early 1980s cast doubt on the relationship between endorphins and the runner's high for several reasons: - The first was that when an antagonist (pharmacological agent that blocks the action for the substance under study) was infused (e.g. naloxone) or ingested (naltrexone) the same changes in mood state occurred as when the person exercised with no blocker. - A study in 2003 by Georgia Tech found that runner's high might be caused by the release of another naturally produced chemical, anandamide.[15][16] The authors suggest that the body produces this chemical to deal with prolonged stress and pain from strenuous exercise, similar to the original theory involving endorphins. However, the release of anandamide was not reported with the cognitive effects of the runner's high; this suggests that anandamide release may not be significantly related to runner's high.[16] ## Relaxation In 2003, clinical researchers reported that profound relaxation in a float tank triggers the production of endorphins.[17] This explains the pain relief experienced during float sessions. [18] ## Acupuncture In 1999, clinical researchers reported that inserting acupuncture needles into specific body points triggers the production of endorphins.[19][20] In another study, higher levels of endorphins were found in cerebrospinal fluid after patients underwent acupuncture.[21] In addition, naloxone appeared to block acupuncture’s pain-relieving effects. ## Pregnancy A placental tissue of foetal origin — i.e. the syncytiotrophoblast — excretes beta-endorphins into the maternal blood system from the 3rd month of pregnancy. A recent study [22] proposes an adaptive background for this phenomenon. The authors argue that foetuses make their mothers endorphin-dependent then manipulate them to increase nutrient allocation to the placenta. Their hypothesis predicts that: (1) anatomic position of endorphin production should mirror its presumed role in foetal-maternal conflict; (2) endorphin levels should co-vary positively with nutrient carrying capacity of maternal blood system; (3) postpartum psychological symptoms (such as postpartum blues, depression and psychosis) in humans are side-effects of this mechanism that can be interpreted as endorphin-deprivation symptoms; (4) shortly after parturition, placentophagy could play an adaptive role in decreasing the negative side-effects of foetal manipulation; (5) later, breast-feeding induced endorphin excretion of the maternal pituitary saves mother from further deprivation symptoms. These predictions appear to be supported by empirical data.[22] # Etymology From French endorphine, from (endo)gène ‘endogenous’ + mo(rphine) ‘morphine’.	https://www.wikidoc.org/index.php/Endorphin
6f5122722a3a34b466c0d6b6738e1f6bcd595036	wikidoc	Endoscopy	Endoscopy # Overview Endoscopy means looking inside and typically refers to looking inside the human body for medical reasons using an instrument called an endoscope. Endoscopy can also refer to using a borescope in technical situations where direct line-of-sight observation is not feasible. # Overview Endoscopy is a minimally invasive diagnostic medical procedure that is used to assess the interior surfaces of an organ by inserting a tube into the body. The instrument may have a rigid or flexible tube and not only provide an image for visual inspection and photography, but also enable taking biopsies and retrieval of foreign objects. Endoscopy is the vehicle for minimally invasive surgery. Many endoscopic procedures are considered to be relatively painless and, at worst, associated with mild discomfort. Most patients tolerate the procedure with only topical anaesthesia of the oropharynx using lignocaine spray (Source: Esophagogastroduodenoscopy, Wikipedia). Complications are rare (only 5% of all operations) but can include perforation of the organ under inspection with the endoscope or biopsy instrument. If that occurs open surgery may be required to repair the injury. # Components An endoscope can consist of - a rigid or flexible tube - a light delivery system to illuminate the organ or object under inspection. The light source is normally outside the body and the light is typically directed via an optical fiber system - a lens system transmitting the image to the viewer from the fiberscope - an additional channel to allow entry of medical instruments or manipulators # Uses Endoscopy can involve - The gastrointestinal tract (GI tract): -esophagus, stomach and duodenum (esophagogastroduodenoscopy) small intestine colon (colonoscopy,proctosigmoidoscopy) Bile duct endoscopic retrograde cholangiopancreatography (ERCP), duodenoscope-assisted cholangiopancreatoscopy, intraoperative cholangioscopy - oesophagus, stomach and duodenum (esophagogastroduodenoscopy) - small intestine - colon (colonoscopy,proctosigmoidoscopy) - Bile duct endoscopic retrograde cholangiopancreatography (ERCP), duodenoscope-assisted cholangiopancreatoscopy, intraoperative cholangioscopy - endoscopic retrograde cholangiopancreatography (ERCP), duodenoscope-assisted cholangiopancreatoscopy, intraoperative cholangioscopy - The respiratory tract The nose (rhinoscopy) The lower respiratory tract (bronchoscopy) - The nose (rhinoscopy) - The lower respiratory tract (bronchoscopy) - The urinary tract (cystoscopy) - The female reproductive system The cervix (colposcopy) The uterus (hysteroscopy) The Fallopian tubes (Falloscopy) - The cervix (colposcopy) - The uterus (hysteroscopy) - The Fallopian tubes (Falloscopy) - Normally closed body cavities (through a small incision): The abdominal or pelvic cavity (laparoscopy) The interior of a joint (arthroscopy) Organs of the chest (thoracoscopy and mediastinoscopy) - The abdominal or pelvic cavity (laparoscopy) - The interior of a joint (arthroscopy) - Organs of the chest (thoracoscopy and mediastinoscopy) - During pregnancy The amnion (amnioscopy) The fetus (fetoscopy) - The amnion (amnioscopy) - The fetus (fetoscopy) - Plastic Surgery - Panendoscopy (or triple endoscopy) Combines laryngoscopy, esophagoscopy, and bronchoscopy - Combines laryngoscopy, esophagoscopy, and bronchoscopy - Non-medical uses for endoscopy The planning and architectural community have found the endoscope useful for pre-visualization of scale models of proposed buildings and cities (architectural endoscopy) Internal inspection of complex technical systems (borescope) Endoscopes are also a tool helpful in the examination of improvised explosive devices by bomb disposal personnel. The FBI uses endoscopes for conducting surveillance via tight spaces. - The planning and architectural community have found the endoscope useful for pre-visualization of scale models of proposed buildings and cities (architectural endoscopy) - Internal inspection of complex technical systems (borescope) - Endoscopes are also a tool helpful in the examination of improvised explosive devices by bomb disposal personnel. - The FBI uses endoscopes for conducting surveillance via tight spaces. # History The first endoscope, of a kind, was developed in 1806 by Philip Bozzini with his introduction of a "Lichtleiter" (light conductor) "for the examinations of the canals and cavities of the human body". However, the Vienna Medical Society disapproved of such curiosity. An endoscope was first introduced into a human in 1822 by William Beaumont, an army surgeon at Mackinac Island, Michigan. The use of electric light was a major step in the improvement of endoscopy. The first such lights were external. Later, smaller bulbs became available making internal light possible, for instance in a hysteroscope by Charles David in 1908. Hans Christian Jacobaeus has been given credit for early endoscopic explorations of the abdomen and the thorax with laparoscopy (1912) and thoracoscopy (1910). Laparoscopy was used in the diagnosis of liver and gallbladder disease by Heinz Kalk in the 1930s. Hope reported in 1937 on the use of laparoscopy to diagnose ectopic pregnancy. In 1944, Raoul Palmer placed his patients in the Trendelenburg position after gaseous distention of the abdomen and thus was able to reliably perform gynecologic laparoscopy. The first gastrocamera was released in 1950 by Olympus Optical Co., Ltd. The device took pictures on monochromatic film using a small light bulb that was triggered manually. The device was of limited use, however, because it did not implement real-time optical capability. Olympus continued its development of endoscopes by incorporating fiber optics in the early 1960s, leading to the first useful endoscopes. In 1964, it released a gastrocamera guided by a fiberscope. A few articles claim that Dr.Basil Hirschowitz of Univ.Of Michigan,Ann Arbor discussed the endoscope in early 50's. As endoscopic technology improved, so did the methods of gastrointestinal endoscopy. Owing primarily to the efforts of Dr. Hiromi Shinya in the late 1960s, GI endoscopy developed into what is more recognizable as today's colonoscopy. While many doctors experimented with techniques to take advantage of the new iterations of endoscopes, Dr. Shinya focused on techniques that would allow for successful operation of the endoscope by an individual, rejecting the common practice at the time of utilizing two people. Consequently, many of the fundamental methods and procedures of modern colonoscopy were developed by Dr. Shinya. Dr. Shinya's other great contribution was to therapeutic endoscopy, in his invention of the electrosurgical polypectomy snare with the aid of Olympus employee Hiroshi Ichikawa. Shinya sketched his first plans for the device on January 8, 1969. He envisioned a loop of wire attached to the end of a colonoscope that would allow for easy removal of polyps during investigation by passing a current through the wire. By September of 1969, the first polypectomy using this device was performed. Polypectomy has since become the most common therapeutic procedure performed with an endoscope. Template:Wikiref By 1980, laparoscopy training was required by gynecologists to perform tubal ligation procedures and diagnostic evaluations of the pelvis. The first laparoscopic cholecystectomy was performed in 1984 and the first video-laparoscopic cholecystectomy in 1987. During the 1990s, laparoscopic surgery was extended to the appendix, spleen, colon, stomach, kidney, and liver. Wireless capsule endoscopy or Capsule Endoscopy is now approved in all the countries including Japan where government reimbusement will be available from Oct.2007.Capsule Endoscopy increases detection of Small Bowel tumors where traditional Endoscopy is not very efficient. # Risks - Infection - Punctured organs - Allergic reactions due to Contrast agents or dyes (such as those used in a CT scan) - Over-sedation - Unnecessary and overuse # After The Endoscopy After the procedure the patient will be observed and monitored by a qualified individual in the endoscopy or a recovery area until a significant portion of the medication has worn off. Occasionally a patient is left with a mild sore throat, which promptly responds to saline gargles, or a feeling of distention from the insufflated air that was used during the procedure. Both problems are mild and fleeting. When fully recovered, the patient will be instructed when to resume his/her usual diet (probably within a few hours) and will be allowed to be taken home. Because of the use of sedation, most facilities mandate that the patient is taken home by another person and not to drive on his/her own or handle machinery for the remainder of the day. # Recent developments With the application of robotic systems, telesurgery was introduced as the surgeon could operate from a site physically removed from the patient. The first transatlantic surgery has been called the Lindbergh Operation.	Endoscopy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Endoscopy means looking inside and typically refers to looking inside the human body for medical reasons using an instrument called an endoscope. Endoscopy can also refer to using a borescope in technical situations where direct line-of-sight observation is not feasible. # Overview Endoscopy is a minimally invasive diagnostic medical procedure that is used to assess the interior surfaces of an organ by inserting a tube into the body. The instrument may have a rigid or flexible tube and not only provide an image for visual inspection and photography, but also enable taking biopsies and retrieval of foreign objects. Endoscopy is the vehicle for minimally invasive surgery. Many endoscopic procedures are considered to be relatively painless and, at worst, associated with mild discomfort. Most patients tolerate the procedure with only topical anaesthesia of the oropharynx using lignocaine spray (Source: Esophagogastroduodenoscopy, Wikipedia). Complications are rare (only 5% of all operations) but can include perforation of the organ under inspection with the endoscope or biopsy instrument. If that occurs open surgery may be required to repair the injury. # Components An endoscope can consist of - a rigid or flexible tube - a light delivery system to illuminate the organ or object under inspection. The light source is normally outside the body and the light is typically directed via an optical fiber system - a lens system transmitting the image to the viewer from the fiberscope - an additional channel to allow entry of medical instruments or manipulators # Uses Endoscopy can involve - The gastrointestinal tract (GI tract): oesophagus, stomach and duodenum (esophagogastroduodenoscopy) small intestine colon (colonoscopy,proctosigmoidoscopy) Bile duct endoscopic retrograde cholangiopancreatography (ERCP), duodenoscope-assisted cholangiopancreatoscopy, intraoperative cholangioscopy - oesophagus, stomach and duodenum (esophagogastroduodenoscopy) - small intestine - colon (colonoscopy,proctosigmoidoscopy) - Bile duct endoscopic retrograde cholangiopancreatography (ERCP), duodenoscope-assisted cholangiopancreatoscopy, intraoperative cholangioscopy - endoscopic retrograde cholangiopancreatography (ERCP), duodenoscope-assisted cholangiopancreatoscopy, intraoperative cholangioscopy - The respiratory tract The nose (rhinoscopy) The lower respiratory tract (bronchoscopy) - The nose (rhinoscopy) - The lower respiratory tract (bronchoscopy) - The urinary tract (cystoscopy) - The female reproductive system The cervix (colposcopy) The uterus (hysteroscopy) The Fallopian tubes (Falloscopy) - The cervix (colposcopy) - The uterus (hysteroscopy) - The Fallopian tubes (Falloscopy) - Normally closed body cavities (through a small incision): The abdominal or pelvic cavity (laparoscopy) The interior of a joint (arthroscopy) Organs of the chest (thoracoscopy and mediastinoscopy) - The abdominal or pelvic cavity (laparoscopy) - The interior of a joint (arthroscopy) - Organs of the chest (thoracoscopy and mediastinoscopy) - During pregnancy The amnion (amnioscopy) The fetus (fetoscopy) - The amnion (amnioscopy) - The fetus (fetoscopy) - Plastic Surgery - Panendoscopy (or triple endoscopy) Combines laryngoscopy, esophagoscopy, and bronchoscopy - Combines laryngoscopy, esophagoscopy, and bronchoscopy - Non-medical uses for endoscopy The planning and architectural community have found the endoscope useful for pre-visualization of scale models of proposed buildings and cities (architectural endoscopy) Internal inspection of complex technical systems (borescope) Endoscopes are also a tool helpful in the examination of improvised explosive devices by bomb disposal personnel. The FBI uses endoscopes for conducting surveillance via tight spaces. - The planning and architectural community have found the endoscope useful for pre-visualization of scale models of proposed buildings and cities (architectural endoscopy) - Internal inspection of complex technical systems (borescope) - Endoscopes are also a tool helpful in the examination of improvised explosive devices by bomb disposal personnel. - The FBI uses endoscopes for conducting surveillance via tight spaces. # History The first endoscope, of a kind, was developed in 1806 by Philip Bozzini with his introduction of a "Lichtleiter" (light conductor) "for the examinations of the canals and cavities of the human body". However, the Vienna Medical Society disapproved of such curiosity. An endoscope was first introduced into a human in 1822 by William Beaumont, an army surgeon at Mackinac Island, Michigan. The use of electric light was a major step in the improvement of endoscopy. The first such lights were external. Later, smaller bulbs became available making internal light possible, for instance in a hysteroscope by Charles David in 1908. Hans Christian Jacobaeus has been given credit for early endoscopic explorations of the abdomen and the thorax with laparoscopy (1912) and thoracoscopy (1910). Laparoscopy was used in the diagnosis of liver and gallbladder disease by Heinz Kalk in the 1930s. Hope reported in 1937 on the use of laparoscopy to diagnose ectopic pregnancy. In 1944, Raoul Palmer placed his patients in the Trendelenburg position after gaseous distention of the abdomen and thus was able to reliably perform gynecologic laparoscopy. The first gastrocamera was released in 1950 by Olympus Optical Co., Ltd. The device took pictures on monochromatic film using a small light bulb that was triggered manually. The device was of limited use, however, because it did not implement real-time optical capability. Olympus continued its development of endoscopes by incorporating fiber optics in the early 1960s, leading to the first useful endoscopes. In 1964, it released a gastrocamera guided by a fiberscope.[2] A few articles claim that Dr.Basil Hirschowitz of Univ.Of Michigan,Ann Arbor discussed the endoscope in early 50's.[3] As endoscopic technology improved, so did the methods of gastrointestinal endoscopy. Owing primarily to the efforts of Dr. Hiromi Shinya in the late 1960s, GI endoscopy developed into what is more recognizable as today's colonoscopy. While many doctors experimented with techniques to take advantage of the new iterations of endoscopes, Dr. Shinya focused on techniques that would allow for successful operation of the endoscope by an individual, rejecting the common practice at the time of utilizing two people. Consequently, many of the fundamental methods and procedures of modern colonoscopy were developed by Dr. Shinya. Dr. Shinya's other great contribution was to therapeutic endoscopy, in his invention of the electrosurgical polypectomy snare with the aid of Olympus employee Hiroshi Ichikawa. Shinya sketched his first plans for the device on January 8, 1969. He envisioned a loop of wire attached to the end of a colonoscope that would allow for easy removal of polyps during investigation by passing a current through the wire. By September of 1969, the first polypectomy using this device was performed. Polypectomy has since become the most common therapeutic procedure performed with an endoscope. Template:Wikiref By 1980, laparoscopy training was required by gynecologists to perform tubal ligation procedures and diagnostic evaluations of the pelvis. The first laparoscopic cholecystectomy was performed in 1984 and the first video-laparoscopic cholecystectomy in 1987. During the 1990s, laparoscopic surgery was extended to the appendix, spleen, colon, stomach, kidney, and liver. Wireless capsule endoscopy or Capsule Endoscopy is now approved in all the countries including Japan where government reimbusement will be available from Oct.2007.Capsule Endoscopy [4] increases detection of Small Bowel tumors where traditional Endoscopy is not very efficient. # Risks - Infection - Punctured organs - Allergic reactions due to Contrast agents or dyes (such as those used in a CT scan) - Over-sedation - Unnecessary and overuse[1][2] # After The Endoscopy After the procedure the patient will be observed and monitored by a qualified individual in the endoscopy or a recovery area until a significant portion of the medication has worn off. Occasionally a patient is left with a mild sore throat, which promptly responds to saline gargles, or a feeling of distention from the insufflated air that was used during the procedure. Both problems are mild and fleeting. When fully recovered, the patient will be instructed when to resume his/her usual diet (probably within a few hours) and will be allowed to be taken home. Because of the use of sedation, most facilities mandate that the patient is taken home by another person and not to drive on his/her own or handle machinery for the remainder of the day. # Recent developments With the application of robotic systems, telesurgery was introduced as the surgeon could operate from a site physically removed from the patient. The first transatlantic surgery has been called the Lindbergh Operation.	https://www.wikidoc.org/index.php/Endoscope
303d535d2817b601ff11d77c965747f5bdc6848a	wikidoc	Endosperm	Endosperm Endosperm is the albumin tissue produced in the seeds of most flowering plants around the time of fertilization. It surrounds the embryo and provides nutrition in the form of starch, though it can also contain oils and protein. This makes endosperm an important source of nutrition in human diet. For example, wheat endosperm is ground into flour for bread (the rest of the grain is included as well in whole wheat flour), while barley endosperm is the main source for beer production. Other examples for edible endosperm are coconut "meat", popcorn and banana. # Origin of endosperm ## Double fertilization Endosperm is formed when the two sperm nuclei inside a pollen grain reach the interior of an embryo sac or female gametophyte. One sperm nucleus fertilizes the egg, forming a zygote, while the other sperm nucleus usually fuses with the two female polar nuclei at the center of the embryo sac, creating endosperm (double fertilization). Thus endosperm cells are usually triploid (containing three sets of chromosomes) but can vary widely from diploid (2n) to 15n. ## Endosperm formation There are two different types of endosperm formation, the nuclear (or liquid endosperm) type, where formation of cell wall is delayed for a number of cell divisions, and the cellular, where cell wall formation is initiated instantly. The nuclear type is the most common one in angiosperms. Sweet corn is picked for eating at the tender liquid endosperm stage, before cell walls have formed and the sugars have been converted to starch. The 'milk' of the coconut is a liquid endosperm. # The role of endosperm in seed development In some species (e.g. grains) the endosperm persists to the mature seed stage as a storage tissue, and in others it is absorbed during embryo development (e.g. common bean, Phaseolus vulgaris) and the function of storage tissue is performed by enlarged seed leaves (cotyledons). In certain species (e.g. corn, Zea mays) the storage function is distributed between both endosperm and the embryo. Some mature endosperm tissues store fats (e.g. castor bean, Ricinis communis) and others (including grains, such as wheat and corn) store mainly starches. The dust-like seeds of orchids have no endosperm. Orchid seedlings are mycoheterotrophic in their early development. In some other species, such as coffee, the endosperm also does not develop. Instead the nucellus produces a nutritive tissue termed perisperm. # Cereal grains Cereal crops are grown for their palatable fruit (grains or caryopsis), which are primarily endosperm. In the caryopsis, the thin fruit wall is fused to the seed coat. Therefore, the nutritious part of the grain is the seed and its endosperm. In some cases (e.g. wheat, rice) the endosperm is selectively retained in food processing (as in white flour), and the embryo and seed coat removed. Endosperm thus has an important role within the human diet, worldwide. The aleurone is a maternal tissue that is retained as part of the seed in many small grains. The aleurone functions for both storage and digestion. During germination it secretes the amylase enzyme that breaks down endosperm starch into sugars to nourish the growing seedling.	Endosperm Endosperm is the albumin tissue produced in the seeds of most flowering plants around the time of fertilization. It surrounds the embryo and provides nutrition in the form of starch, though it can also contain oils and protein. This makes endosperm an important source of nutrition in human diet. For example, wheat endosperm is ground into flour for bread (the rest of the grain is included as well in whole wheat flour), while barley endosperm is the main source for beer production. Other examples for edible endosperm are coconut "meat", popcorn and banana. # Origin of endosperm ## Double fertilization Endosperm is formed when the two sperm nuclei inside a pollen grain reach the interior of an embryo sac or female gametophyte. One sperm nucleus fertilizes the egg, forming a zygote, while the other sperm nucleus usually fuses with the two female polar nuclei at the center of the embryo sac, creating endosperm (double fertilization). Thus endosperm cells are usually triploid (containing three sets of chromosomes) but can vary widely from diploid (2n) to 15n. [1] ## Endosperm formation There are two different types of endosperm formation, the nuclear (or liquid endosperm) type, where formation of cell wall is delayed for a number of cell divisions, and the cellular, where cell wall formation is initiated instantly. The nuclear type is the most common one in angiosperms. Sweet corn is picked for eating at the tender liquid endosperm stage, before cell walls have formed and the sugars have been converted to starch. The 'milk' of the coconut is a liquid endosperm. # The role of endosperm in seed development In some species (e.g. grains) the endosperm persists to the mature seed stage as a storage tissue, and in others it is absorbed during embryo development (e.g. common bean, Phaseolus vulgaris) and the function of storage tissue is performed by enlarged seed leaves (cotyledons). In certain species (e.g. corn, Zea mays) the storage function is distributed between both endosperm and the embryo. Some mature endosperm tissues store fats (e.g. castor bean, Ricinis communis) and others (including grains, such as wheat and corn) store mainly starches. The dust-like seeds of orchids have no endosperm. Orchid seedlings are mycoheterotrophic in their early development. In some other species, such as coffee, the endosperm also does not develop.[2] Instead the nucellus produces a nutritive tissue termed perisperm. # Cereal grains Cereal crops are grown for their palatable fruit (grains or caryopsis), which are primarily endosperm. In the caryopsis, the thin fruit wall is fused to the seed coat. Therefore, the nutritious part of the grain is the seed and its endosperm. In some cases (e.g. wheat, rice) the endosperm is selectively retained in food processing (as in white flour), and the embryo and seed coat removed. Endosperm thus has an important role within the human diet, worldwide. The aleurone is a maternal tissue that is retained as part of the seed in many small grains. The aleurone functions for both storage and digestion. During germination it secretes the amylase enzyme that breaks down endosperm starch into sugars to nourish the growing seedling.[1]	https://www.wikidoc.org/index.php/Endosperm
64e0459e78c69551e6165516683e1cb90b3cbe24	wikidoc	Endospore	Endospore # Overview An endospore is a dormant, tough, and non-reproductive structure produced by a small number of bacteria from the Firmicute phylum. The primary function of most endospores is to ensure the survival of a bacterium through periods of environmental stress. They are therefore resistant to ultraviolet and gamma radiation, desiccation, lysozyme, temperature, starvation, and chemical disinfectants. Endospores are commonly found in soil and water, where they may survive for long periods of time. Some bacteria produce exospores or cysts instead. # Structure In contrast to eukaryotic spores, which are produced by many eukaryotes for reproductive purposes, bacteria will produce a single endospore internally. The spore is often surrounded by a thin covering known as the exosporium, which overlies the spore coat. The spore coat is impermeable to many toxic molecules and may also contain enzymes that are involved in germination. The cortex lies beneath the spore coat and consists of peptidoglycan. The core wall lies beneath the cortex and surrounds the protoplast or core of the endospore. The core has normal cell structures, such as DNA and ribosomes, but is metabolically inactive. Up to 15% of the dry weight of the endospore consists of calcium dipicolinate within the core, which is thought to stabilize the DNA. Dipicolinic acid could be responsible for the heat resistance of the spore, and calcium may aid in resistance to heat and oxidizing agents. However, mutants resistant to heat but lacking dipicolinic acid have been isolated, suggesting other mechanisms contributing to heat resistance are at work. # Location The position of the endospore differs among bacterial species and is useful in identification. The main types within the cell are terminal, subterminal and centrally placed endospores. Terminal endospores are seen at the poles of cells, whereas central endospores are more or less in the middle. Subterminal endospores are those between these two extremes, usually seen far enough towards the poles but close enough to the center so as not to be considered either terminal or central. Lateral endospores are seen occasionally. Examples of bacteria having terminal endospores include Clostridium tetani, the pathogen which causes the disease tetanus. Bacteria having a centrally placed endospore include Bacillus cereus, and those having a subterminal endospore include Bacillus subtilis. Sometimes the endospore can be so large the cell can be distended around the endospore, this is typical of Clostridium tetani. Visualising endospores under the light microscope can be difficult due to the impermeability of the endospore wall to dyes and stains. While the rest of a bacterial cell may stain, the endospore is left colourless. To combat this, a special stain technique called a Moeller stain is used. That allows the endospore to show up as red, while the rest of the cell stains blue. Another staining technique for endospores is the Schaffer-Fulton stain, which stains endospores green and bacterial bodies red. # Formation and destruction When a bacterium detects environmental conditions are becoming unfavourable it may start the process of sporulation, which takes about eight hours. The DNA is replicated and a membrane wall known as a spore septum begins to form between it and the rest of the cell. The plasma membrane of the cell surrounds this wall and pinches off to leave a double membrane around the DNA, and the developing structure is now known as a forespore. Calcium dipicolinate is incorporated into the forespore during this time. Next the peptidoglycan cortex forms between the two layers and the bacterium adds a spore coat to the outside of the forespore. Sporulation is now complete, and the mature endospore will be released when the surrounding vegetative cell is degraded. Endospores are resistant to most agents which would normally kill the vegetative cells they formed from. Household cleaning products generally have no effect, nor do most alcohols, quaternary ammonium compounds or detergents. Alkylating agents however, such as ethylene oxide, are effective against endospores. Whilst resistant to extreme heat and radiation, endospores can be destroyed by burning or autoclaving. Exposure to extreme heat for a long enough period will generally have some effect, though many endospores can survive hours of boiling or cooking. Prolonged exposure to high energy radiation, such as xrays and gamma rays, will also kill most endospores. # Reactivation Reactivation of the endospore occurs when conditions are more favourable and involves activation, germination, and outgrowth. Even if an endospore is located in plentiful nutrients, it may fail to germinate unless activation has taken place. This may be triggered by heating the endospore. Germination involves the dormant endospore starting metabolic activity and thus breaking hibernation. It is commonly characterised by rupture or absorption of the spore coat, swelling of the endospore, an increase in metabolic activity, and loss of resistance to environmental stress. Outgrowth proceeds germination and involves the core of the endospore manufacturing new chemical components and exiting the old spore coat to develop into a fully functional vegetative bacterial cell, which can divide to produce more cells. # Importance As a simplified model for cellular differentiation, the molecular details of endospore formation have been extensively studied, especially in the model organism Bacillus subtilis. These studies have contributed much to our understanding of the regulation of gene expression, transcription factors, and the sigma factor subunits of RNA polymerase. Endospores of the bacterium Bacillus anthracis were used in the 2001 anthrax attacks. The powder found in contaminated postal letters was composed of extracellular anthrax endospores. Inhalation, ingestion or skin contamination of these endospores, which were technically incorrectly labelled as "spores", led to a number of deaths. # Endospore-Forming Anaerobes Examples of endospore-forming bacteria include the genera: - Bacillus - Clostridium - Desulfotomaculum - Sporolactobacillus - Sporosarcina - Thermoactinomyces	Endospore Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An endospore is a dormant, tough, and non-reproductive structure produced by a small number of bacteria from the Firmicute phylum. The primary function of most endospores is to ensure the survival of a bacterium through periods of environmental stress. They are therefore resistant to ultraviolet and gamma radiation, desiccation, lysozyme, temperature, starvation, and chemical disinfectants. Endospores are commonly found in soil and water, where they may survive for long periods of time. Some bacteria produce exospores or cysts instead. # Structure In contrast to eukaryotic spores, which are produced by many eukaryotes for reproductive purposes, bacteria will produce a single endospore internally. The spore is often surrounded by a thin covering known as the exosporium, which overlies the spore coat. The spore coat is impermeable to many toxic molecules and may also contain enzymes that are involved in germination. The cortex lies beneath the spore coat and consists of peptidoglycan. The core wall lies beneath the cortex and surrounds the protoplast or core of the endospore. The core has normal cell structures, such as DNA and ribosomes, but is metabolically inactive. Up to 15% of the dry weight of the endospore consists of calcium dipicolinate within the core, which is thought to stabilize the DNA. Dipicolinic acid could be responsible for the heat resistance of the spore, and calcium may aid in resistance to heat and oxidizing agents. However, mutants resistant to heat but lacking dipicolinic acid have been isolated, suggesting other mechanisms contributing to heat resistance are at work[1]. # Location The position of the endospore differs among bacterial species and is useful in identification. The main types within the cell are terminal, subterminal and centrally placed endospores. Terminal endospores are seen at the poles of cells, whereas central endospores are more or less in the middle. Subterminal endospores are those between these two extremes, usually seen far enough towards the poles but close enough to the center so as not to be considered either terminal or central. Lateral endospores are seen occasionally. Examples of bacteria having terminal endospores include Clostridium tetani, the pathogen which causes the disease tetanus. Bacteria having a centrally placed endospore include Bacillus cereus, and those having a subterminal endospore include Bacillus subtilis. Sometimes the endospore can be so large the cell can be distended around the endospore, this is typical of Clostridium tetani. Visualising endospores under the light microscope can be difficult due to the impermeability of the endospore wall to dyes and stains. While the rest of a bacterial cell may stain, the endospore is left colourless. To combat this, a special stain technique called a Moeller stain is used. That allows the endospore to show up as red, while the rest of the cell stains blue. Another staining technique for endospores is the Schaffer-Fulton stain, which stains endospores green and bacterial bodies red. # Formation and destruction When a bacterium detects environmental conditions are becoming unfavourable it may start the process of sporulation, which takes about eight hours. The DNA is replicated and a membrane wall known as a spore septum begins to form between it and the rest of the cell. The plasma membrane of the cell surrounds this wall and pinches off to leave a double membrane around the DNA, and the developing structure is now known as a forespore. Calcium dipicolinate is incorporated into the forespore during this time. Next the peptidoglycan cortex forms between the two layers and the bacterium adds a spore coat to the outside of the forespore. Sporulation is now complete, and the mature endospore will be released when the surrounding vegetative cell is degraded. Endospores are resistant to most agents which would normally kill the vegetative cells they formed from. Household cleaning products generally have no effect, nor do most alcohols, quaternary ammonium compounds or detergents. Alkylating agents however, such as ethylene oxide, are effective against endospores. Whilst resistant to extreme heat and radiation, endospores can be destroyed by burning or autoclaving. Exposure to extreme heat for a long enough period will generally have some effect, though many endospores can survive hours of boiling or cooking. Prolonged exposure to high energy radiation, such as xrays and gamma rays, will also kill most endospores. # Reactivation Reactivation of the endospore occurs when conditions are more favourable and involves activation, germination, and outgrowth. Even if an endospore is located in plentiful nutrients, it may fail to germinate unless activation has taken place. This may be triggered by heating the endospore. Germination involves the dormant endospore starting metabolic activity and thus breaking hibernation. It is commonly characterised by rupture or absorption of the spore coat, swelling of the endospore, an increase in metabolic activity, and loss of resistance to environmental stress. Outgrowth proceeds germination and involves the core of the endospore manufacturing new chemical components and exiting the old spore coat to develop into a fully functional vegetative bacterial cell, which can divide to produce more cells. # Importance As a simplified model for cellular differentiation, the molecular details of endospore formation have been extensively studied, especially in the model organism Bacillus subtilis. These studies have contributed much to our understanding of the regulation of gene expression, transcription factors, and the sigma factor subunits of RNA polymerase. Endospores of the bacterium Bacillus anthracis were used in the 2001 anthrax attacks. The powder found in contaminated postal letters was composed of extracellular anthrax endospores. Inhalation, ingestion or skin contamination of these endospores, which were technically incorrectly labelled as "spores", led to a number of deaths. # Endospore-Forming Anaerobes Examples of endospore-forming bacteria include the genera: - Bacillus - Clostridium - Desulfotomaculum - Sporolactobacillus - Sporosarcina - Thermoactinomyces	https://www.wikidoc.org/index.php/Endospore
b4e5b3be155c99c4fdb0a0c0969cf75bef6886d4	wikidoc	Endothall	Endothall Endothall is used as an herbicide for both terrestrial and aquatic plants. It is used as an aquatic herbicide for submerged aquatic plants and algae in lakes, ponds and irrigation canals. It is used as a desiccant on potatoes, hops, cotton, clover and alfalfa. It is used as a biocide to control mollusks and algae in cooling towers. The chemical formula for endothall is C8H10O5. Its Chemical Abstracts Service (CAS) name is 7-oxabicycloheptane-2,3-dicarboxylic acid. Endothall is an organic acid but is used as the dipotassium salt or the mono-N,N-dimethylalkylamine salt. Endothall is considered safe in drinking water by the EPA up to a maximum contaminant level of 0.1 mg/L (100 ppb). Some people who drink water contaminated by endothall above the maximum contaminant level set by the EPA for many years may experience stomach or intestinal problems.	Endothall Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Endothall is used as an herbicide for both terrestrial and aquatic plants. It is used as an aquatic herbicide for submerged aquatic plants and algae in lakes, ponds and irrigation canals.[1] It is used as a desiccant on potatoes, hops, cotton, clover and alfalfa. It is used as a biocide to control mollusks and algae in cooling towers. The chemical formula for endothall is C8H10O5. Its Chemical Abstracts Service (CAS) name is 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid. Endothall is an organic acid but is used as the dipotassium salt or the mono-N,N-dimethylalkylamine salt.[2] Endothall is considered safe in drinking water by the EPA up to a maximum contaminant level of 0.1 mg/L (100 ppb). Some people who drink water contaminated by endothall above the maximum contaminant level set by the EPA for many years may experience stomach or intestinal problems.[3]	https://www.wikidoc.org/index.php/Endothall
6b2af1e59357eb35b65419cbbf8830161ca1efaa	wikidoc	Enoxolone	Enoxolone # Overview Enoxolone (INN, BAN), glycyrrhetinic acid or glycyrrhetic acid is a pentacyclic triterpenoid derivative of the beta-amyrin type obtained from the hydrolysis of glycyrrhizic acid, which was obtained from the herb liquorice. It is used in flavoring and it masks the bitter taste of drugs like aloe and quinine. It is effective in the treatment of peptic ulcer and also has expectorant (antitussive) properties. It has some additional pharmacological properties including antiviral, antifungal, antiprotozoal, and antibacterial activities. # Mechanism of action Glycyrrhetinic acid inhibits the enzymes (15-hydroxyprostaglandin dehydrogenase and delta-13-prostaglandin) that metabolize the prostaglandins PGE-2 and PGF-2α to their respective 15-keto-13,14-dihydro metabolites which are inactive. This causes an increased level of prostaglandins in the digestive system. Prostaglandins inhibit gastric secretion but stimulate pancreatic secretion and mucous secretion in the intestines and markedly increase intestinal motility. They also cause cell proliferation in the stomach. The effect on gastric acid secretion, promotion of mucous secretion and cell proliferation shows why licorice has potential in treating peptic ulcer. PGF-2α stimulates activity of the uterus during pregnancy and can cause abortion, therefore, licorice should not be taken during pregnancy. The structure of glycyrrhetinic acid is similar to that of cortisone. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory action. 3-β-D-(Monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of 'active' cortisol to 'inactive' cortisone in the kidneys. This occurs via inhibition of the enzyme by inhibiting the enzyme 11-β-hydroxysteroid dehydrogenase. As a result, cortisol levels are high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like aldosterone and increases sodium reabsorption) that work on ENaC channels in the collecting duct. Hypertension develops due to this mechanism of sodium retention. People often have high blood pressure with a low renin and low aldosterone blood level. The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, high blood pressure and inhibition of the renin-angiotensin-aldosterone system. Therefore licorice should not be given to patients with a known history of hypertension in doses sufficient to inhibit 11-β-hydroxysteroid dehydrogenase. # Derivatives In glycyrrhetinic acid, the functional group (R) is a hydroxyl group. Research in 2005 demonstrated that with a proper functional group a very effective glycyrrhetinic artificial sweetener can be obtained. When R is an anionic NHCO(CH2)CO2K side chain, the sweetening effect is found to 1200 times that of sugar (human sensory panel data). A shorter or longer spacer reduces the sweetening effect. One explanation is that the taste bud cell receptor has 1.3 nanometers (13 angstroms) available for docking with the sweetener molecule. In addition the sweetener molecule requires three proton donor positions of which two reside at the extremities to be able to interact efficiently with the receptor cavity. A synthetic analog, carbenoxolone, was developed in Britain. Both glycyrrhetinic acid and carbenoxolone have a modulatory effect on neural signaling through gap junction channels. Acetoxolone, the acetyl derivative of glycyrrhetinic acid, is a drug used in the treatment of peptic ulcer and gastroesophageal reflux disease.	Enoxolone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Enoxolone (INN, BAN), glycyrrhetinic acid or glycyrrhetic acid is a pentacyclic triterpenoid derivative of the beta-amyrin type obtained from the hydrolysis of glycyrrhizic acid, which was obtained from the herb liquorice. It is used in flavoring and it masks the bitter taste of drugs like aloe and quinine. It is effective in the treatment of peptic ulcer and also has expectorant (antitussive) properties.[1] It has some additional pharmacological properties including antiviral, antifungal, antiprotozoal, and antibacterial activities.[2][3][4][5] # Mechanism of action Glycyrrhetinic acid inhibits the enzymes (15-hydroxyprostaglandin dehydrogenase and delta-13-prostaglandin) that metabolize the prostaglandins PGE-2 and PGF-2α to their respective 15-keto-13,14-dihydro metabolites which are inactive. This causes an increased level of prostaglandins in the digestive system. Prostaglandins inhibit gastric secretion but stimulate pancreatic secretion and mucous secretion in the intestines and markedly increase intestinal motility. They also cause cell proliferation in the stomach. The effect on gastric acid secretion, promotion of mucous secretion and cell proliferation shows why licorice has potential in treating peptic ulcer. PGF-2α stimulates activity of the uterus during pregnancy and can cause abortion, therefore, licorice should not be taken during pregnancy. The structure of glycyrrhetinic acid is similar to that of cortisone. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory action. 3-β-D-(Monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of 'active' cortisol to 'inactive' cortisone in the kidneys. This occurs via inhibition of the enzyme by inhibiting the enzyme 11-β-hydroxysteroid dehydrogenase. As a result, cortisol levels are high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like aldosterone and increases sodium reabsorption) that work on ENaC channels in the collecting duct. Hypertension develops due to this mechanism of sodium retention. People often have high blood pressure with a low renin and low aldosterone blood level. The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, high blood pressure and inhibition of the renin-angiotensin-aldosterone system. Therefore licorice should not be given to patients with a known history of hypertension in doses sufficient to inhibit 11-β-hydroxysteroid dehydrogenase. # Derivatives In glycyrrhetinic acid, the functional group (R) is a hydroxyl group. Research in 2005 demonstrated that with a proper functional group a very effective glycyrrhetinic artificial sweetener can be obtained.[6] When R is an anionic NHCO(CH2)CO2K side chain, the sweetening effect is found to 1200 times that of sugar (human sensory panel data). A shorter or longer spacer reduces the sweetening effect. One explanation is that the taste bud cell receptor has 1.3 nanometers (13 angstroms) available for docking with the sweetener molecule. In addition the sweetener molecule requires three proton donor positions of which two reside at the extremities to be able to interact efficiently with the receptor cavity. A synthetic analog, carbenoxolone, was developed in Britain.[citation needed] Both glycyrrhetinic acid and carbenoxolone have a modulatory effect on neural signaling through gap junction channels. Acetoxolone, the acetyl derivative of glycyrrhetinic acid, is a drug used in the treatment of peptic ulcer and gastroesophageal reflux disease.	https://www.wikidoc.org/index.php/Enoxolone
9232cb1cc66dbc88a635829c167c851f57c3ea81	wikidoc	Entamoeba	Entamoeba Entamoeba is a genus of Amoebozoa found as internal parasites or commensals of animals. Several species are found in humans. Entamoeba histolytica is the pathogen responsible for amoebiasis (which includes amoebic dysentery and amoebic liver abscesses), while others such as Entamoeba coli and E. dispar are harmless. With the exception of Entamoeba gingivalis, which lives in the mouth, and E. moshkovskii, which is frequently isolated from river and lake sediments, all Entamoeba species are found in the intestines of the animals they infect. Entamoeba cells are small, with a single nucleus and typically a single lobose pseudopod taking the form of a clear anterior bulge. They have a simple life cycle. The trophozoite (feeding-dividing form) is approximately 10-20 μm in diameter and feeds primarily on bacteria. It divides by simple binary fission to form two smaller daughter cells. Almost all species form cysts, the stage involved in transmission (the exception is E. gingivalis). Depending on the species, these can have one, four or eight nuclei and are variable in size; these characteristics help in species identification. Entamoeba belongs to the Archamoebae, which are unusual in lacking mitochondria. This group also includes Endolimax, which also lives in animals and is similar in appearance to Entamoeba, although this may partly be due to convergence. Certain other genera of symbiotic amoebae, such as Endamoeba, might prove to be synonyms of Entamoeba but this is still unclear. Studying Entamoeba invadens, David Biron of the Weizmann Institute of Science and coworkers found that about one third of the cells are unable to separate unaided and recruit a neighboring amoeba (dubbed the "midwife") to complete the fission. He writes: They also reported a similar behavior in Dictyostelium.	Entamoeba Entamoeba is a genus of Amoebozoa found as internal parasites or commensals of animals. Several species are found in humans. Entamoeba histolytica is the pathogen responsible for amoebiasis (which includes amoebic dysentery and amoebic liver abscesses), while others such as Entamoeba coli and E. dispar are harmless. With the exception of Entamoeba gingivalis, which lives in the mouth, and E. moshkovskii, which is frequently isolated from river and lake sediments, all Entamoeba species are found in the intestines of the animals they infect. Entamoeba cells are small, with a single nucleus and typically a single lobose pseudopod taking the form of a clear anterior bulge. They have a simple life cycle. The trophozoite (feeding-dividing form) is approximately 10-20 μm in diameter and feeds primarily on bacteria. It divides by simple binary fission to form two smaller daughter cells. Almost all species form cysts, the stage involved in transmission (the exception is E. gingivalis). Depending on the species, these can have one, four or eight nuclei and are variable in size; these characteristics help in species identification. Entamoeba belongs to the Archamoebae, which are unusual in lacking mitochondria. This group also includes Endolimax, which also lives in animals and is similar in appearance to Entamoeba, although this may partly be due to convergence. Certain other genera of symbiotic amoebae, such as Endamoeba, might prove to be synonyms of Entamoeba but this is still unclear. Studying Entamoeba invadens, David Biron of the Weizmann Institute of Science and coworkers found that about one third of the cells are unable to separate unaided and recruit a neighboring amoeba (dubbed the "midwife") to complete the fission.[1] He writes: They also reported a similar behavior in Dictyostelium.	https://www.wikidoc.org/index.php/Entamoeba
29a6b3488dc3bf59f7253dc8fc2f94d76d2f9edd	wikidoc	Entropion	Entropion # Overview Entropion is a medical condition in which the eyelids fold inward. It is very uncomfortable, as the eyelashes rub against the cornea constantly. Entropion is usually caused by genetic factors and may be congenital. Trachoma infection may cause scarring of the inner eyelid, which may cause entropion. Symptoms of entropion include: - Redness and pain around the eye - Sensitivity to light and wind - Sagging skin around the eye - Excessive tearing - Decreased vision, especially if the cornea is damaged Treatment is a simple surgery in which excess skin of the outer lids is removed. Prognosis is excellent if surgery is performed before the cornea is damaged. # Causes - Congenital - Aging - Scarring - Spasm # Entropion in dogs Entropion has been documented in most dog breeds, although there are some breeds (particularly purebreds) that are more commonly affected than others. These include the Pug, Chow Chow, Shar Pei, St. Bernard, Cocker Spaniel, Boxer, Springer Spaniel, Labrador Retriever, Cavalier King Charles Spaniel, Bull Mastiff, Great Dane, Irish Setter, and Poodle. The condition is usually present by six months of age. Entropion can also occur secondary to pain in the eye, scarring of the eyelid, or nerve damage. The upper or lower eyelid can be involved, and one or both eyes may be affected. When entropion occurs in both eyes, this is known as "bilateral entropion." Upper lid entropion involves the eyelashes rubbing on the eye, but the lower lid usually has no eyelashes, so hair rubs on the eye. Surgical correction is used in more severe cases. A strip of skin and orbicularis oculi muscle are removed parallel to the affected portion of the lid and then the skin is sutured. Shar Peis, who often are affected as young as two or three weeks old, respond well to temporary eyelid tacking. The entropion is often corrected after three to four weeks, and the sutures are removed.	Entropion Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Entropion is a medical condition in which the eyelids fold inward. It is very uncomfortable, as the eyelashes rub against the cornea constantly. Entropion is usually caused by genetic factors and may be congenital. Trachoma infection may cause scarring of the inner eyelid, which may cause entropion. Symptoms of entropion include: - Redness and pain around the eye - Sensitivity to light and wind - Sagging skin around the eye - Excessive tearing - Decreased vision, especially if the cornea is damaged Treatment is a simple surgery in which excess skin of the outer lids is removed. Prognosis is excellent if surgery is performed before the cornea is damaged. # Causes - Congenital - Aging - Scarring - Spasm # Entropion in dogs Entropion has been documented in most dog breeds, although there are some breeds (particularly purebreds) that are more commonly affected than others. These include the Pug, Chow Chow, Shar Pei, St. Bernard, Cocker Spaniel, Boxer, Springer Spaniel, Labrador Retriever, Cavalier King Charles Spaniel, Bull Mastiff, Great Dane, Irish Setter, and Poodle.[1] The condition is usually present by six months of age. Entropion can also occur secondary to pain in the eye, scarring of the eyelid, or nerve damage. The upper or lower eyelid can be involved, and one or both eyes may be affected. When entropion occurs in both eyes, this is known as "bilateral entropion." Upper lid entropion involves the eyelashes rubbing on the eye, but the lower lid usually has no eyelashes, so hair rubs on the eye. Surgical correction is used in more severe cases. A strip of skin and orbicularis oculi muscle are removed parallel to the affected portion of the lid and then the skin is sutured. Shar Peis, who often are affected as young as two or three weeks old, respond well to temporary eyelid tacking. The entropion is often corrected after three to four weeks, and the sutures are removed.[1]	https://www.wikidoc.org/index.php/Entropion
1414c5661337b956a0fbaf215496b8e833520c1c	wikidoc	Eperisone	Eperisone # Overview Eperisone (formulated as the eperisone hydrochloride salt) is an antispasmodic drug. Eperisone acts by relaxing both skeletal muscles and vascular smooth muscles, and demonstrates a variety of effects such as reduction of myotonia, improvement of circulation, and suppression of the pain reflex. The drug inhibits the vicious circle of myotonia by decreasing pain, ischaemia, and hypertonia in skeletal muscles, thus alleviating stiffness and spasticity, and facilitating muscle movement Eperisone also improves dizziness and tinnitus associated with cerebrovascular disorders or cervical spondylosis. Eperisone has a relatively low incidence of sedation when compared with other antispasmodic drugs; this simplifies the clinical application of the drug and makes it an attractive choice for patients who require antispasmodic therapy without a reduction in alertness. Eperisone also facilitates voluntary movement of the upper and lower extremities without reducing muscle power; it is therefore useful during the initial stage of rehabilitation and as a supporting drug during subsequent rehabilitative therapy. # Indications - Spastic paralysis in conditions such as cerebrovascular disease - Spastic spinal paralysis - Cervical spondylosis - Postoperative sequelae (including from cerebrospinal tumour) - Sequelae to trauma (e.g. spinal trauma or head injury) - Amyotrophic lateral sclerosis - Cerebral palsy - Spinocerebellar degeneration - Spinal vascular diseases and other encephalomyelopathies - Cervical syndrome, periarthritis of the shoulder, and lumbago. # Presentation Eperisone hydrochloride is available as the brand name preparation Myonal as 50 mg sugar coated tablets, or as 10% granules for oral administration. An experimental form of the drug, as a transdermal patch system, has shown promising results in laboratory tests on rodents; however, this product is not currently available for human use. It is also available as the brand name Epry as 50 mg as sugar coated tablets. # Dosage and administration In adults, the usual dose of eperisone is 50–150 mg per day, in divided doses, after meals. However, the dosage is adjusted by the prescribing clinician depending on factors such as severity of symptoms, patient age and response. Eperisone has not been established as definitely safe for paediatric use, therefore its use in paediatrics cannot be recommended without further study. If elderly patients are treated with eperisone, a reduced dose is recommended, and the patient should be closely monitored for signs of psychological hypofunction during treatment. # Safety during pregnancy and breast-feeding Eperisone has not been established to be safe for use by pregnant women; therefore the drug should only be used in pregnant women, or women who may be pregnant, if the expected therapeutic benefits will outweigh the possible risks associated with treatment. The manufacturers of Myonal recommend the drug not be used during lactation (breast-feeding). If eperisone must be used, the patient is advised to stop breast-feeding for the duration of treatment. Eperisone has beed reported to be excreted in breast milk in an animal study (in rats). # Pharmacology - Skeletal muscle relaxation - Relaxation of hypertonic skeletal muscles - Improves intramuscular blood flow - Suppression of spinal reflex potentials - Reduction of muscle spindle sensitivity via motor neurons - Vasodilatation and augmentation of blood flow - Analgesic action and inhibition of the pain reflex in the spinal cord # Contraindications Eperisone is contraindicated in patients with known hypersensitivity to the drug. Side effects: 'very rare' excessive relaxation, stomachache, nausea, vertigo, anorexia, drowsiness, skin rashes, diarrhoea, vomiting, indigestion, GI disturbances, insomnia, headache, constipation etc. # Cautions Eperisone should be administered with care in patients with a history of hypersensitivity to any medication, or with disorders of liver function (it may aggravate hepatic dysfunction). Weakness, light-headedness, sleepiness or other symptoms may occur. In the event of such symptoms, the dosage should be reduced or treatment discontinued. Patients should be cautioned against engaging in potentially hazardous activities requiring alertness, such as operating machinery or driving a car. # Side effects - Shock and anaphylactoid reactions: In the event of symptoms such as redness, itching, urticaria, oedema of the face and other parts of the body, dyspnoea, etc., treatment should be discontinued and appropriate measues taken. - Other side effects: anaemia, rash, pruritus, sleepiness, insomnia, headache, nausea and vomiting, anorexia, abdominal pain, diarrhoea, constipation, urinary retention or incontinence. # Drug interactions There have been reports of disturbances in ocular accommodation occurring after the concomitant use of the related drug tolperisone hydrochloride and methocarbamol. # Safety in overdose Seizures have been reported in an infant after accidental ingestion of eperisone. # Future developments Eperisone suffers from a very low bioavailability when taken orally, as a result of high first pass intestinal metabolism; a transdermal patch containing eperisone is currently in development in South Korea. This has shown promise, with the antispasmodic effect lasting over 24 hours, compared to one to two hours following oral administration. Eperisone is also under investigation as an antihypertensive agent, with promising results from trials on beagles. # Brand names Eperisone is sold in Bangladesh, China, India, Indonesia, Japan, United Arab Emirates, Malaysia, the Philippines, Thailand, Sudan and Pakistan under the brand name Myonal and in Italy under the brand name Expose.	Eperisone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Eperisone (formulated as the eperisone hydrochloride salt) is an antispasmodic drug. Eperisone acts by relaxing both skeletal muscles and vascular smooth muscles, and demonstrates a variety of effects such as reduction of myotonia, improvement of circulation, and suppression of the pain reflex. The drug inhibits the vicious circle of myotonia by decreasing pain, ischaemia, and hypertonia in skeletal muscles, thus alleviating stiffness and spasticity, and facilitating muscle movement[1] Eperisone also improves dizziness and tinnitus associated with cerebrovascular disorders or cervical spondylosis. Eperisone has a relatively low incidence of sedation when compared with other antispasmodic drugs; this simplifies the clinical application of the drug and makes it an attractive choice for patients who require antispasmodic therapy without a reduction in alertness. Eperisone also facilitates voluntary movement of the upper and lower extremities without reducing muscle power; it is therefore useful during the initial stage of rehabilitation and as a supporting drug during subsequent rehabilitative therapy. # Indications - Spastic paralysis in conditions such as cerebrovascular disease[2] - Spastic spinal paralysis - Cervical spondylosis[3] - Postoperative sequelae (including from cerebrospinal tumour)[4] - Sequelae to trauma (e.g. spinal trauma or head injury)[4] - Amyotrophic lateral sclerosis - Cerebral palsy - Spinocerebellar degeneration - Spinal vascular diseases and other encephalomyelopathies - Cervical syndrome, periarthritis of the shoulder, and lumbago.[5] # Presentation Eperisone hydrochloride is available as the brand name preparation Myonal as 50 mg sugar coated tablets, or as 10% granules for oral administration.[6] An experimental form of the drug, as a transdermal patch system, has shown promising results in laboratory tests on rodents; however, this product is not currently available for human use.[7] It is also available as the brand name Epry as 50 mg as sugar coated tablets. # Dosage and administration In adults, the usual dose of eperisone is 50–150 mg per day, in divided doses, after meals. However, the dosage is adjusted by the prescribing clinician depending on factors such as severity of symptoms, patient age and response. Eperisone has not been established as definitely safe for paediatric use, therefore its use in paediatrics cannot be recommended without further study.[6] If elderly patients are treated with eperisone, a reduced dose is recommended, and the patient should be closely monitored for signs of psychological hypofunction during treatment.[6] # Safety during pregnancy and breast-feeding Eperisone has not been established to be safe for use by pregnant women; therefore the drug should only be used in pregnant women, or women who may be pregnant, if the expected therapeutic benefits will outweigh the possible risks associated with treatment. The manufacturers of Myonal recommend the drug not be used during lactation (breast-feeding). If eperisone must be used, the patient is advised to stop breast-feeding for the duration of treatment. Eperisone has beed reported to be excreted in breast milk in an animal study (in rats). # Pharmacology - Skeletal muscle relaxation - Relaxation of hypertonic skeletal muscles - Improves intramuscular blood flow - Suppression of spinal reflex potentials - Reduction of muscle spindle sensitivity via motor neurons - Vasodilatation and augmentation of blood flow - Analgesic action and inhibition of the pain reflex in the spinal cord # Contraindications Eperisone is contraindicated in patients with known hypersensitivity to the drug.[8] Side effects: 'very rare' excessive relaxation, stomachache, nausea, vertigo, anorexia, drowsiness, skin rashes, diarrhoea, vomiting, indigestion, GI disturbances, insomnia, headache, constipation etc.[9] # Cautions Eperisone should be administered with care in patients with a history of hypersensitivity to any medication, or with disorders of liver function (it may aggravate hepatic dysfunction). Weakness, light-headedness, sleepiness or other symptoms may occur. In the event of such symptoms, the dosage should be reduced or treatment discontinued. Patients should be cautioned against engaging in potentially hazardous activities requiring alertness, such as operating machinery or driving a car.[6] # Side effects - Shock and anaphylactoid reactions: In the event of symptoms such as redness, itching, urticaria, oedema of the face[10] and other parts of the body, dyspnoea, etc., treatment should be discontinued and appropriate measues taken. - Other side effects: anaemia, rash, pruritus, sleepiness, insomnia, headache, nausea and vomiting, anorexia, abdominal pain, diarrhoea, constipation, urinary retention or incontinence.[citation needed] # Drug interactions There have been reports of disturbances in ocular accommodation occurring after the concomitant use of the related drug tolperisone hydrochloride and methocarbamol. # Safety in overdose Seizures have been reported in an infant after accidental ingestion of eperisone.[11] # Future developments Eperisone suffers from a very low bioavailability when taken orally, as a result of high first pass intestinal metabolism; a transdermal patch containing eperisone is currently in development in South Korea.[1] This has shown promise, with the antispasmodic effect lasting over 24 hours, compared to one to two hours following oral administration. Eperisone is also under investigation as an antihypertensive agent, with promising results from trials on beagles.[12] # Brand names Eperisone is sold in Bangladesh, China, India, Indonesia, Japan, United Arab Emirates, Malaysia, the Philippines, Thailand, Sudan and Pakistan under the brand name Myonal[13] and in Italy under the brand name Expose.[14]	https://www.wikidoc.org/index.php/Eperisone
d5fcf2a32a74927159b58137e1bbb5c3ead7a624	wikidoc	Ephedrine	Ephedrine # Overview Ephedrine (EPH) is a sympathomimetic amine similar in structure to the synthetic derivatives amphetamine and methamphetamine. Ephedrine is commonly used as a stimulant, appetite suppressant, concentration aid, decongestant and to treat hypotension associated with regional anaesthesia. Chemically, it is an alkaloid derived from various plants in the genus Ephedra (family Ephedraceae). It is most usually marketed in the hydrochloride and sulfate forms. In traditional Chinese medicines, the herb ma huang (Ephedra sinica) contains ephedrine and pseudoephedrine as its principal active constituents. The same is true of other herbal products containing extracts from Ephedra species. Nagayoshi Nagai was the first one to isolate ephedrine from Ephedra vulgaris in 1885. The substance called soma mentioned in old Hindu books such as the Rig Veda, may have been ephedra extract. The production of ephedrine in China has become a multi-million dollar export industry. Companies producing for export extract US$13 million worth of ephedrine from 30,000 tons of ephedra annually, 10 times the amount that is used in traditional Chinese medicine. # Chemistry Ephedrine exhibits optical isomerism and has two chiral centres. By convention the enantiomers with opposite stereochemistry around the chiral centres are designated ephedrine, while pseudoephedrine has same stereochemistry around the chiral carbons. That is, (1R,2R)- and (1S,2S)-enantiomers are designated pseudoephedrine; while (1R,2S)- and (1S,2R)-enantiomers are designated ephedrine. The isomer which is marketed is (-)-(1R,2S)-ephedrine. As with other phenylethylamines, it is also somewhat chemically similar to methamphetamine, although the amphetamines are more potent and have additional biological effects. Ephedrine may also be referred to as: (αR)-α-benzenemethanol, α-benzyl alcohol, or L-erythro-2-(methylamino)-1-phenylpropan-1-ol. Ephedrine hydrochloride has a melting point of 187-188°C. # Mode of action Ephedrine is a sympathomimetic amine - that is, its principal mechanism of action relies on its direct and indirect actions on the adrenergic receptor system, which is part of the sympathetic nervous system or SNS. Central nervous system or CNS involvement is present, but the predominant clinical effects are caused by involvement with the sympathetic segment of the peripheral nervous system due to the fact that while ephedrine does cross the blood-brain barrier, it doesn't do this very efficiently (efficient crossers with similar modes of action would include amphetamine and methamphetamine). Ephedrine increases post-synaptic noradrenergic receptor activity by (weakly) directly activating post-synaptic α-receptors and β-receptors, but the bulk of its effect comes from the pre-synaptic neuron being unable to distinguish between real adrenaline or noradrenaline from ephedrine. The ephedrine, mixed with noradrenaline, is transported through the noradrenaline reuptake complex and packaged (along with real noradrenaline) into vesicles that reside at the terminal button of a nerve cell. As an alkaloid, having some small amount of ephedrine within a noradrenaline vesicle reduces the overall pH of the vesicle. This has the effect of increasing likelihood that the affected vesicle will be released during any subsequent action potential the nerve cell experiences. The nerve cells in question generally fire at some regular baseline rate; the effect of adding ephedrine is to increase the number of vesicles released during each action potential and possibly to extend the time during which noradrenaline has an opportunity to have an effect on the post-synaptic neuron by virtue of the fact that the reuptake complex has to process both noradrenaline AND ephedrine, presumably a longer process. Ephedrine's mechanism of action on neurotransmission in the brain is wide. Its action as an agonist at most major noradrenaline receptors and its ability to increase the release of both dopamine and to a lesser extent, serotonin by the same mechanism as explained above for norepinephrine, is presumed to have a major role in its mechanism of action. Because of ephedrine's ability to potentiate dopamine neurotransmission it is thought to have addictive properties by some researchers. The ability to potentiate serotonin and noradrenergic activity is clinically relevant, but is not thought to contribute to the potential for abuse. While ephedrine's role in the serotonin system is less understood there is preliminary documentation of clinically significant agonism at excitory serotonin receptors, perhaps as a downstream response to the large release of norepinephrine in the nucleus accumbens (commonly referred to as the "pleasure center" of the brain). In mice, stereotypical behaviour was both easily induced by administration of ephedrine and it's primary alkaloids and reversed when serotonin antagonists were administered. # Clinical use ## Indications Ephedrine was once widely used as a topical decongestant and as a bronchodilator in the treatment for asthma. It continues to be used for these indications, although its popularity is waning due to the availability of more effective agents for these indications which exhibit fewer adverse effects. The role in nasal congestion has largely been replaced by more potent α-adrenergic receptor agonists (e.g. oxymetazoline). Similarly the role of ephedrine in asthma has been almost entirely replaced by β2-adrenergic receptor agonists (e.g. salbutamol). Ephedrine continues to be used intravenously in the reversal of hypotension from spinal/epidural anaesthesia. It is also used in other hypotensive states, including overdose with ganglionic blocking agents, antiadrenergic agents, or other medications that lower blood pressure. It can be used in narcolepsy and nocturnal enuresis. In traditional Chinese medicine, ephedrine has been used in the treatment of asthma and bronchitis for centuries. An ECA stack is a component found in thermogenic weight loss pills, composed of ephedrine, caffeine and aspirin (many supplement manufacturers include salicin instead of aspirin) working to speed up the metabolism and thus cause food energy to burn faster. The ECA stack is a popular supplement taken by body builders before workouts due to the increased amount of energy and alertness. For many years, the US Coast Guard recommended ephedrine together with an equal 25 mg dose of promethazine to its sailors to combat seasickness. Promethazine manages nausea and ephedrine fights the ensuing drowsiness. Commonly referred to as the Coast Guard cocktail, ephedrine may still be available for prescription for this purpose. ## Adverse effects Adverse drug reactions (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include: - Cardiovascular: tachycardia, cardiac arrhythmias, Angina pectoris, vasoconstriction with hypertension - Dermatological: flushing, sweating, acne vulgaris - Gastrointestinal: nausea, appetite loss - Genitourinary: increased urine output due to increased blood flow (difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation) - Nervous system:restlessness, confusion, insomnia, mild euphoria, mania/hallucinations (rare except in previously existing psychiatric conditions), delusions, formication (may be possible, but lacks documented evidence) paranoia, hostility, panic, agitation - Respiratory: dyspnea, pulmonary edema - Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions The approved maximum daily dosage of ephedrine for use as a bronchodilator is 150mg, as specified on the packaging of the bronchodilator and expectorant combination, Bronkaid, made by Bayer pharmaceuticals. Overdose can lead to death, although the approved dose is not likely to cause severe reactions when used as directed. Ephedrine can also lead to damage of the brain receptors over a period of high usage; this is because of its constant action on the neurochemicals. It also leads to high increase in blood pressure which over time can lead to damage in the blood vessels. ## Contraindications Ephedrine should not be used in conjunction with certain antidepressants, namely SNRIs (Selective norepinephrine re-uptake inhibitors), as this increases the risk of the above symptoms due to excessive serum levels of norepinephrine. Wellbutrin is an example of an antidepressant with an amphetamine-like structure similar to ephedrine. It has a similar action but also releases serotonin from presynaptic clefts. It should not be used with ephedrine as it may increase the likelihood of the above side effects. Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal BP > 130/80 mmHg, and lactation. Contraindications for the use of ephedrine include: closed angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly cyclopropane or halothane), tachyarrhythmias or ventricular fibrillation, hypersensitivity to ephedrine or other stimulants. Ephedrine should NOT be used at any time during pregnancy unless specifically indicated by a qualified physician and ONLY when other options are unavailable. # Recreational and illicit use Anecdotal reports have suggested that ephedrine helps studying, thinking, or concentrating to a greater extent than caffeine. Some students and some white-collar workers have used ephedrine (or Ephedra-containing herbal supplements) for this purpose, as well as some professional athletes and weightlifters. It is common for many athletes to use stimulants while exercising. Such use of ephedrine has been associated with stimulant dependence, as well as deaths from heatstroke in athletes and circulatory problems such as aortic aneurysm in weightlifters, though these side effects are rare. As a phenylethylamine, ephedrine has a similar chemical structure to amphetamines. Ephedrine can be used in the synthesis of methamphetamine by chemical reduction; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine. The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in that it uses anhydrous ammonia and lithium metal in the reaction. The second most popular method uses red phosphorus, iodine, and ephedrine in the reaction. Through oxidation, ephedrine can be easily synthesized into methcathinone. Ephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. Ephedrine has been reported to cause both physical and psychological dependence after excessive long-term use. This is particularly true with oral forms of ephedrine, since parenteral administration is unlikely to occur over long periods. ## Neurotoxicity of Ephedrine As a sympathomimetic agent similar in structure and activity to amphetamines, there has been a dispute over whether ephedrine produces any neurodegenerative effects. It has not been shown clinically that certain amphetamines (namely (d)-amphetamine and (d)-methamphetamine) can cause varying levels of long-term dopamine depletion in dopamine-rich brain and nervous centers such as the putamen and the basal ganglia. Several studies have recently compared the quantities of such neurotransmitters as serotonin, dopamine, glutamate, and epinephrine after concurrent administration of ephedrine and various amphetamine-like agents. The results showed that ephedrine has no neurotoxic effect nor has amphetamine counterparts. Ephedrine increases serum dopamine levels minimally in comparison with an equivalent dose of dextroamphetamine (Dexedrine®). Dextromethamphetamine (Desoxyn®) raises dopamine levels dramatically (more than two times that of an equivalent dose of dextroamphetamine). This supports the general consensus that ephedrine has more of a peripheral action on the sympathetic nervous system, whereas amphetamines appear to cross the blood brain barrier more freely and tend to have a stronger central action. The fact that dopamine is believed to play a major role in the addiction response has been used in recent years as justification for controlling the distribution of dextroamphetamine and dextromethamphetamine, along with various other amphetamines. ## Legality in USA Ephedrine itself has never been illegal in the United States. In 1997, the FDA proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8 mg (of active ephedrine) with no more than 24 mg per day. This proposed rule was withdrawn in part in 2000 because of "concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products." In 2004, the FDA created a ban on ephedrine alkaloids that are marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use. On April 14, 2005, the U.S. District Court for the District of Utah ruled that the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe, but on August 17, 2006, the U.S. Court of Appeals for the Tenth Circuit in Denver upheld the FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States. Ephedrine is, however, still legal in many applications outside of dietary supplements. However, purchasing is currently limited and monitored, with specifics varying from state to state. The House passed the Combat Methamphetamine Epidemic Act of 2005 as an amendment to the renewal of the USA PATRIOT Act. Signed into law by president George W. Bush on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of ephedrine-containing products. The federal statute included the following requirements for merchants who sell these products: - A retrievable record of all purchases identifying the name and address of each party to be kept for two years. - Required verification of proof of identity of all purchasers - Required protection and disclosure methods in the collection of personal information - Reports to the Attorney General of any suspicious payments or disappearances of the regulated products - Non-liquid dose form of regulated product may only be sold in unit dose blister packs - Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access - Daily sales of regulated products not to exceed 3.6 grams without regard to the number of transactions - Monthly sales not to exceed 9 grams of pseudoephedrine base in regulated products The law gives similar regulations to mail-order purchases, except the monthly sales limit is only 7.5 grams.	Ephedrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Ephedrine (EPH) is a sympathomimetic amine similar in structure to the synthetic derivatives amphetamine and methamphetamine. Ephedrine is commonly used as a stimulant, appetite suppressant, concentration aid, decongestant and to treat hypotension associated with regional anaesthesia. Chemically, it is an alkaloid derived from various plants in the genus Ephedra (family Ephedraceae). It is most usually marketed in the hydrochloride and sulfate forms. In traditional Chinese medicines, the herb ma huang (Ephedra sinica) contains ephedrine and pseudoephedrine as its principal active constituents. The same is true of other herbal products containing extracts from Ephedra species. Nagayoshi Nagai was the first one to isolate ephedrine from Ephedra vulgaris in 1885. The substance called soma mentioned in old Hindu books such as the Rig Veda, may have been ephedra extract. The production of ephedrine in China has become a multi-million dollar export industry. Companies producing for export extract US$13 million worth of ephedrine from 30,000 tons of ephedra annually, 10 times the amount that is used in traditional Chinese medicine.[1] # Chemistry Ephedrine exhibits optical isomerism and has two chiral centres. By convention the enantiomers with opposite stereochemistry around the chiral centres are designated ephedrine, while pseudoephedrine has same stereochemistry around the chiral carbons. That is, (1R,2R)- and (1S,2S)-enantiomers are designated pseudoephedrine; while (1R,2S)- and (1S,2R)-enantiomers are designated ephedrine. The isomer which is marketed is (-)-(1R,2S)-ephedrine.[2] As with other phenylethylamines, it is also somewhat chemically similar to methamphetamine, although the amphetamines are more potent and have additional biological effects. Ephedrine may also be referred to as: (αR)-α-[(1S)-1-(methylamino)ethyl]benzenemethanol, α-[1-(methylamino)ethyl]benzyl alcohol, or L-erythro-2-(methylamino)-1-phenylpropan-1-ol. Ephedrine hydrochloride has a melting point of 187-188°C.[3] # Mode of action Ephedrine is a sympathomimetic amine - that is, its principal mechanism of action relies on its direct and indirect actions on the adrenergic receptor system, which is part of the sympathetic nervous system or SNS. Central nervous system or CNS involvement is present, but the predominant clinical effects are caused by involvement with the sympathetic segment of the peripheral nervous system due to the fact that while ephedrine does cross the blood-brain barrier, it doesn't do this very efficiently (efficient crossers with similar modes of action would include amphetamine and methamphetamine). Ephedrine increases post-synaptic noradrenergic receptor activity by (weakly) directly activating post-synaptic α-receptors and β-receptors, but the bulk of its effect comes from the pre-synaptic neuron being unable to distinguish between real adrenaline or noradrenaline from ephedrine. The ephedrine, mixed with noradrenaline, is transported through the noradrenaline reuptake complex and packaged (along with real noradrenaline) into vesicles that reside at the terminal button of a nerve cell. As an alkaloid, having some small amount of ephedrine within a noradrenaline vesicle reduces the overall pH of the vesicle. This has the effect of increasing likelihood that the affected vesicle will be released during any subsequent action potential the nerve cell experiences. The nerve cells in question generally fire at some regular baseline rate; the effect of adding ephedrine is to increase the number of vesicles released during each action potential and possibly to extend the time during which noradrenaline has an opportunity to have an effect on the post-synaptic neuron by virtue of the fact that the reuptake complex has to process both noradrenaline AND ephedrine, presumably a longer process. Ephedrine's mechanism of action on neurotransmission in the brain is wide. Its action as an agonist at most major noradrenaline receptors and its ability to increase the release of both dopamine and to a lesser extent, serotonin by the same mechanism as explained above for norepinephrine, is presumed to have a major role in its mechanism of action. Because of ephedrine's ability to potentiate dopamine neurotransmission it is thought to have addictive properties by some researchers. The ability to potentiate serotonin and noradrenergic activity is clinically relevant, but is not thought to contribute to the potential for abuse. While ephedrine's role in the serotonin system is less understood there is preliminary documentation of clinically significant agonism at excitory serotonin receptors, perhaps as a downstream response to the large release of norepinephrine in the nucleus accumbens (commonly referred to as the "pleasure center" of the brain). In mice, stereotypical behaviour was both easily induced by administration of ephedrine and it's primary alkaloids and reversed when serotonin antagonists were administered. # Clinical use ## Indications Ephedrine was once widely used as a topical decongestant and as a bronchodilator in the treatment for asthma. It continues to be used for these indications, although its popularity is waning due to the availability of more effective agents for these indications which exhibit fewer adverse effects.[4] The role in nasal congestion has largely been replaced by more potent α-adrenergic receptor agonists (e.g. oxymetazoline). Similarly the role of ephedrine in asthma has been almost entirely replaced by β2-adrenergic receptor agonists (e.g. salbutamol). Ephedrine continues to be used intravenously in the reversal of hypotension from spinal/epidural anaesthesia.[4] It is also used in other hypotensive states, including overdose with ganglionic blocking agents, antiadrenergic agents, or other medications that lower blood pressure.[5] It can be used in narcolepsy and nocturnal enuresis. In traditional Chinese medicine, ephedrine has been used in the treatment of asthma and bronchitis for centuries.[6] An ECA stack is a component found in thermogenic weight loss pills, composed of ephedrine, caffeine and aspirin (many supplement manufacturers include salicin instead of aspirin) working to speed up the metabolism and thus cause food energy to burn faster. The ECA stack is a popular supplement taken by body builders before workouts due to the increased amount of energy and alertness. For many years, the US Coast Guard recommended ephedrine together with an equal 25 mg dose of promethazine to its sailors to combat seasickness. Promethazine manages nausea and ephedrine fights the ensuing drowsiness. Commonly referred to as the Coast Guard cocktail, ephedrine may still be available for prescription for this purpose. ## Adverse effects Adverse drug reactions (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include:[4] - Cardiovascular: tachycardia, cardiac arrhythmias, Angina pectoris, vasoconstriction with hypertension - Dermatological: flushing, sweating, acne vulgaris - Gastrointestinal: nausea, appetite loss - Genitourinary: increased urine output due to increased blood flow (difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation) - Nervous system:restlessness, confusion, insomnia, mild euphoria, mania/hallucinations (rare except in previously existing psychiatric conditions), delusions, formication (may be possible, but lacks documented evidence) paranoia, hostility, panic, agitation - Respiratory: dyspnea, pulmonary edema - Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions The approved maximum daily dosage of ephedrine for use as a bronchodilator is 150mg, as specified on the packaging of the bronchodilator and expectorant combination, Bronkaid, made by Bayer pharmaceuticals. Overdose can lead to death, although the approved dose is not likely to cause severe reactions when used as directed. Ephedrine can also lead to damage of the brain receptors over a period of high usage; this is because of its constant action on the neurochemicals. It also leads to high increase in blood pressure which over time can lead to damage in the blood vessels. ## Contraindications Ephedrine should not be used in conjunction with certain antidepressants, namely SNRIs (Selective norepinephrine re-uptake inhibitors), as this increases the risk of the above symptoms due to excessive serum levels of norepinephrine. Wellbutrin is an example of an antidepressant with an amphetamine-like structure similar to ephedrine. It has a similar action but also releases serotonin from presynaptic clefts. It should not be used with ephedrine as it may increase the likelihood of the above side effects. Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal BP > 130/80 mmHg, and lactation.[7] Contraindications for the use of ephedrine include: closed angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly cyclopropane or halothane), tachyarrhythmias or ventricular fibrillation, hypersensitivity to ephedrine or other stimulants. Ephedrine should NOT be used at any time during pregnancy unless specifically indicated by a qualified physician and ONLY when other options are unavailable.[7] # Recreational and illicit use Anecdotal reports have suggested that ephedrine helps studying, thinking, or concentrating to a greater extent than caffeine. Some students and some white-collar workers have used ephedrine (or Ephedra-containing herbal supplements) for this purpose, as well as some professional athletes and weightlifters. It is common for many athletes to use stimulants while exercising. Such use of ephedrine has been associated with stimulant dependence, as well as deaths from heatstroke in athletes and circulatory problems such as aortic aneurysm in weightlifters, though these side effects are rare. As a phenylethylamine, ephedrine has a similar chemical structure to amphetamines. Ephedrine can be used in the synthesis of methamphetamine by chemical reduction; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine. The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in that it uses anhydrous ammonia and lithium metal in the reaction. The second most popular method uses red phosphorus, iodine, and ephedrine in the reaction. Through oxidation, ephedrine can be easily synthesized into methcathinone. Ephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[8] Ephedrine has been reported to cause both physical and psychological dependence after excessive long-term use. This is particularly true with oral forms of ephedrine, since parenteral administration is unlikely to occur over long periods.[7] ## Neurotoxicity of Ephedrine As a sympathomimetic agent similar in structure and activity to amphetamines, there has been a dispute over whether ephedrine produces any neurodegenerative effects. It has not been shown clinically that certain amphetamines (namely (d)-amphetamine and (d)-methamphetamine) can cause varying levels of long-term dopamine depletion in dopamine-rich brain and nervous centers such as the putamen and the basal ganglia. Several studies have recently compared the quantities of such neurotransmitters as serotonin, dopamine, glutamate, and epinephrine after concurrent administration of ephedrine and various amphetamine-like agents. The results showed that ephedrine has no neurotoxic effect nor has amphetamine counterparts. Ephedrine increases serum dopamine levels minimally in comparison with an equivalent dose of dextroamphetamine (Dexedrine®). Dextromethamphetamine (Desoxyn®) raises dopamine levels dramatically (more than two times that of an equivalent dose of dextroamphetamine). This supports the general consensus that ephedrine has more of a peripheral action on the sympathetic nervous system, whereas amphetamines appear to cross the blood brain barrier more freely and tend to have a stronger central action. The fact that dopamine is believed to play a major role in the addiction response has been used in recent years as justification for controlling the distribution of dextroamphetamine and dextromethamphetamine, along with various other amphetamines.[9] ## Legality in USA Ephedrine itself has never been illegal in the United States. In 1997, the FDA proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8 mg (of active ephedrine) with no more than 24 mg per day.[2] This proposed rule was withdrawn in part in 2000 because of "concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products."[3] In 2004, the FDA created a ban on ephedrine alkaloids that are marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use.[4] On April 14, 2005, the U.S. District Court for the District of Utah ruled that the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe,[5] but on August 17, 2006, the U.S. Court of Appeals for the Tenth Circuit in Denver upheld the FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States.[6] Ephedrine is, however, still legal in many applications outside of dietary supplements. However, purchasing is currently limited and monitored, with specifics varying from state to state. The House passed the Combat Methamphetamine Epidemic Act of 2005 as an amendment to the renewal of the USA PATRIOT Act. Signed into law by president George W. Bush on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of ephedrine-containing products. The federal statute included the following requirements for merchants who sell these products: - A retrievable record of all purchases identifying the name and address of each party to be kept for two years. - Required verification of proof of identity of all purchasers - Required protection and disclosure methods in the collection of personal information - Reports to the Attorney General of any suspicious payments or disappearances of the regulated products - Non-liquid dose form of regulated product may only be sold in unit dose blister packs - Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access - Daily sales of regulated products not to exceed 3.6 grams without regard to the number of transactions - Monthly sales not to exceed 9 grams of pseudoephedrine base in regulated products The law gives similar regulations to mail-order purchases, except the monthly sales limit is only 7.5 grams.	https://www.wikidoc.org/index.php/Ephedrine
f45622c1d4e3ff377f1b284233bcd0c57e868631	wikidoc	Ephrin A1	Ephrin A1 Ephrin A1 is a protein that in humans is encoded by the EFNA1 gene. This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNA class ephrin which binds to the EPHA2, EPHA4, EPHA5, EPHA6, and EPHA7 receptors. Two transcript variants that encode different isoforms were identified through sequence analysis. # Model organisms Model organisms have been used in the study of EFNA1 function. A conditional knockout mouse line, called Efna1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on homozygous mutant mice and one significant abnormality was observed: a transformation in vertebral number from lumbar vertebrae to sacral vertebrae.	Ephrin A1 Ephrin A1 is a protein that in humans is encoded by the EFNA1 gene.[1][2][3] This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNA class ephrin which binds to the EPHA2, EPHA4, EPHA5, EPHA6, and EPHA7 receptors. Two transcript variants that encode different isoforms were identified through sequence analysis.[3] # Model organisms Model organisms have been used in the study of EFNA1 function. A conditional knockout mouse line, called Efna1tm1a(EUCOMM)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[12][13][14] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on homozygous mutant mice and one significant abnormality was observed: a transformation in vertebral number from lumbar vertebrae to sacral vertebrae.[8]	https://www.wikidoc.org/index.php/Ephrin_A1
0e5c2a989deacad065ca2f8901fe75190a4022db	wikidoc	Ephrin A5	Ephrin A5 Ephrin A5 is a protein that in humans is encoded by the EFNA5 gene. Ephrin A5 is a glycosylphosphatidylinositol (GPI)-anchored protein of the ephrin-A subclass of ephrin ligands that binds to the EphA subclass of Eph receptors. Ephrin A5 has also been shown to bind to the EphB2 receptor. # Reverse signaling in growth cone survival "Reverse" signaling is one unique property of ephrin ligands that allows for the transmission of an intracellular signal in ephrin-expressing cells that is distinct from the signal transmitted in Eph receptor-expressing cells. Although the mechanism of "reverse" signaling by ephrin-As is not well understood, it is relatively surprising considering that ephrin-A ligands are attached to the cell membrane solely by a GPI linkage and unlike ephrin-Bs, lack a potential intracellular signaling domain. Nonetheless, certain ephrin-A ligands are known to initiate reverse signaling cascades like ephrin A5, which has been shown to stimulate the spreading of growth cones in cultures of mouse spinal motor neurons. Reverse signaling by ephrin A5 was demonstrated to be GPI-dependent as the elimination of all GPI linkages by the application of a phosphatidlyinositol-specific phospholipase C abolished the positive effects of ephrin A5 on growth cone spreading. Additionally, EphA receptors were shown to exert opposite effects on motor neuron growth cones by reducing growth cone size. ## Formation of the retinotopic map This finding that ephrin A5 promotes growth cone survival that is opposite of EphA signaling and mediated directly by ephrin A5 reverse signaling has important implications for axon guidance as it provides a mechanism by which migrating axons expressing EphAs would preferentially avoid ephrin A5 expressing cells and possibly migrate towards cells with lower expression of ephrin A5. This mechanism is in fact the same one that mediates the guidance of retinal ganglion cells to distinct regions in the superior colliculus during the formation of the retinotopic map. High ephrin A5 expression on cells in the posterior region of the SC bind to EphAs expressed in RGCs migrating from the temporal retina, inducing growth cone collapse and repelling these RGCs away from the posterior SC towards a region of low ephrin A5 expression in the anterior SC.	Ephrin A5 Ephrin A5 is a protein that in humans is encoded by the EFNA5 gene.[1][2][3] Ephrin A5 is a glycosylphosphatidylinositol (GPI)-anchored protein of the ephrin-A subclass of ephrin ligands that binds to the EphA subclass of Eph receptors. Ephrin A5 has also been shown to bind to the EphB2 receptor.[4] # Reverse signaling in growth cone survival "Reverse" signaling is one unique property of ephrin ligands that allows for the transmission of an intracellular signal in ephrin-expressing cells that is distinct from the signal transmitted in Eph receptor-expressing cells. Although the mechanism of "reverse" signaling by ephrin-As is not well understood, it is relatively surprising considering that ephrin-A ligands are attached to the cell membrane solely by a GPI linkage and unlike ephrin-Bs, lack a potential intracellular signaling domain. Nonetheless, certain ephrin-A ligands are known to initiate reverse signaling cascades like ephrin A5, which has been shown to stimulate the spreading of growth cones in cultures of mouse spinal motor neurons.[5] Reverse signaling by ephrin A5 was demonstrated to be GPI-dependent as the elimination of all GPI linkages by the application of a phosphatidlyinositol-specific phospholipase C abolished the positive effects of ephrin A5 on growth cone spreading. Additionally, EphA receptors were shown to exert opposite effects on motor neuron growth cones by reducing growth cone size. ## Formation of the retinotopic map This finding that ephrin A5 promotes growth cone survival that is opposite of EphA signaling and mediated directly by ephrin A5 reverse signaling has important implications for axon guidance as it provides a mechanism by which migrating axons expressing EphAs would preferentially avoid ephrin A5 expressing cells and possibly migrate towards cells with lower expression of ephrin A5.[5] This mechanism is in fact the same one that mediates the guidance of retinal ganglion cells to distinct regions in the superior colliculus during the formation of the retinotopic map. High ephrin A5 expression on cells in the posterior region of the SC bind to EphAs expressed in RGCs migrating from the temporal retina, inducing growth cone collapse and repelling these RGCs away from the posterior SC towards a region of low ephrin A5 expression in the anterior SC.[6]	https://www.wikidoc.org/index.php/Ephrin_A5
f5f3bb581c8919d128264068b1db183b4f7794f8	wikidoc	Ephrin B1	Ephrin B1 Ephrin-B1 is a protein that in humans is encoded by the EFNB1 gene. This gene encodes a member of the ephrin family. The encoded protein is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system. Mutations in this protein are responsible for most cases of craniofrontonasal syndrome. # Interactions EFNB1 has been shown to interact with SDCBP.	Ephrin B1 Ephrin-B1 is a protein that in humans is encoded by the EFNB1 gene.[1][2] This gene encodes a member of the ephrin family. The encoded protein is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system.[3] Mutations in this protein are responsible for most cases of craniofrontonasal syndrome.[4][5][6] # Interactions EFNB1 has been shown to interact with SDCBP.[7]	https://www.wikidoc.org/index.php/Ephrin_B1
4241e8c58c651646d4001953c34a4997ad462ac9	wikidoc	Ephrin B3	Ephrin B3 Ephrin-B3 is a protein that in humans is encoded by the EFNB3 gene. EFNB3, a member of the ephrin gene family, is important in brain development as well as in its maintenance. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases. EPH receptors typically have a single kinase domain and an extracellular region containing a Cysteine-rich domain and 2 fibronectin type III repeats. The ephrin ligands and receptors have been named by the Eph Nomenclature Committee (1997) based on their structures and sequence relationships. Ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. Ephrin-B ligands also contain an intracellular tail with highly conserved tyrosine residues and a PDZ-binding motif at the C-terminus. This tail functions as a mechanism for reverse signaling, where signaling occurs into the ligand-containing cell, as opposed to the cell with the receptor. Upon receptor-ligand interaction the tyrosine residues become phosphorylated and there is recruitment of PDZ domain-containing proteins. The Eph family of receptors are similarly divided into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. EphrinB3 has been implicated in mediating various developmental events, particularly in the nervous system. EphrinB3 reverse signaling is important for axon pruning and synapse and spine formation during postnatal development of the nervous system. Previous work has also shown that signaling through this ligand is important for radial migration during cortical development. Moreover, levels of EFNB3 expression are particularly high in several forebrain subregions compared to other brain subregions, and may play a pivotal role in forebrain function. It has been suggested that ephrinB3 signaling is necessary for synaptic plasticity to occur in the hippocampus; this implicates ephrinB3 as a major player in learning and memory. More recently, ephrinB3 has been shown to regulate proliferation of neural stem cells in the adult subventricular zone (SVZ).	Ephrin B3 Ephrin-B3 is a protein that in humans is encoded by the EFNB3 gene.[1][2] EFNB3, a member of the ephrin gene family, is important in brain development as well as in its maintenance. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases. EPH receptors typically have a single kinase domain and an extracellular region containing a Cysteine-rich domain and 2 fibronectin type III repeats. The ephrin ligands and receptors have been named by the Eph Nomenclature Committee (1997) based on their structures and sequence relationships. Ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. Ephrin-B ligands also contain an intracellular tail with highly conserved tyrosine residues and a PDZ-binding motif at the C-terminus.[3] This tail functions as a mechanism for reverse signaling, where signaling occurs into the ligand-containing cell, as opposed to the cell with the receptor. Upon receptor-ligand interaction the tyrosine residues become phosphorylated and there is recruitment of PDZ domain-containing proteins.[3] The Eph family of receptors are similarly divided into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands.[2] EphrinB3 has been implicated in mediating various developmental events, particularly in the nervous system. EphrinB3 reverse signaling is important for axon pruning and synapse and spine formation during postnatal development of the nervous system.[4][5] Previous work has also shown that signaling through this ligand is important for radial migration during cortical development.[4] Moreover, levels of EFNB3 expression are particularly high in several forebrain subregions compared to other brain subregions, and may play a pivotal role in forebrain function. It has been suggested that ephrinB3 signaling is necessary for synaptic plasticity to occur in the hippocampus; this implicates ephrinB3 as a major player in learning and memory.[5] More recently, ephrinB3 has been shown to regulate proliferation of neural stem cells in the adult subventricular zone (SVZ).[4][6]	https://www.wikidoc.org/index.php/Ephrin_B3
22a7218abb43209601ada6894386dad702b711f6	wikidoc	Epimedium	Epimedium Epimedium, also known as Barrenwort, Bishop's Hat, Fairy Wings, Horny Goatweed, or Yin Yang Huo (Chinese : 淫羊藿), is a genus of about 60 or more species of herbaceous flowering plants in the family Berberidaceae. The large majority are endemic to southern China, with further outposts in Europe, and central, southern and eastern Asia. Epimedium species are hardy perennials. The majority have four-petaled "spider-like" flowers in spring. Many are believed to be aphrodisiacs. # Aphrodisiac Many species of Epimedium are alleged to have aphrodisiac qualities. According to legend, this property was discovered by a Chinese goat herder who noticed sexual activity in his flock after they ate the weed. It is sold as a health supplement, usually in raw herb or pill form and sometimes blended with other supplements. The over-exploitation of wild populations of Epimedium for use in traditional Chinese medicine is having potentially serious consequences for the long-term survival of several species, none of which are widely cultivated for medicinal purposes. The "active ingredient" in Epimedium is icariin, which can be found in standardized extracts from 5% up to 60% potent. Strengths above that are usually reserved for lab use. Icariin is purported to work by increasing levels of nitric oxide, which relax smooth muscle. It has been demonstrated to relax rabbit penile tissue by nitric oxide and PDE-5 activity . Other research has demonstrated that injections of Epimedium extract, directly into the penis of the rat results in an increase in penile blood pressure. Like Viagra, icariin, the active compound in Epimedium, inhibits the activity of PDE-5. In vitro assays have demonstrated that icariin inhibits PDE-5 with an IC50 of around 1 micromolar, while Viagra has an IC50 of about 6.6 nanomolar (.0066 micromolar) and Levitra has an IC50 of about 0.7 nanomolar (.0007 micromolar). Measured differently, the EC50 of icariin is approximately 4.62 micromolar, while Viagra is .42 micromolar. The amount of oral administration of Epidemium extract necessary to achieve these relative concentrations is unclear from the literature, and may not be relevant if the herb works through multiple mechanisms, as has been suggested. Epimedium has been shown to up-regulate genes associated with nitric oxide production and changes in adenosine/guanine monophosphate balance in ways that other PDE5 inhibitors do not. # Cultivation Hugely popular as garden plants for centuries in Japan, Epimedium are only just beginning to garner attention in the West. Whilst they vary somewhat in their respective hardiness, all are essentially dwellers of the forest floor, and, as such, all require fundamentally similar conditions of moist, free draining, humus rich soil and cool shade, with some shelter for the newly emerging leaves. Some of the more robust varieties are often recommended as plants for dry shade, and whilst their tough foliage and stout rhizomes can allow them to grow successfully in such conditions, (and in more open, exposed positions too, in some instances) they will certainly not give their best. Furthermore, dryness and exposure will pretty much guarantee the early death of many of the newer and more delicate species. Given suitable conditions most Epimedium will form beautiful ground cover plants, often with magnificent new leaves tinted in bronze, copper and reds combining with a huge variety of flower colours and forms in spring. Handsome and dense-growing foliage remains present for much of the year, with the leaves often turning purple, crimson and scarlet in autumn in some forms, and remaining evergreen in others. With all varieties, however, the foliage is best cut off at ground level shortly before new leaves emerge, so as to fully reveal their beauty of form and colour. Ideally, a mulch should then be applied to protect the new growth from frosts. From the gardeners point of view Epimedium flowers comprise two main parts, the inner sepals, which are petal-like and four in number (the four outer sepals are small, insignificant, and rapidly shed as the flowers open) and the petals, which are held within the sepals. In some species these petals have developed long spurs and in such plants they greatly exceed the size of the surrounding sepals, producing a flower shaped like an inverted crown, and also giving rise to the one of the common names for Epimedium- bishops hat. In other species, however, (such as E. perraldianum) the petals are reduced to tiny spurs, and it is the greatly enlarged and highly coloured sepals that have expanded to catch the attention of the wandering insect. Some varieties and hybrids have been in Western cultivation for the last 100/150 years, but there are now a stunning array of new Chinese species (many newly discovered and a number which have yet to be named) and Japanese hybrids and forms arriving in the west to extend the boundaries of the genus in cultivation. The majority of the Chinese species have not been fully tested for hardiness or indeed for any other aspect of their culture. The initial assumptions that the plants would only thrive where their native conditions could be closely replicated have proven to be overly cautious, and most are proving extraordinarily amenable to general garden and container cultivation. Whilst they can be successfully propagated in early spring, Epimedium are best divided in late August, with the aim of promoting rapid re-growth of roots and shoots before the onset of winter. Several breeders (in particular Darrell Probst, Tim Branney & Robin White) have also undertaken their own hybridization programmes with the genus Epimedium, and various new nursery selections are gradually appearing in the nursery trade, the best of which are extending the colour and shape range of the flowers available to the gardener. # Further reading - William T. Stearn, The Genus Epimedium, revised edition 2002, ISBN 0-88192-543-8 - ↑ Chiu JH, Chen KK, Chien TM, Chiou WF, Chen CC, Wang JY, Lui WY, Wu CW. Epimedium brevicornum Maxim extract relaxes rabbit cEC50orpus cavernosum through multitargets on nitric oxide/cyclic guanosine monophosphate signaling pathway.Int J Impot Res. 2006 Jul-Aug;18(4):335-42. Epub 2006 Jan 5. PMID: 16395327 - ↑ Chen KK, Chiu JH. Effect of Epimedium brevicornum Maxim extract on elicitation of penile erection in the rat. Urology. 2006 Mar;67(3):631-5. PMID: 16527595 - ↑ Ning, H., Xin, Z., Lin, G., Banie, L., Lue, T.F., Lin, C., et al. Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells. Urology,(2006) 68(6), 1350-4. - ↑ Xin, Z.C., Kim, E.K., Lin, C.S., Liu, W.J., Tian, L., Yuan, Y.M., et al. Effects of icariin on cGMP-specific PDE5 and cAMP-specific PDE4 activities. Asian journal of andrology,(2003) 5(1), 15-8. PMID: 12646997 - ↑ Saenz de Tejada I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A, Lledo E, Korschen HG, Niewohner U, Haning H, Pages E, Bischoff E, et al. [ The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. International Journal of Impotence Research,(2001) Oct;13(5):282-90. PMID: 12646997 - ↑ Jiang Z, Hu B, Wang J, Tang Q, Tan Y, Xiang J, Liu J. et al. Effect of icariin on cyclic GMP levels and on the mRNA expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in penile cavernosum. Journal of Huazhong University Scientific Technology Medical Science.(2006);26(4):460-2. nl:Epimedium	Epimedium Epimedium, also known as Barrenwort, Bishop's Hat, Fairy Wings, Horny Goatweed, or Yin Yang Huo (Chinese : 淫羊藿), is a genus of about 60 or more species of herbaceous flowering plants in the family Berberidaceae. The large majority are endemic to southern China, with further outposts in Europe, and central, southern and eastern Asia. Epimedium species are hardy perennials. The majority have four-petaled "spider-like" flowers in spring. Many are believed to be aphrodisiacs. # Aphrodisiac Many species of Epimedium are alleged to have aphrodisiac qualities. According to legend, this property was discovered by a Chinese goat herder who noticed sexual activity in his flock after they ate the weed. It is sold as a health supplement, usually in raw herb or pill form and sometimes blended with other supplements. The over-exploitation of wild populations of Epimedium for use in traditional Chinese medicine is having potentially serious consequences for the long-term survival of several species, none of which are widely cultivated for medicinal purposes. The "active ingredient" in Epimedium is icariin, which can be found in standardized extracts from 5% up to 60% potent. Strengths above that are usually reserved for lab use. Icariin is purported to work by increasing levels of nitric oxide, which relax smooth muscle. It has been demonstrated to relax rabbit penile tissue by nitric oxide and PDE-5 activity [1]. Other research has demonstrated that injections of Epimedium extract, directly into the penis of the rat results in an increase in penile blood pressure.[2] Like Viagra, icariin, the active compound in Epimedium, inhibits the activity of PDE-5. In vitro assays have demonstrated that icariin inhibits PDE-5 with an IC50 of around 1 micromolar,[3][4] while Viagra has an IC50 of about 6.6 nanomolar (.0066 micromolar) and Levitra has an IC50 of about 0.7 nanomolar (.0007 micromolar).[5] Measured differently, the EC50 of icariin is approximately 4.62 micromolar, while Viagra is .42 micromolar.[6] The amount of oral administration of Epidemium extract necessary to achieve these relative concentrations is unclear from the literature, and may not be relevant if the herb works through multiple mechanisms, as has been suggested. Epimedium has been shown to up-regulate genes associated with nitric oxide production and changes in adenosine/guanine monophosphate balance in ways that other PDE5 inhibitors do not. # Cultivation Template:Wikify Hugely popular as garden plants for centuries in Japan, Epimedium are only just beginning to garner attention in the West. Whilst they vary somewhat in their respective hardiness, all are essentially dwellers of the forest floor, and, as such, all require fundamentally similar conditions of moist, free draining, humus rich soil and cool shade, with some shelter for the newly emerging leaves. Some of the more robust varieties are often recommended as plants for dry shade, and whilst their tough foliage and stout rhizomes can allow them to grow successfully in such conditions, (and in more open, exposed positions too, in some instances) they will certainly not give their best. Furthermore, dryness and exposure will pretty much guarantee the early death of many of the newer and more delicate species. Given suitable conditions most Epimedium will form beautiful ground cover plants, often with magnificent new leaves tinted in bronze, copper and reds combining with a huge variety of flower colours and forms in spring. Handsome and dense-growing foliage remains present for much of the year, with the leaves often turning purple, crimson and scarlet in autumn in some forms, and remaining evergreen in others. With all varieties, however, the foliage is best cut off at ground level shortly before new leaves emerge, so as to fully reveal their beauty of form and colour. Ideally, a mulch should then be applied to protect the new growth from frosts. From the gardeners point of view Epimedium flowers comprise two main parts, the inner sepals, which are petal-like and four in number (the four outer sepals are small, insignificant, and rapidly shed as the flowers open) and the petals, which are held within the sepals. In some species these petals have developed long spurs and in such plants they greatly exceed the size of the surrounding sepals, producing a flower shaped like an inverted crown, and also giving rise to the one of the common names for Epimedium- bishops hat. In other species, however, (such as E. perraldianum) the petals are reduced to tiny spurs, and it is the greatly enlarged and highly coloured sepals that have expanded to catch the attention of the wandering insect. Some varieties and hybrids have been in Western cultivation for the last 100/150 years, but there are now a stunning array of new Chinese species (many newly discovered and a number which have yet to be named) and Japanese hybrids and forms arriving in the west to extend the boundaries of the genus in cultivation. The majority of the Chinese species have not been fully tested for hardiness or indeed for any other aspect of their culture. The initial assumptions that the plants would only thrive where their native conditions could be closely replicated have proven to be overly cautious, and most are proving extraordinarily amenable to general garden and container cultivation. Whilst they can be successfully propagated in early spring, Epimedium are best divided in late August, with the aim of promoting rapid re-growth of roots and shoots before the onset of winter. Several breeders (in particular Darrell Probst, Tim Branney & Robin White) have also undertaken their own hybridization programmes with the genus Epimedium, and various new nursery selections are gradually appearing in the nursery trade, the best of which are extending the colour and shape range of the flowers available to the gardener. # Further reading - William T. Stearn, The Genus Epimedium, revised edition 2002, ISBN 0-88192-543-8 - ↑ Chiu JH, Chen KK, Chien TM, Chiou WF, Chen CC, Wang JY, Lui WY, Wu CW. Epimedium brevicornum Maxim extract relaxes rabbit cEC50orpus cavernosum through multitargets on nitric oxide/cyclic guanosine monophosphate signaling pathway.Int J Impot Res. 2006 Jul-Aug;18(4):335-42. Epub 2006 Jan 5. PMID: 16395327 - ↑ Chen KK, Chiu JH. Effect of Epimedium brevicornum Maxim extract on elicitation of penile erection in the rat. Urology. 2006 Mar;67(3):631-5. PMID: 16527595 - ↑ Ning, H., Xin, Z., Lin, G., Banie, L., Lue, T.F., Lin, C., et al. Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells. Urology,(2006) 68(6), 1350-4. - ↑ Xin, Z.C., Kim, E.K., Lin, C.S., Liu, W.J., Tian, L., Yuan, Y.M., et al. Effects of icariin on cGMP-specific PDE5 and cAMP-specific PDE4 activities. Asian journal of andrology,(2003) 5(1), 15-8. PMID: 12646997 - ↑ Saenz de Tejada I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A, Lledo E, Korschen HG, Niewohner U, Haning H, Pages E, Bischoff E, et al. [http://www.nature.com/ijir/journal/v13/n5/abs/3900726a.html The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. International Journal of Impotence Research,(2001) Oct;13(5):282-90. PMID: 12646997 - ↑ Jiang Z, Hu B, Wang J, Tang Q, Tan Y, Xiang J, Liu J. et al. Effect of icariin on cyclic GMP levels and on the mRNA expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in penile cavernosum. Journal of Huazhong University Scientific Technology Medical Science.(2006);26(4):460-2. nl:Epimedium Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Epimedium
32ea2d04769f1937286a2764296221824781adff	wikidoc	Episclera	Episclera # Overview The episclera is the outermost layer of the sclera. It is composed of loose, fibrous, elastic tissue and attaches to Tenon's capsule. In episcleritis, the episclera and Tenon's capsule are infiltrated with inflammatory cells . The episclera is a Vascular plexus that lies between the conjunctiva and the sclera and consists of two layers of vessels: the superficial episcleral vessels and the deep episcleral vessels.	Episclera Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The episclera is the outermost layer of the sclera[1]. It is composed of loose, fibrous, elastic tissue and attaches to Tenon's capsule[1]. In episcleritis, the episclera and Tenon's capsule are infiltrated with inflammatory cells [2]. The episclera is a Vascular plexus that lies between the conjunctiva and the sclera and consists of two layers of vessels: the superficial episcleral vessels and the deep episcleral vessels.	https://www.wikidoc.org/index.php/Episclera
56f41c17bd1b3a81aa9d81feaf34e8f0cf9504e9	wikidoc	Epizootic	Epizootic In epizoology, an epizootic (from Greek epi- upon + zoion animal) is a disease that appears as new cases in a given animal population, during a given period, at a rate that substantially exceeds what is "expected" based on recent experience (i.e. a sharp elevation in the incidence rate). (An epidemic is the same term applied to human populations.) High population density is a major contributing factor to epizootics, with aquaculture being an example of an industry sometimes plagued by disease because of the large number of fish confined to a small area. Defining an epizootic can be subjective, depending in part on what is "expected". An epizootic may be: a) restricted to a specific locale (an outbreak), b) general (an "epizootic") or c) widespread (panzootic). Because it is based on what is "expected" or thought normal, a few cases of a very rare disease (like a TSE outbreak in a Cervid population) might be classified as an "epizootic," while many cases of a common disease (like lymphocystis in Esocids) would not. Common diseases that occur at a constant but relatively high rate in the population are said to be "enzootic." An example of an enzootic disease would be the influenza virus in some bird populations or, at a lower incidence, the Type IVb strain of VHS in certain Atlantic fish populations. An example of an epizootic would be the 1990 outbreak of Newcastle disease virus in double-crested cormorant colonies on the Great Lakes that resulted in the death of some 10000 birds. # Zambia EUS outbreak On September 14, 2007, epizootic ulcerative sydrome (EUS), a mysterious disease killed hundreds of sore-covered fish in River Zambezi. Zambia Agriculture Minister Ben Kapita asked experts to investigate the outbreak to probe the cause to find out if the disease can be transmitted to humans.	Epizootic In epizoology, an epizootic (from Greek epi- upon + zoion animal) is a disease that appears as new cases in a given animal population, during a given period, at a rate that substantially exceeds what is "expected" based on recent experience (i.e. a sharp elevation in the incidence rate). (An epidemic is the same term applied to human populations.) High population density is a major contributing factor to epizootics, with aquaculture being an example of an industry sometimes plagued by disease because of the large number of fish confined to a small area. Defining an epizootic can be subjective, depending in part on what is "expected". An epizootic may be: a) restricted to a specific locale (an outbreak), b) general (an "epizootic") or c) widespread (panzootic). Because it is based on what is "expected" or thought normal, a few cases of a very rare disease (like a TSE outbreak in a Cervid population) might be classified as an "epizootic," while many cases of a common disease (like lymphocystis in Esocids) would not. Common diseases that occur at a constant but relatively high rate in the population are said to be "enzootic." An example of an enzootic disease would be the influenza virus in some bird populations [1] or, at a lower incidence, the Type IVb strain of VHS in certain Atlantic fish populations. [2] An example of an epizootic would be the 1990 outbreak of Newcastle disease virus in double-crested cormorant colonies on the Great Lakes that resulted in the death of some 10000 birds. [3] ## Zambia EUS outbreak On September 14, 2007, epizootic ulcerative sydrome (EUS), a mysterious disease killed hundreds of sore-covered fish in River Zambezi. Zambia Agriculture Minister Ben Kapita asked experts to investigate the outbreak to probe the cause to find out if the disease can be transmitted to humans.[1]	https://www.wikidoc.org/index.php/Epizootic
1cd7220c5462fd972c64ebad4e13eaacd1ec8b62	wikidoc	Equagesic	Equagesic Equagesic (Template:PronEng) is a combination drug indicated for short-term pain treatment accompanied by tension and/or anxiety in patients with musculoskeletal disease or tension headache. # Composition It combines - aspirin 325mg (for pain relief) and - meprobamate 200mg (used here as a muscle relaxant). - In some formulations it is also quoted to contain ethoheptazine, an opioid analgesic. # Problems Equagesic was discontinued in the UK in 2002, possibly because of more adequate drugs available. Specifically, meprobamate is more toxic than benzodiazepines, which are also useful as a muscle relaxant. Martial artist Bruce Lee died of cerebral oedema thought to have been a reaction to his taking of Equagesic.	Equagesic Equagesic (Template:PronEng) is a combination drug indicated for short-term pain treatment accompanied by tension and/or anxiety in patients with musculoskeletal disease or tension headache. # Composition It combines[1] - aspirin 325mg (for pain relief) and - meprobamate 200mg (used here as a muscle relaxant). - In some formulations[2] it is also quoted to contain ethoheptazine, an opioid analgesic. # Problems Equagesic was discontinued in the UK in 2002, possibly because of more adequate drugs available. Specifically, meprobamate is more toxic than benzodiazepines, which are also useful as a muscle relaxant. Martial artist Bruce Lee died of cerebral oedema thought to have been a reaction to his taking of Equagesic.	https://www.wikidoc.org/index.php/Equagesic
0dd97648404e5ddc0d84dce4d69e2c681e241568	wikidoc	Erbovirus	Erbovirus # Overview Erbovirus is a viral genus of the Picornaviridae family. Viruses belonging to the Erbovirus genus have been isolated in horses with acute upper febrile respiratory disease. The structure of the erbovirus virion is icosahedral, having a diameter of 27-30nm. # Physical characteristics The virion essentially is a nucleocapsid that is visible under an electron microscope and is able to infect cultured cells from a broad range of mammals including rabbit kidney (RK13), African green monkey kidney (Vero), equine foetal kidney (EFK), and is able to infect humans. The RNA genome of the virion is inside the capsid that is composed by twelve capsomers, which are cup-shaped pentamers. The erbovirus particles are non-enveloped and the molecular mass of the virions is around 8-9 x 106 Daltons. They are resistant to inactivation by non-ionic detergent treatment. Erbovirus, as a typical picornavirus, has a single-stranded positive-sense RNA genome. A feature of the picornavirus genome is the virus protein that is linked at the 5’ end of the genome, known as "VPg" (Virus-Protein-attached-to-the-Genome). In addition, the 3’ end of the genome has a poly-A tail. The transcription of the erbovirus genome gives rise to a polyprotein which is further more processed and cleaved to give the mature viral proteins, in order from 5' to 3' : L ("Leader"), VP4, VP2, VP3, VP1, 2A, 2B, 2C, 3A (Vpg), 3B, 3Cpro, 3Dpol. The type (and only) species of the Erbovirus genus is Equine rhinitis B virus which was recently found to have three phylogenetically distinct types, equine rhinitis B virus (ERBV)-1, ERBV-2 and ERBV-3. One such phylogenetic group was found to mostly comprise of "acid stable" virus isolates, surviving pH 3.6 for 1 hour at room temperature. # Epidemiology ERBV's appear to infect most foals and weanlings, eliciting a low serum antibody response in stark contrast to equine rhinitis A virus (ERAV), which is the only species of the genus Aphthovirus that is not a foot-and-mouth disease virus (FMDV), and appears to only infect horses once they begin training for racing (approx. 2 years old). ERAV enters the blood and elicits a very high serum antibody response that seems to then limit the spread of the virus by herd-immunity, given that only approximately 40% of horses have detectable ERAV antibody. The low serum antibody response of ERBV appears to allow the continual, seasonal re-infection of horses. Horses are also known to shed ERBV for up to two years, possibly more.	Erbovirus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Erbovirus is a viral genus of the Picornaviridae family.[1] Viruses belonging to the Erbovirus genus have been isolated in horses with acute upper febrile respiratory disease.[2] The structure of the erbovirus virion is icosahedral,[1] having a diameter of 27-30nm.[3] # Physical characteristics The virion essentially is a nucleocapsid that is visible under an electron microscope and is able to infect cultured cells from a broad range of mammals including rabbit kidney (RK13), African green monkey kidney (Vero), equine foetal kidney (EFK), and is able to infect humans.[4] The RNA genome of the virion is inside the capsid that is composed by twelve capsomers, which are cup-shaped pentamers. The erbovirus particles are non-enveloped and the molecular mass of the virions is around 8-9 x 106 Daltons.[3] They are resistant to inactivation by non-ionic detergent treatment.[3] Erbovirus, as a typical picornavirus, has a single-stranded positive-sense RNA genome. A feature of the picornavirus genome is the virus protein that is linked at the 5’ end of the genome, known as "VPg" (Virus-Protein-attached-to-the-Genome).[1] In addition, the 3’ end of the genome has a poly-A tail.[1] The transcription of the erbovirus genome gives rise to a polyprotein which is further more processed and cleaved to give the mature viral proteins, in order from 5' to 3' : L ("Leader"), VP4, VP2, VP3, VP1, 2A, 2B, 2C, 3A (Vpg), 3B, 3Cpro, 3Dpol.[5] The type (and only) species of the Erbovirus genus is Equine rhinitis B virus which was recently found to have three phylogenetically distinct types, equine rhinitis B virus (ERBV)-1, ERBV-2 and ERBV-3.[6] One such phylogenetic group was found to mostly comprise of "acid stable" virus isolates, surviving pH 3.6 for 1 hour at room temperature.[7] # Epidemiology ERBV's appear to infect most foals and weanlings, eliciting a low serum antibody response in stark contrast to equine rhinitis A virus (ERAV), which is the only species of the genus Aphthovirus that is not a foot-and-mouth disease virus (FMDV), and appears to only infect horses once they begin training for racing (approx. 2 years old). ERAV enters the blood and elicits a very high serum antibody response that seems to then limit the spread of the virus by herd-immunity, given that only approximately 40% of horses have detectable ERAV antibody.[8] The low serum antibody response of ERBV appears to allow the continual, seasonal re-infection of horses. Horses are also known to shed ERBV for up to two years, possibly more.	https://www.wikidoc.org/index.php/Erbovirus
0d4011d7ff4009ced8ce092ee6094ccb27520aa2	wikidoc	Erlotinib	Erlotinib # 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 Erlotinib is a tyrosine kinase nhibitor that is FDA approved for the treatment of non small cell lung cancer (NSCLC), pancreatic cancer. Common adverse reactions include edema，alopecia，pruritus，rash，decreased weight，abdominal pain，diarrhea，flatulence, indigestion，inflammatory disease of mucous membrane，loss of appetite，nausea，vomiting, hyperbilirubinemia, increased liver enzymes，infectious disease，bone pain，myalgia，headache，conjunctivitis, keratoconjunctivitis sicca，anxiety，depression，cough，dyspnea，fatigue, fever.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Non-Small Cell Lung Cancer (NSCLC) - Dosing information - Recommended daily dosage: 150 mg PO qdtaken on an empty stomach, - i.e., at least one hour before or two hours after the ingestion of food. - Treatment should continue until disease progression or unacceptable toxicity occurs. ### Pancreatic Cancer - Dosing information - Recommended daily dosage: 100 mg taken PO qd in combination with gemcitabine. - Take Erlotinib on an empty stomach, i.e., at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs ## Dose Modifications Discontinue Erlotinib for: - Interstitial Lung Disease (ILD) - Severe hepatotoxicity that does not improve significantly or resolve within three weeks - Gastrointestinal perforation - Severe bullous, blistering or exfoliating skin conditions - Corneal perforation or severe ulceration Withhold Erlotinib: - During diagnostic evaluation for possible ILD. - For severe (CTCAE grade 3 to 4) renal toxicity, and consider discontinuation of Erlotinib. - In patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal, and consider discontinuation of Erlotinib. - In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline and consider discontinuation of Erlotinib. - For persistent severe diarrhea not responsive to medical management (e.g., loperamide). - For severe rash not responsive to medical management. - For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks. - For acute/worsening ocular disorders such as eye pain, and consider discontinuation of Erlotinib Reduce Erlotinib by 50 mg decrements: - If severe reactions occur with concomitant use of strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., ciprofloxacin). Avoid concomitant use if possible. - When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1. Increase Erlotinib by 50 mg increments as tolerated for: - Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s Wort. Increase doses by 50 mg increments at 2 week intervals to a maximum of 450 mg. Avoid concomitant use, if possible - Concurrent cigarette smoking. Increase by 50 mg increments at 2 week intervals to a maximum of 300 mg. Immediately reduce the dose of Erlotinib to the recommended dose (150 mg or 100 mg daily) upon cessation of smoking Drugs Affecting Gastric pH - Avoid concomitant use of Erlotinib with proton pump inhibitors if possible. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period. - If treatment with an H2-receptor antagonist such as ranitidine is required, Erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist. - Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the Erlotinib dose should be separated by several hours, if an antacid is necessary. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Erlotinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Erlotinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Erlotinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Erlotinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Erlotinib in pediatric patients. # Contraindications None # Warnings ## Interstitial Lung Disease (ILD) Cases of serious ILD, including fatal cases, can occur with Erlotinib treatment. The overall incidence of ILD in approximately 32,000 Erlotinib-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating Erlotinib therapy. Withhold Erlotinib for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue Erlotinib. ## Renal Failure Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with Erlotinib treatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration. The pooled incidence of severe renal impairment in the 3 monotherapy lung cancer studies was 0.5% in the Erlotinib arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the Erlotinib plus gemcitabine arm and 0.4% in the control arm. Withhold Erlotinib in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during Erlotinib treatment. ## Hepatotoxicity with or without Hepatic Impairment Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In clinical studies where patients with moderate to severe hepatic impairment were excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in the Erlotinib arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0.4% in the control arm. In a pharmacokinetic study in 15 patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of these 15 patients died within 30 days of the last Erlotinib dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN. Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with Erlotinib. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold Erlotinib in patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal. Withhold Erlotinib in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue Erlotinib in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within three weeks. ## Gastrointestinal Perforation Gastrointestinal perforation, including fatal cases, can occur with Erlotinib treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation. The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the Erlotinib arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. Permanently discontinue Erlotinib in patients who develop gastrointestinal perforation. ## Bullous and Exfoliative Skin Disorders Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal, can occur with Erlotinib treatment . The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the Erlotinib arms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. Discontinue Erlotinib treatment if the patient develops severe bullous, blistering or exfoliating conditions . ## Myocardial Infarction/Ischemia In the pancreatic carcinoma trial, six patients (incidence of 2.1%) in the Erlotinib/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the Erlotinib arms and 0.4% in the control arms. ## Cerebrovascular Accident In the pancreatic carcinoma trial, seven patients in the Erlotinib/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the Erlotinib arms and 0.9% in the control arms. ## Microangiopathic Hemolytic Anemia with Thrombocytopenia The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the Erlotinib arms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. ## Ocular Disorders Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with Erlotinib treatment and can lead to corneal perforation or ulceration. The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the Erlotinib arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the Erlotinib plus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue Erlotinib therapy if patients present with acute or worsening ocular disorders such as eye pain. ## Hemorrhage in Patients Taking Warfarin Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when Erlotinib and warfarin are administered concurrently. Regularly monitor prothrombin time and INR during Erlotinib treatment in patients taking warfarin or other coumarin-derivative anticoagulants. ## Embryo-Fetal Toxicity Based on its mechanism of action, Erlotinib can cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If Erlotinib is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 2 weeks after the last dose of Erlotinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Erlotinib. # 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. - Safety evaluation of Erlotinib is based on more than 1200 cancer patients who received Erlotinib as monotherapy, more than 300 patients who received Erlotinib 100 or 150 mg plus gemcitabine, and 1228 patients who received Erlotinib concurrently with other chemotherapies. - The most common adverse reactions with Erlotinib are rash and diarrhea usually with onset during the first month of treatment. - The incidences of rash and diarrhea from clinical studies of Erlotinib for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea. Non-Small Cell Lung Cancer First-Line Treatment of Patients with EGFR Mutations The most frequent (≥ 30%) adverse reactions in Erlotinib-treated patients were diarrhea, asthenia, rash, cough, dyspnea and decreased appetite. In Erlotinib-treated patients the median time to onset of rash was 15 days and the median time to onset of diarrhea was 32 days. The most frequent Grade 3-4 adverse reactions in Erlotinib-treated patients were rash and diarrhea. Dose interruptions or reductions due to adverse reactions occurred in 37% of Erlotinib-treated patients, and 14.3% of Erlotinib-treated patients discontinued therapy due to adverse reactions. In Erlotinib-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%). Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received Erlotinib or chemotherapy and an increase in ≥ 5% in the Erlotinib treated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1. The median duration of Erlotinib treatment was 9.6 months in Study 4. Hepatic Toxicity: One Erlotinib-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 4 Maintenance Treatment Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent Erlotinib at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTC (version 3.0) Grade in Table 2. The most common adverse reactions in patients receiving single-agent Erlotinib 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in Erlotinib-treated patients. rash and diarrhea resulted in study discontinuation in 1% and 0.5% of Erlotinib-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In Erlotinib-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days. Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of Erlotinib-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of Erlotinib-treated patients and in < 1% in the placebo group. Second/Third Line Treatment Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent Erlotinib at 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 3. The most common adverse reactions in this patient population were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 6%, respectively, in Erlotinib-treated patients. rash and diarrhea each resulted in study discontinuation in 1% of Erlotinib-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days. Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent Erlotinib 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 (> 2.5 – 5.0 x ULN) ALT elevations occurred in 4% and 5.0 – 20.0 x ULN) elevations were not observed in Erlotinib-treated patients. Erlotinib dosing should be interrupted or discontinued if changes in liver function are severe Pancreatic Cancer - Erlotinib Administered Concurrently with gemcitabine This was a randomized, double blind placebo-controlled study of Erlotinib (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m2 IV) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). The safety population comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo group (256 in the 100 mg cohort and 24 in the 150 mg cohort). Adverse reactions that occurred in at least 10% of patients treated with Erlotinib 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4. The most common adverse reactions in pancreatic cancer patients receiving Erlotinib 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the Erlotinib plus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving Erlotinib plus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the Erlotinib plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption. Ten patients (4%) in the Erlotinib/gemcitabine group and three patients (1%) in the placebo/gemcitabine group developed deep venous thrombosis. The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis was 11% for Erlotinib plus gemcitabine and 9% for placebo plus gemcitabine. The incidences of liver test abnormalities (≥ Grade 2) in Study 2 are provided in Table 5 NSCLC and Pancreatic Indications: Selected Low Frequency Adverse Reactions Gastrointestinal Disorders Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration . These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of Erlotinib. 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. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis, in combination with statin therapy. Eye Disorders: ocular inflammation including uveitis. # Drug Interactions CYP3A4 Inhibitors Erlotinib is metabolized predominantly by CYP3A4. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 67%. When Erlotinib was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure and maximum concentration increased by 39% and 17%, respectively. Dose modifications are recommended. CYP3A4 Inducers Pre-treatment with the CYP3A4 inducer rifampicin for 7-11 days prior to Erlotinib decreased erlotinib AUC by 58% to 80%. Dose modifications are recommended. Drugs Affecting Gastric pH Co-administration of Erlotinib with omeprazole decreased erlotinib AUC by 46% and co-administration of Erlotinib with ranitidine 300 mg decreased erlotinib AUC by 33%. When Erlotinib was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), erlotinib AUC decreased by 15%. Increasing the dose of Erlotinib when co-administered with such agents is not likely to compensate for the loss of exposure. Scheduling modifications are recommended. Cigarette Smoking Cigarette smoking results in reductions in erlotinib AUC. Dose modifications are recommended. Anticoagulants Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving Erlotinib. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. Dose modifications of Erlotinib are not recommended # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Risk Summary Based on its mechanism of action, Erlotinib can cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If Erlotinib is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus Animal Data Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m2/day or 60 mg/m2/day (0.3 or 0.7 times the recommended daily dose, on a mg/m2 basis) of erlotinib had an increase in early resorptions that resulted in a decrease in the number of live fetuses. No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m2/day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m2/day in the rat (0.7 times the recommended dose of 150 mg/day on a mg/m2 basis). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Erlotinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Erlotinib during labor and delivery. ### Nursing Mothers It is not known whether erlotinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Erlotinib, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use The safety and effectiveness of Erlotinib in pediatric patients have not been established. ### Geriatic Use Of the 1297 subjects in clinical studies of Erlotinib for the treatment of NSCLC and pancreatic cancer 40% were 65 and older while 10% were 75 and older. No overall differences in safety or efficacy were observed between subjects 65 years and older and those younger than 65. ### Gender There is no FDA guidance on the use of Erlotinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Erlotinib with respect to specific racial populations. ### Renal Impairment Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function. ### Hepatic Impairment Patients with hepatic impairment (total bilirubin > upper limit of normal (ULN) or Child-Pugh A, B and C) should be closely monitored during therapy with Erlotinib. Treatment with Erlotinib should be used with extra caution in patients with total bilirubin > 3 x ULN In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases ### Females of Reproductive Potential and Males Contraception Females Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with Erlotinib, and for at least 2 weeks after the last dose of Erlotinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Erlotinib ### Immunocompromised Patients There is no FDA guidance one the use of Erlotinib in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Erlotinib contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility # Overdosage Single oral doses of Erlotinib up to 1,000 mg in healthy subjects and weekly doses up to 1,600 mg in cancer patients have been tolerated. Repeated twice-daily doses of 200 mg single-agent Erlotinib in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, an unacceptable incidence of severe adverse reactions, such as diarrhea, rash, and liver transaminase elevation, may occur above the recommended dose . In case of suspected overdose, Erlotinib should be withheld and symptomatic treatment instituted. # Pharmacology ## Mechanism of Action Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells. In some tumor cells signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild type receptor. Erlotinib inhibition of other tyrosine kinase receptors has not been fully characterized. ## Structure Erlotinib (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Erlotinib contains erlotinib as the hydrochloride salt that has the following structural formula: Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane. Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2. Erlotinib tablets for oral administration are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg erlotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C Yellow #6 (25 mg only) for product identification. ## Pharmacodynamics There is limited information regarding Erlotinib Pharmacodynamics in the drug label. ## Pharmacokinetics ### Absorption and Distribution: Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Co-administration of Erlotinib with omeprazole, a proton pump inhibitor, decreased the erlotinib exposure and maximum concentration by 46% and 61%, respectively. When Erlotinib was administered 2 hours following a 300 mg dose of ranitidine, an H2 receptor antagonist, the erlotinib AUC was reduced by 33% and Cmax by 54%. When Erlotinib was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the erlotinib AUC and Cmax decreased by 15% and 17%, respectively. Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters. ### Metabolism and Excretion: A population pharmacokinetic analysis in 591 patients receiving the single-agent Erlotinib 2nd/3rd line regimen showed a median half-life of 36.2 hours. Time to reach steady state plasma concentration would therefore be 7 – 8 days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had a 24% higher rate of erlotinib clearance. An additional population pharmacokinetic analysis was conducted in 291 NSCLC patients administered single-agent erlotinib as maintenance treatment. This analysis demonstrated that covariates affecting erlotinib clearance in this patient population were similar to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. A third population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine. Similar results were observed to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Co-administration of gemcitabine had no effect on erlotinib plasma clearance. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent). Cigarette smoking reduces erlotinib exposure. In the Phase 3 NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which were approximately 2-fold less than the former smokers or patients who had never smoked. This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance. In a separate study which evaluated the single-dose pharmacokinetics of erlotinib in healthy volunteers, current smokers cleared the drug faster than former smokers or volunteers who had never smoked. The AUC0-infinity in smokers was about 1/3 to 1/2 of that in never/former smokers. In another study which was conducted in NSCLC patients (N=35) who were current smokers, pharmacokinetic analyses at steady-state indicated a dose-proportional increase in erlotinib exposure when the Erlotinib dose was increased from 150 mg to 300 mg. However, the exact dose to be recommended for patients who currently smoke is unknown. Special Populations: Patients with Hepatic Impairment hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases. Patients with Renal Impairment Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function. ## Nonclinical Toxicology ### ]Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in mice and rats with erlotinib at oral doses of up to 60 mg/kg/day in mice, 5 mg/kg/day in female rats, and 10 mg/kg/day in male rats. The studies were negative for carcinogenic findings. Exposure in mice at the highest dose tested was approximately 10 times the exposure in humans at the erlotinib dose of 150 mg/day. The highest dose evaluated in male rats resulted in exposures that were twice those in humans and exposures at the highest tested dose in female rats were slightly lower than those in humans. Erlotinib did not cause genetic damage in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration and mammalian cell mutation) and in the in vivo mouse bone marrow micronucleus test. Erlotinib did not impair fertility in either male or female rats. # Clinical Studies ### Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment of Patients with EGFR Mutations The safety and efficacy of Erlotinib as monotherapy for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations was demonstrated in a randomized, open-label, clinical trial conducted in Europe (Study 4). One hundred seventy-four (174) White patients were randomized 1:1 to receive erlotinib 150 mg once daily until disease progression (n=86) or four cycles of a standard platinum-based doublet chemotherapy (n=88); standard chemotherapy regimens were cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. Randomization was stratified by EGFR mutation (exon 19 deletion or exon 21 (L858R) substitution) and ECOG PS (0 vs. 1 vs. 2). EGFR mutation status for screening and enrollment of patients was determined by a clinical trials assay (CTA). Tumor samples from 134 patients (69 patients from the erlotinib arm and 65 patients from the chemotherapy arm) were tested retrospectively by the FDA-approved companion diagnostic, the cobas® EGFR Mutation Test. The baseline demographics of the overall study population were as follows: female (72%), white (99%), age ≥ 65 years (51%), ECOG PS 1 (53%), with ECOG PS 0 (33%), and ECOG PS 2 (14%), current smoker (11%), past-smoker (20%), and never smoker (69%). The disease characteristics were 93% stage IV and 7% Stage IIIb with pleural effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition), 93% adenocarcinoma histology, 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by a CTA. A statistically significant improvement in investigator-determined PFS was demonstrated for patients randomized to erlotinib compared to those randomized chemotherapy. Similar results for PFS were observed for the subgroup evaluated by an independent-review committee (approximately 75% of patients in Study 4 evaluated) and in the subgroup of 134 patients (77% of the Study 4 population) with EGFR mutations confirmed by the cobas® EGFR Mutation Test. A protocol-specified analysis of overall survival conducted at the time of the final analysis of PFS showed no statistically significant difference between the Erlotinib and chemotherapy arms. At the time of the data cut-off, 84% of patients in the chemotherapy arm had received at least one subsequent treatment, of whom 97% received an EGFR tyrosine kinase inhibitor. In the Erlotinib arm, 66% of patients had received at least one subsequent treatment. In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was 0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions and 0.52 (95% CI 0.29 to 0.95) in patients with exon 21 (L858R) substitution. The HR for OS was 0.94 (95% CI 0.57 to 1.54) in the exon 19 deletion subgroup and 0.99 (95% CI 0.56 to 1.76) in the exon 21 (L858R) substitution subgroup. ### NSCLC - Maintenance Treatment The efficacy and safety of Erlotinib as maintenance treatment of NSCLC were demonstrated in a randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with locally advanced or metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy (Study 3). Patients were randomized 1:1 to receive Erlotinib 150 mg or placebo orally once daily (438 Erlotinib, 451 placebo) until disease progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of Erlotinib after standard platinum-based chemotherapy in the treatment of NSCLC resulted in improved progression free survival (PFS) when compared with placebo, in all patients or in patients with EGFR immunohistochemistry (IHC) positive tumors. Demographic characteristics were balanced between the two treatment groups. Baseline demographics of the overall study population were as follows: male (74%), age < 65 years (66%), ECOG PS 1 (69%), ECOG PS 0 (31%), white (84%), Asian (15%), current smoker (55%), past-smoker (27%), and never smoker (17%). Disease characteristics were as follows: Stage IV (75%), Stage IIIb with effusion (25%) as classified by AJCC (6th edition) with histologic subtypes of adenocarcinoma including bronchioalveolar (45%), squamous (40%) and large cell (5%); and EGFR IHC positive (70%), negative (14%), indeterminate (4%), and missing (12%). Figure 2 depicts the Kaplan-Meier Curves for Overall Survival (ITT Population). Note: HR is from a univariate Cox regression model. The PFS and OS Hazard Ratios, respectively, in patients with EGFR IHC-positive tumors were 0.69 (95% CI: 0.58, 0.82) and 0.77 (95% CI: 0.64, 0.93). The PFS and OS Hazard Ratios in patients with IHC-negative tumors were 0.77 (95% CI: 0.51, 1.14) and 0.91 (95% CI: 0.59, 1.38), respectively. Patients with adenocarcinoma had an OS Hazard Ratio of 0.77 (95% CI: 0.61, 0.97) and patients with squamous histology had an OS Hazard Ratio of 0.86 (95% CI: 0.68, 1.10). ### NSCLC –Second/Third Line Treatment The efficacy and safety of single-agent Erlotinib was assessed in a randomized, double blind, placebo-controlled trial in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen (Study 1). Patients were randomized 2:1 to receive Erlotinib 150 mg or placebo (488 Erlotinib, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Study endpoints included overall survival, response rate, and progression-free survival (PFS). Duration of response was also examined. The primary endpoint was survival. The study was conducted in 17 countries. Baseline demographics of the overall study population were as follows: male (65%), white (78%), Asian (12%), black (4%), age < 65 years (62%), ECOG PS 1 (53%), ECOG PS 0 (13%), ECOG PS 2 (25%), ECOG PS 3 (9%), current or ex-smoker (75%), never smoker (20%), and exposure to prior platinum therapy (93%). Tumor characteristics were as follows: adenocarcinoma (50%), squamous (30%), undifferentiated large cell (9%), and mixed non-small cell (2%). The results of the study are shown in Table 8. Survival was evaluated in the intent-to-treat population. Figure 3 depicts the Kaplan-Meier curves for overall survival. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. Note: HR is from Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. P-value is from two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. ### NSCLC – Lack of Efficacy of Erlotinib Administered Concurrently with Chemotherapy Results from two, multicenter, placebo-controlled, randomized, trials in over 1000 patients conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Erlotinib with platinum-based chemotherapy . ### Pancreatic Cancer - Erlotinib Administered Concurrently with gemcitabine The efficacy and safety of Erlotinib in combination with gemcitabine as a first-line treatment was assessed in a randomized, double blind, placebo-controlled trial in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). Patients were randomized 1:1 to receive Erlotinib (100 mg or 150 mg) or placebo once daily on a continuous schedule plus gemcitabine IV (1000 mg/m2, Cycle 1 - Days 1, 8, 15, 22, 29, 36 and 43 of an 8 week cycle; Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4-week cycle. Erlotinib or placebo was taken orally once daily until disease progression or unacceptable toxicity. The primary endpoint was survival. Secondary endpoints included response rate, and progression-free survival (PFS). Duration of response was also examined. The study was conducted in 18 countries. A total of 285 patients were randomized to receive gemcitabine plus Erlotinib (261 patients in the 100 mg cohort and 24 patients in the 150 mg cohort) and 284 patients were randomized to receive gemcitabine plus placebo (260 patients in the 100 mg cohort and 24 patients in the 150 mg cohort). Too few patients were treated in the 150 mg cohort to draw conclusions. In the 100 mg cohort, baseline demographics of the overall study population were as follows: male (52%), white (88%), Asian (7%), black (2%), age < 65 years (53%), ECOG PS 1 (51%), ECOG PS 0 (32%), and ECOG PS 2 (17%). There was a slightly larger proportion of females in the Erlotinib arm (51%) compared with the placebo arm (44%). The median time from initial diagnosis to randomization was approximately 1.0 month. The majority of the patients (76%) had distant metastases at baseline and 24% had locally advanced disease. The results of the study are shown in Table 9. Survival was evaluated in the intent-to-treat population. Figure 4 depicts the Kaplan-Meier curves for overall survival in the 100 mg cohort. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status and extent of disease. Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. The p-value is from two-sided Log-Rank test stratified by ECOG performance status and extent of disease. # How Supplied 25 mg Tablets Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side; supplied in: Bottles of 30: NDC 50242-062-01 100 mg Tablets Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side; supplied in: Bottles of 30: NDC 50242-063-01 150 mg Tablets Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side; supplied in: Bottles of 30: NDC 50242-064-01 ## Storage Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). See USP Controlled Room Temperature. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients to contact their health care provider for: - Severe or persistent diarrhea, nausea, anorexia, or vomiting - Onset or worsening of unexplained shortness of breath or cough - Eye irritation - Onset or worsening of skin rash or development of bullous lesions or desquamation. - Any changes in smoking status Advise patients on the presentation of skin, hair and nail disorders. - In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade 3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed areas. Symptoms associated with rash may include itching, tenderness and/or burning. - Hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash. - Hair and nail disorders, including hirsutism and brittle and loose nails, have been reported. Instruct patients on initial management of rash or diarrhea. - Given that skin reactions are anticipated when taking Erlotinib, proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure - Management of rash may include topical corticosteroids or antibiotics with anti-inflammatory properties. These approaches were used in the NSCLC and pancreatic pivotal clinical trials. Acne preparations with drying properties may aggravate the dry skin and erythema. Treatment of rash has not been formally studied and should be based on rash severity. - Diarrhea can usually be managed with loperamide. Counsel patients on pregnancy planning and prevention. - Advise females of reproductive potential to use highly effective contraception during treatment with Erlotinib, and for at least 2 weeks after the last dose of Erlotinib. - Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Erlotinib. - Advise breast-feeding mothers to discontinue nursing while receiving Erlotinib . Advise patients to stop smoking. Advise patients that the dose of Erlotinib may need to be adjusted if they smoke. # Precautions with Alcohol Alcohol-Erlotinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tarceva # Look-Alike Drug Names There is limited information regarding Erlotinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Erlotinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [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 Erlotinib is a tyrosine kinase nhibitor that is FDA approved for the treatment of non small cell lung cancer (NSCLC), pancreatic cancer. Common adverse reactions include edema，alopecia，pruritus，rash，decreased weight，abdominal pain，diarrhea，flatulence, indigestion，inflammatory disease of mucous membrane，loss of appetite，nausea，vomiting, hyperbilirubinemia, increased liver enzymes，infectious disease，bone pain，myalgia，headache，conjunctivitis, keratoconjunctivitis sicca，anxiety，depression，cough，dyspnea，fatigue, fever.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Non-Small Cell Lung Cancer (NSCLC) - Dosing information - Recommended daily dosage: 150 mg PO qdtaken on an empty stomach, - i.e., at least one hour before or two hours after the ingestion of food. - Treatment should continue until disease progression or unacceptable toxicity occurs. ### Pancreatic Cancer - Dosing information - Recommended daily dosage: 100 mg taken PO qd in combination with gemcitabine. - Take Erlotinib on an empty stomach, i.e., at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs ## Dose Modifications Discontinue Erlotinib for: - Interstitial Lung Disease (ILD) - Severe hepatotoxicity that does not improve significantly or resolve within three weeks - Gastrointestinal perforation - Severe bullous, blistering or exfoliating skin conditions - Corneal perforation or severe ulceration Withhold Erlotinib: - During diagnostic evaluation for possible ILD. - For severe (CTCAE grade 3 to 4) renal toxicity, and consider discontinuation of Erlotinib. - In patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal, and consider discontinuation of Erlotinib. - In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline and consider discontinuation of Erlotinib. - For persistent severe diarrhea not responsive to medical management (e.g., loperamide). - For severe rash not responsive to medical management. - For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks. - For acute/worsening ocular disorders such as eye pain, and consider discontinuation of Erlotinib Reduce Erlotinib by 50 mg decrements: - If severe reactions occur with concomitant use of strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., ciprofloxacin). Avoid concomitant use if possible. - When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1. Increase Erlotinib by 50 mg increments as tolerated for: - Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s Wort. Increase doses by 50 mg increments at 2 week intervals to a maximum of 450 mg. Avoid concomitant use, if possible - Concurrent cigarette smoking. Increase by 50 mg increments at 2 week intervals to a maximum of 300 mg. Immediately reduce the dose of Erlotinib to the recommended dose (150 mg or 100 mg daily) upon cessation of smoking Drugs Affecting Gastric pH - Avoid concomitant use of Erlotinib with proton pump inhibitors if possible. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period. - If treatment with an H2-receptor antagonist such as ranitidine is required, Erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist. - Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the Erlotinib dose should be separated by several hours, if an antacid is necessary. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Erlotinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Erlotinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Erlotinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Erlotinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Erlotinib in pediatric patients. # Contraindications None # Warnings ## Interstitial Lung Disease (ILD) Cases of serious ILD, including fatal cases, can occur with Erlotinib treatment. The overall incidence of ILD in approximately 32,000 Erlotinib-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating Erlotinib therapy. Withhold Erlotinib for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue Erlotinib. ## Renal Failure Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with Erlotinib treatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration. The pooled incidence of severe renal impairment in the 3 monotherapy lung cancer studies was 0.5% in the Erlotinib arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the Erlotinib plus gemcitabine arm and 0.4% in the control arm. Withhold Erlotinib in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during Erlotinib treatment. ## Hepatotoxicity with or without Hepatic Impairment Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In clinical studies where patients with moderate to severe hepatic impairment were excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in the Erlotinib arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0.4% in the control arm. In a pharmacokinetic study in 15 patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of these 15 patients died within 30 days of the last Erlotinib dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN. Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with Erlotinib. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold Erlotinib in patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal. Withhold Erlotinib in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue Erlotinib in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within three weeks. ## Gastrointestinal Perforation Gastrointestinal perforation, including fatal cases, can occur with Erlotinib treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation. The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the Erlotinib arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. Permanently discontinue Erlotinib in patients who develop gastrointestinal perforation. ## Bullous and Exfoliative Skin Disorders Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal, can occur with Erlotinib treatment . The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the Erlotinib arms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. Discontinue Erlotinib treatment if the patient develops severe bullous, blistering or exfoliating conditions . ## Myocardial Infarction/Ischemia In the pancreatic carcinoma trial, six patients (incidence of 2.1%) in the Erlotinib/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the Erlotinib arms and 0.4% in the control arms. ## Cerebrovascular Accident In the pancreatic carcinoma trial, seven patients in the Erlotinib/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the Erlotinib arms and 0.9% in the control arms. ## Microangiopathic Hemolytic Anemia with Thrombocytopenia The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the Erlotinib arms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. ## Ocular Disorders Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with Erlotinib treatment and can lead to corneal perforation or ulceration. The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the Erlotinib arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the Erlotinib plus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue Erlotinib therapy if patients present with acute or worsening ocular disorders such as eye pain. ## Hemorrhage in Patients Taking Warfarin Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when Erlotinib and warfarin are administered concurrently. Regularly monitor prothrombin time and INR during Erlotinib treatment in patients taking warfarin or other coumarin-derivative anticoagulants. ## Embryo-Fetal Toxicity Based on its mechanism of action, Erlotinib can cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If Erlotinib is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 2 weeks after the last dose of Erlotinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Erlotinib. # 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. - Safety evaluation of Erlotinib is based on more than 1200 cancer patients who received Erlotinib as monotherapy, more than 300 patients who received Erlotinib 100 or 150 mg plus gemcitabine, and 1228 patients who received Erlotinib concurrently with other chemotherapies. - The most common adverse reactions with Erlotinib are rash and diarrhea usually with onset during the first month of treatment. - The incidences of rash and diarrhea from clinical studies of Erlotinib for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea. Non-Small Cell Lung Cancer First-Line Treatment of Patients with EGFR Mutations The most frequent (≥ 30%) adverse reactions in Erlotinib-treated patients were diarrhea, asthenia, rash, cough, dyspnea and decreased appetite. In Erlotinib-treated patients the median time to onset of rash was 15 days and the median time to onset of diarrhea was 32 days. The most frequent Grade 3-4 adverse reactions in Erlotinib-treated patients were rash and diarrhea. Dose interruptions or reductions due to adverse reactions occurred in 37% of Erlotinib-treated patients, and 14.3% of Erlotinib-treated patients discontinued therapy due to adverse reactions. In Erlotinib-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%). Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received Erlotinib or chemotherapy and an increase in ≥ 5% in the Erlotinib treated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1. The median duration of Erlotinib treatment was 9.6 months in Study 4. Hepatic Toxicity: One Erlotinib-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 4 Maintenance Treatment Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent Erlotinib at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTC (version 3.0) Grade in Table 2. The most common adverse reactions in patients receiving single-agent Erlotinib 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in Erlotinib-treated patients. rash and diarrhea resulted in study discontinuation in 1% and 0.5% of Erlotinib-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In Erlotinib-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days. Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of Erlotinib-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of Erlotinib-treated patients and in < 1% in the placebo group. Second/Third Line Treatment Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent Erlotinib at 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 3. The most common adverse reactions in this patient population were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 6%, respectively, in Erlotinib-treated patients. rash and diarrhea each resulted in study discontinuation in 1% of Erlotinib-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days. Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent Erlotinib 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 (> 2.5 – 5.0 x ULN) ALT elevations occurred in 4% and < 1% of Erlotinib and placebo treated patients, respectively. Grade 3 (> 5.0 – 20.0 x ULN) elevations were not observed in Erlotinib-treated patients. Erlotinib dosing should be interrupted or discontinued if changes in liver function are severe Pancreatic Cancer - Erlotinib Administered Concurrently with gemcitabine This was a randomized, double blind placebo-controlled study of Erlotinib (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m2 IV) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). The safety population comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo group (256 in the 100 mg cohort and 24 in the 150 mg cohort). Adverse reactions that occurred in at least 10% of patients treated with Erlotinib 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4. The most common adverse reactions in pancreatic cancer patients receiving Erlotinib 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the Erlotinib plus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving Erlotinib plus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the Erlotinib plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption. Ten patients (4%) in the Erlotinib/gemcitabine group and three patients (1%) in the placebo/gemcitabine group developed deep venous thrombosis. The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis was 11% for Erlotinib plus gemcitabine and 9% for placebo plus gemcitabine. The incidences of liver test abnormalities (≥ Grade 2) in Study 2 are provided in Table 5 NSCLC and Pancreatic Indications: Selected Low Frequency Adverse Reactions Gastrointestinal Disorders Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration . These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of Erlotinib. 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. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis, in combination with statin therapy. Eye Disorders: ocular inflammation including uveitis. # Drug Interactions CYP3A4 Inhibitors Erlotinib is metabolized predominantly by CYP3A4. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 67%. When Erlotinib was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17%, respectively. Dose modifications are recommended. CYP3A4 Inducers Pre-treatment with the CYP3A4 inducer rifampicin for 7-11 days prior to Erlotinib decreased erlotinib AUC by 58% to 80%. Dose modifications are recommended. Drugs Affecting Gastric pH Co-administration of Erlotinib with omeprazole decreased erlotinib AUC by 46% and co-administration of Erlotinib with ranitidine 300 mg decreased erlotinib AUC by 33%. When Erlotinib was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), erlotinib AUC decreased by 15%. Increasing the dose of Erlotinib when co-administered with such agents is not likely to compensate for the loss of exposure. Scheduling modifications are recommended. Cigarette Smoking Cigarette smoking results in reductions in erlotinib AUC. Dose modifications are recommended. Anticoagulants Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving Erlotinib. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. Dose modifications of Erlotinib are not recommended # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Risk Summary Based on its mechanism of action, Erlotinib can cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If Erlotinib is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus Animal Data Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m2/day or 60 mg/m2/day (0.3 or 0.7 times the recommended daily dose, on a mg/m2 basis) of erlotinib had an increase in early resorptions that resulted in a decrease in the number of live fetuses. No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m2/day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m2/day in the rat (0.7 times the recommended dose of 150 mg/day on a mg/m2 basis). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Erlotinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Erlotinib during labor and delivery. ### Nursing Mothers It is not known whether erlotinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Erlotinib, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use The safety and effectiveness of Erlotinib in pediatric patients have not been established. ### Geriatic Use Of the 1297 subjects in clinical studies of Erlotinib for the treatment of NSCLC and pancreatic cancer 40% were 65 and older while 10% were 75 and older. No overall differences in safety or efficacy were observed between subjects 65 years and older and those younger than 65. ### Gender There is no FDA guidance on the use of Erlotinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Erlotinib with respect to specific racial populations. ### Renal Impairment Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function. ### Hepatic Impairment Patients with hepatic impairment (total bilirubin > upper limit of normal (ULN) or Child-Pugh A, B and C) should be closely monitored during therapy with Erlotinib. Treatment with Erlotinib should be used with extra caution in patients with total bilirubin > 3 x ULN In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases ### Females of Reproductive Potential and Males Contraception Females Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with Erlotinib, and for at least 2 weeks after the last dose of Erlotinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Erlotinib ### Immunocompromised Patients There is no FDA guidance one the use of Erlotinib in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Erlotinib contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility # Overdosage Single oral doses of Erlotinib up to 1,000 mg in healthy subjects and weekly doses up to 1,600 mg in cancer patients have been tolerated. Repeated twice-daily doses of 200 mg single-agent Erlotinib in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, an unacceptable incidence of severe adverse reactions, such as diarrhea, rash, and liver transaminase elevation, may occur above the recommended dose . In case of suspected overdose, Erlotinib should be withheld and symptomatic treatment instituted. # Pharmacology ## Mechanism of Action Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells. In some tumor cells signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild type receptor. Erlotinib inhibition of other tyrosine kinase receptors has not been fully characterized. ## Structure Erlotinib (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Erlotinib contains erlotinib as the hydrochloride salt that has the following structural formula: Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane. Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2. Erlotinib tablets for oral administration are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg erlotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C Yellow #6 (25 mg only) for product identification. ## Pharmacodynamics There is limited information regarding Erlotinib Pharmacodynamics in the drug label. ## Pharmacokinetics ### Absorption and Distribution: Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Co-administration of Erlotinib with omeprazole, a proton pump inhibitor, decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively. When Erlotinib was administered 2 hours following a 300 mg dose of ranitidine, an H2 receptor antagonist, the erlotinib AUC was reduced by 33% and Cmax by 54%. When Erlotinib was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the erlotinib AUC and Cmax decreased by 15% and 17%, respectively. Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters. ### Metabolism and Excretion: A population pharmacokinetic analysis in 591 patients receiving the single-agent Erlotinib 2nd/3rd line regimen showed a median half-life of 36.2 hours. Time to reach steady state plasma concentration would therefore be 7 – 8 days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had a 24% higher rate of erlotinib clearance. An additional population pharmacokinetic analysis was conducted in 291 NSCLC patients administered single-agent erlotinib as maintenance treatment. This analysis demonstrated that covariates affecting erlotinib clearance in this patient population were similar to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. A third population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine. Similar results were observed to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Co-administration of gemcitabine had no effect on erlotinib plasma clearance. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent). Cigarette smoking reduces erlotinib exposure. In the Phase 3 NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which were approximately 2-fold less than the former smokers or patients who had never smoked. This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance. In a separate study which evaluated the single-dose pharmacokinetics of erlotinib in healthy volunteers, current smokers cleared the drug faster than former smokers or volunteers who had never smoked. The AUC0-infinity in smokers was about 1/3 to 1/2 of that in never/former smokers. In another study which was conducted in NSCLC patients (N=35) who were current smokers, pharmacokinetic analyses at steady-state indicated a dose-proportional increase in erlotinib exposure when the Erlotinib dose was increased from 150 mg to 300 mg. However, the exact dose to be recommended for patients who currently smoke is unknown. Special Populations: Patients with Hepatic Impairment hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases. Patients with Renal Impairment Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function. ## Nonclinical Toxicology ### ]Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in mice and rats with erlotinib at oral doses of up to 60 mg/kg/day in mice, 5 mg/kg/day in female rats, and 10 mg/kg/day in male rats. The studies were negative for carcinogenic findings. Exposure in mice at the highest dose tested was approximately 10 times the exposure in humans at the erlotinib dose of 150 mg/day. The highest dose evaluated in male rats resulted in exposures that were twice those in humans and exposures at the highest tested dose in female rats were slightly lower than those in humans. Erlotinib did not cause genetic damage in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration and mammalian cell mutation) and in the in vivo mouse bone marrow micronucleus test. Erlotinib did not impair fertility in either male or female rats. # Clinical Studies ### Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment of Patients with EGFR Mutations The safety and efficacy of Erlotinib as monotherapy for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations was demonstrated in a randomized, open-label, clinical trial conducted in Europe (Study 4). One hundred seventy-four (174) White patients were randomized 1:1 to receive erlotinib 150 mg once daily until disease progression (n=86) or four cycles of a standard platinum-based doublet chemotherapy (n=88); standard chemotherapy regimens were cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. Randomization was stratified by EGFR mutation (exon 19 deletion or exon 21 (L858R) substitution) and ECOG PS (0 vs. 1 vs. 2). EGFR mutation status for screening and enrollment of patients was determined by a clinical trials assay (CTA). Tumor samples from 134 patients (69 patients from the erlotinib arm and 65 patients from the chemotherapy arm) were tested retrospectively by the FDA-approved companion diagnostic, the cobas® EGFR Mutation Test. The baseline demographics of the overall study population were as follows: female (72%), white (99%), age ≥ 65 years (51%), ECOG PS 1 (53%), with ECOG PS 0 (33%), and ECOG PS 2 (14%), current smoker (11%), past-smoker (20%), and never smoker (69%). The disease characteristics were 93% stage IV and 7% Stage IIIb with pleural effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition), 93% adenocarcinoma histology, 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by a CTA. A statistically significant improvement in investigator-determined PFS was demonstrated for patients randomized to erlotinib compared to those randomized chemotherapy. Similar results for PFS were observed for the subgroup evaluated by an independent-review committee (approximately 75% of patients in Study 4 evaluated) and in the subgroup of 134 patients (77% of the Study 4 population) with EGFR mutations confirmed by the cobas® EGFR Mutation Test. A protocol-specified analysis of overall survival conducted at the time of the final analysis of PFS showed no statistically significant difference between the Erlotinib and chemotherapy arms. At the time of the data cut-off, 84% of patients in the chemotherapy arm had received at least one subsequent treatment, of whom 97% received an EGFR tyrosine kinase inhibitor. In the Erlotinib arm, 66% of patients had received at least one subsequent treatment. In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was 0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions and 0.52 (95% CI 0.29 to 0.95) in patients with exon 21 (L858R) substitution. The HR for OS was 0.94 (95% CI 0.57 to 1.54) in the exon 19 deletion subgroup and 0.99 (95% CI 0.56 to 1.76) in the exon 21 (L858R) substitution subgroup. ### NSCLC - Maintenance Treatment The efficacy and safety of Erlotinib as maintenance treatment of NSCLC were demonstrated in a randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with locally advanced or metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy (Study 3). Patients were randomized 1:1 to receive Erlotinib 150 mg or placebo orally once daily (438 Erlotinib, 451 placebo) until disease progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of Erlotinib after standard platinum-based chemotherapy in the treatment of NSCLC resulted in improved progression free survival (PFS) when compared with placebo, in all patients or in patients with EGFR immunohistochemistry (IHC) positive tumors. Demographic characteristics were balanced between the two treatment groups. Baseline demographics of the overall study population were as follows: male (74%), age < 65 years (66%), ECOG PS 1 (69%), ECOG PS 0 (31%), white (84%), Asian (15%), current smoker (55%), past-smoker (27%), and never smoker (17%). Disease characteristics were as follows: Stage IV (75%), Stage IIIb with effusion (25%) as classified by AJCC (6th edition) with histologic subtypes of adenocarcinoma including bronchioalveolar (45%), squamous (40%) and large cell (5%); and EGFR IHC positive (70%), negative (14%), indeterminate (4%), and missing (12%). Figure 2 depicts the Kaplan-Meier Curves for Overall Survival (ITT Population). Note: HR is from a univariate Cox regression model. The PFS and OS Hazard Ratios, respectively, in patients with EGFR IHC-positive tumors were 0.69 (95% CI: 0.58, 0.82) and 0.77 (95% CI: 0.64, 0.93). The PFS and OS Hazard Ratios in patients with IHC-negative tumors were 0.77 (95% CI: 0.51, 1.14) and 0.91 (95% CI: 0.59, 1.38), respectively. Patients with adenocarcinoma had an OS Hazard Ratio of 0.77 (95% CI: 0.61, 0.97) and patients with squamous histology had an OS Hazard Ratio of 0.86 (95% CI: 0.68, 1.10). ### NSCLC –Second/Third Line Treatment The efficacy and safety of single-agent Erlotinib was assessed in a randomized, double blind, placebo-controlled trial in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen (Study 1). Patients were randomized 2:1 to receive Erlotinib 150 mg or placebo (488 Erlotinib, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Study endpoints included overall survival, response rate, and progression-free survival (PFS). Duration of response was also examined. The primary endpoint was survival. The study was conducted in 17 countries. Baseline demographics of the overall study population were as follows: male (65%), white (78%), Asian (12%), black (4%), age < 65 years (62%), ECOG PS 1 (53%), ECOG PS 0 (13%), ECOG PS 2 (25%), ECOG PS 3 (9%), current or ex-smoker (75%), never smoker (20%), and exposure to prior platinum therapy (93%). Tumor characteristics were as follows: adenocarcinoma (50%), squamous (30%), undifferentiated large cell (9%), and mixed non-small cell (2%). The results of the study are shown in Table 8. Survival was evaluated in the intent-to-treat population. Figure 3 depicts the Kaplan-Meier curves for overall survival. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. Note: HR is from Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. P-value is from two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. ### NSCLC – Lack of Efficacy of Erlotinib Administered Concurrently with Chemotherapy Results from two, multicenter, placebo-controlled, randomized, trials in over 1000 patients conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Erlotinib with platinum-based chemotherapy [carboplatin and paclitaxel (Erlotinib, N = 526) or gemcitabine and cisplatin (Erlotinib, N = 580)]. ### Pancreatic Cancer - Erlotinib Administered Concurrently with gemcitabine The efficacy and safety of Erlotinib in combination with gemcitabine as a first-line treatment was assessed in a randomized, double blind, placebo-controlled trial in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). Patients were randomized 1:1 to receive Erlotinib (100 mg or 150 mg) or placebo once daily on a continuous schedule plus gemcitabine IV (1000 mg/m2, Cycle 1 - Days 1, 8, 15, 22, 29, 36 and 43 of an 8 week cycle; Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4-week cycle. Erlotinib or placebo was taken orally once daily until disease progression or unacceptable toxicity. The primary endpoint was survival. Secondary endpoints included response rate, and progression-free survival (PFS). Duration of response was also examined. The study was conducted in 18 countries. A total of 285 patients were randomized to receive gemcitabine plus Erlotinib (261 patients in the 100 mg cohort and 24 patients in the 150 mg cohort) and 284 patients were randomized to receive gemcitabine plus placebo (260 patients in the 100 mg cohort and 24 patients in the 150 mg cohort). Too few patients were treated in the 150 mg cohort to draw conclusions. In the 100 mg cohort, baseline demographics of the overall study population were as follows: male (52%), white (88%), Asian (7%), black (2%), age < 65 years (53%), ECOG PS 1 (51%), ECOG PS 0 (32%), and ECOG PS 2 (17%). There was a slightly larger proportion of females in the Erlotinib arm (51%) compared with the placebo arm (44%). The median time from initial diagnosis to randomization was approximately 1.0 month. The majority of the patients (76%) had distant metastases at baseline and 24% had locally advanced disease. The results of the study are shown in Table 9. Survival was evaluated in the intent-to-treat population. Figure 4 depicts the Kaplan-Meier curves for overall survival in the 100 mg cohort. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status and extent of disease. Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. The p-value is from two-sided Log-Rank test stratified by ECOG performance status and extent of disease. # How Supplied 25 mg Tablets Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side; supplied in: Bottles of 30: NDC 50242-062-01 100 mg Tablets Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side; supplied in: Bottles of 30: NDC 50242-063-01 150 mg Tablets Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side; supplied in: Bottles of 30: NDC 50242-064-01 ## Storage Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). See USP Controlled Room Temperature. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients to contact their health care provider for: - Severe or persistent diarrhea, nausea, anorexia, or vomiting - Onset or worsening of unexplained shortness of breath or cough - Eye irritation - Onset or worsening of skin rash or development of bullous lesions or desquamation. - Any changes in smoking status Advise patients on the presentation of skin, hair and nail disorders. - In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade 3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed areas. Symptoms associated with rash may include itching, tenderness and/or burning. - Hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash. - Hair and nail disorders, including hirsutism and brittle and loose nails, have been reported. Instruct patients on initial management of rash or diarrhea. - Given that skin reactions are anticipated when taking Erlotinib, proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure - Management of rash may include topical corticosteroids or antibiotics with anti-inflammatory properties. These approaches were used in the NSCLC and pancreatic pivotal clinical trials. Acne preparations with drying properties may aggravate the dry skin and erythema. Treatment of rash has not been formally studied and should be based on rash severity. - Diarrhea can usually be managed with loperamide. Counsel patients on pregnancy planning and prevention. - Advise females of reproductive potential to use highly effective contraception during treatment with Erlotinib, and for at least 2 weeks after the last dose of Erlotinib. - Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Erlotinib. - Advise breast-feeding mothers to discontinue nursing while receiving Erlotinib . Advise patients to stop smoking. Advise patients that the dose of Erlotinib may need to be adjusted if they smoke. # Precautions with Alcohol Alcohol-Erlotinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tarceva # Look-Alike Drug Names There is limited information regarding Erlotinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Erlotinib
ad6c5e612da1dbc9715281980332cb8666f50320	wikidoc	Esophagus	Esophagus # Overview The esophagus (American English) or oesophagus (British English), commonly known as the foodpipe or gullet, is an organ in vertebrates which consists of a fibromuscular tube through which food passes, aided by peristaltic contractions, from the pharynx to the stomach. In humans, the esophagus is usually 18–25 centimeters (cm) long. During swallowing the epiglottis tilts backwards to prevent food from going down the larynx. The esophagus travels behind the trachea and heart, passes through the diaphragm and empties into the cardia of the stomach. The word esophagus derives from the Greek word oisophagos, which means "to carry to eat." The wall of the esophagus from the lumen outwards consists of mucosa, sub-mucosa (connective tissue), layers of muscle fibers between layers of fibrous tissue, and an outer layer of connective tissue. The mucosa is a stratified squamous epithelium (multiple layers of cells topped by a layer of flat cells) which contrasts to the single layer of columnar cells of the stomach. The transition between these two type of epithelium is visible as a zig-zag line. Most of the muscle is smooth muscle although striated muscle predominates in its upper two thirds. It has two muscular rings or sphincters in its wall, one at the top and one at the bottom. The lower sphincter helps to prevent reflux of acidic stomach content. The esophagus has a rich blood supply and vascular drainage. Its smooth muscle is innervated by involuntary nerves (sympathetic nerves via the sympathetic trunk and parasympathetic nerves via the vagus nerve) and in addition voluntary nerves (lower motor neurons) are carried in the vagus nerve to innervate its striated muscle. The esophagus may be affected by gastric reflux, cancer, prominent dilated blood vessels called varices that can bleed heavily, tears, constrictions, and disorders of motility. Clinical investigations include X-rays using barium, endoscopy, and CT scans. # Structure The esophagus is one of the upper parts of the digestive system. At the mouth opening, it is continuous with the back of the oral cavity, passing downwards through the rear part of the mediastinum, through the diaphragm, and into the stomach. In humans, the esophagus generally starts around the level of the sixth cervical vertebra (C6) behind the cricoid cartilage, enters the diaphragm at about the level of the tenth thoracic vertebra (T10), and ends at the cardia of the stomach, at the level of the eleventh thoracic vertebra (T11). The esophagus is usually about 25 cm (10 in) in length. Many blood vessels serve the esophagus, with blood supply varying along its course. The cervical parts of the esophagus and the upper esophageal sphincter receive blood from inferior thyroid artery, the parts of the esophagus in the thorax from the bronchial arteries and branches directly from the thoracic aorta, and the lower parts of the esophagus and the lower esophageal sphincter (LES) receive blood from the left gastric artery and the left inferior phrenic artery. The venous drainage also differs along the course of the esophagus. The upper and lower parts of the esophagus drain into the azygos and hemiazygos veins, and blood from the middle part drains into the left gastric vein. All these veins drain into the superior vena cava, with the exception of the left gastric vein, which is a branch of the portal vein. Lymphatically, the upper third of the esophagus drains into the deep cervical lymph nodes, the middle into the superior and posterior mediastinal lymph nodes, and the lower esophagus into the gastric and celiac lymph nodes. The esophagus is innervated by the vagus nerve and the cervical and thoracic sympathetic trunk. The vagus nerve has a parasympathetic function, supplying the muscles of the esophagus and stimulating glandular contraction. Two sets of nerve fibres travel in the vagus nerve to supply the muscles. The upper striated muscle, and upper esophageal sphincter, are supplied by neurons with bodies in the nucleus ambiguus, whereas fibres that supply the smooth muscle and lower esophageal sphincter have bodies situated in the dorsal motor nucleus. The vagus nerve plays the primary role in initiating peristalsis. The sympathetic trunk has a sympathetic function. It may enhance the function of the vagus nerve, increasing peristalsis and glandular activity, and causing sphincter contraction. In addition, sympathetic activation may relax the muscle wall and cause blood vessel constriction. Sensation along the esophagus is supplied by both nerves, with gross sensation being passed in the vagus nerve and pain passed up the sympathetic trunk. The upper esophagus lies at the back of the mediastinum behind the trachea, and in front of the erector spinae muscles and the vertebral column. The lower esophagus lies behind the heart and curves in front of thoracic aorta. From the bifurcation of the trachea downwards, the esophagus passes behind the right pulmonary artery, left main bronchus, and left atrium. At this point it passes through the diaphragm. The thoracic duct, which drains the majority of the body's lymph, passes behind the esophagus, curving from lying behind the esophagus on the right in the lower part of the esophagus, to lying behind the esophagus on the left in the upper esophagus. The esophagus also lies in front of parts of the hemiazygos veins and the intercostal veins on the right side. The vagus nerve divides and covers the esophagus in a plexus. The esophagus has four points of constriction. When corrosive substances are ingested, or a solid object is swallowed, it is most likely to lodge and damage these four points. These constrictions are because of particular structures that compress on the esophagus. These constrictions are: - At the start of the esophagus, where the pharynx joins the esophagus, behind the cricoid cartilage - Where it is crossed on the front by the aortic arch and the left main bronchus - Where it passes through the diaphragm ## Sphincters The esophagus is surrounded at the top and bottom by two muscular rings, known respectively as the upper esophageal sphincter and the lower esophageal sphincter. These sphincters act to close the esophagus when food is not being swallowed. The esophageal sphincters are functional, but not anatomical sphincters, meaning that they are sections of the esophageal wall that act as a sphincter, but do not have distinct thickenings like other sphincters. The upper esophageal sphincter surrounds the upper part of the esophagus. It consists of skeletal muscle, but is not under conscious control. Opening of the upper esophageal sphincter is triggered by the swallow reflex. The primary muscle of the upper esophageal sphincter is the cricopharyngeus portion of the inferior pharyngeal constrictor. The lower esophageal sphincter surrounds the lower part of the esophagus. This sphincter surrounds the junction between the esophagus and the stomach. ## Gastro-esophageal junction The gastro-esophageal junction (also known at the esophagogastic junction) is the junction between the esophagus and the stomach, and it is situated at the lower end of the esophagus. The pink color of the esophageal mucosa contrasts to the a deeper red of the gastric mucosa, and the mucosal transition can be seen as an irregular zig-zag line, which is often called the z-line. Similarly, by direct vision of fresh specimens, grey-pink of the esophageal mucosa contrasts with the darker gastric mucosa, but in embalmed cadavers a color contrast may not be apparent. Histological examination reveals abrupt transition between the nonkeratinized stratified squamous epithelium of the esophagus and the simple columnar epithelium of the stomach. Normally, the cardia of the stomach is immediately distal to the z-line and the z-line coincides with the upper limit of the gastric folds of the cardia; however, when the anatomy of the mucosa is distorted in Barrets esophagus the true gastro-eshophageal junction can be identified by the upper limit of the gastric folds rather than the mucosal transition. The functional location of LES is generally situated about 3 cm distal to the z-line. ## Histology The human esophagus has a mucosa consisting of a tough stratified squamous epithelium without keratin, a smooth lamina propria, and a muscularis mucosa. The epithelium of the esophagus has a relatively rapid turnover, and serves a protective function against the abrasive effects of food. In many animals the epithelium contains a layer of keratin, representing a coarser diet. Protection is conferred by the secretion of mucus from glands. There are two types of glands, with mucus-secreting esophageal glands being found in the submucosa, and esophageal cardiac glands, similar to cardiac glands of the stomach, located in the lamina propria and most frequent in the terminal part of the organ. The submucosa also contains the submucosal plexus, a network of nerve cells part of the enteric nervous system. The muscularis propria of the esophagus has two types of muscle. The upper third of the esophagus contains striated muscle and the lower third contain smooth muscle, with the middle third containing a mixture of both. Muscle is arranged in two layers: one in which the muscle fibres run longitudinal to the esophagus, and the other in which the fibres encircle the esophagus. These are separated by the myenteric plexus, a tangled interpolation of nerve fibres involved in the secretion of mucus and peristalsis of the smooth muscle of the esophagus. The esophagus also has an adventitia, but not a serosa. This makes it distinct from many other structures in the gastrointestinal tract. # Development The esophagus develops from the embryonic gut tube, an endodermal structure. Early in development, the human embryo has three layers and abuts an embryonic yolk sac. During the second week of embryological development, as the embryo grows, it begins to surround and envelop portions of this sac. The enveloped portions form the basis for the adult gastrointestinal tract. Sections of this gut begin to differentiate into the organs of the gastrointestinal tract, such as the esophagus, stomach, and intestines. The sac is surrounded by a network of arteries called the vitelline plexus. Over time, these arteries consolitate into three main arteries that supply the developing gastrointestinal tract: the celiac artery, superior mesenteric artery, and inferior mesenteric artery. The areas supplied by these arteries are used to define the midgut, hindgut and foregut. The esophagus develops as part of the foregut tube. The innervation of the esophagus develops from the branchial arches. # Function ## Swallowing In humans and other animals, food is ingested through the mouth. During swallowing, food passes from the mouth through the pharynx into the esophagus. The esophagus is thus one of the first components of the human digestive system and the human gastrointestinal tract. After food passes through the esophagus, it enters the stomach. When food is being swallowed, the epiglottis moves backward to cover the larynx, preventing food from entering the trachea. At the same time, the upper esophageal sphincter relaxes, allowing a bolus of food to enter. Rhythmic contraction of the esophageal muscle called peristalsis pushes the food down the esophagus. These rhythmic contractions occur both as a reflex response to food that is in the mouth, and also as a response to the sensation of food within the esophagus itself. Along with the peristalsis, the lower esophageal sphincter relaxes. ## Reducing gastric reflux The stomach generates strong acids, including hydrochloric acid (HCl), and enzymes to aid in food digestion. This digestive mixture is called gastric juice. Constriction of the upper and lower esophageal sphincters help to prevent reflux of gastric contents and juices into the esophagus, protecting the esophageal mucosa. In addition, the acute angle of His and the lower crura of the diaphragm helps this sphincteric action. # Clinical significance The main conditions affecting the esophagus are described here. For a more complete list, see esophageal disease. ## Inflammation Inflammation of the esophagus is known as esophagitis. Reflux of gastric acids from the stomach, infection, substances ingested (for example, corrosives), some medications (such as bisphosphonates), food allergies, and can all lead to esophagitis. As of 2014 the cause of some forms of esophagitis, such as eosinophilic esophagitis, is not known. Esophagitis can cause painful swallowing and is usually treated by managing the cause of the esophagitis - such as managing reflux or treating infection. ## Cancer Cancer of the esophagus may occur in two forms. If the cancer occurs in the squamous cells lining the esophagus, it is called a carcinoma. Such a cancer is more common in China and Iran. If the cancer occurs in the glands or columnar tissue of the esophagus, then the cancer is an adenocarcinoma. This is most common in Western countries in those with Barrett's esophagus, and occurs in the cuboidal cells. In its early stages, esophageal cancer may not have any symptoms at all. When severe, esophageal cancer may eventually cause obstruction of the esophagus, making swallowing of any solid foods very difficult and causing weight loss. The progress of the cancer is staged using a system that measures how far into the esophageal wall the cancer has invaded, how many lymph nodes possess the cancer, and whether there are any metastases in different parts of the body. Esophageal cancer is often managed with radiotherapy, chemotherapy, and may also be managed by partial surgical removal of the esophagus. Inserting a stent into the esophagus, or inserting a nasogastric tube, may also be used to ensure that a person is able to digest enough food and water. As of 2014, the prognosis for esophageal cancer is still poor, so palliative therapy may also be a focus of treatment. ## Barrett's esophagus Prolonged esophagitis, particularly from gastric reflux, is one factor thought to play a role in the development of Barrett's esophagus. In this condition, there is metaplasia of the lining of the lower esophagus, which changes from stratified squamous epithelia to simple columnar epithelia. Barrett's esophagus is thought to be one of the main contributors to the development of esophageal cancer. ## Varices Esophageal varices refer to engorged blood vessels present within the esophageal walls. These blood vessels are engorged more than normal, and in the worst cases may partially obstruct the esophagus. These blood vessels develop as part of a collateral circulation that occurs to drain blood from the abdomen as a result of portal hypertension, usually as a result of liver diseases such as cirrhosis. This collateral circulation occurs because the lower part of the esophagus drains into the left gastric vein, which is a branch of the portal vein. Because of the extensive venous plexus that exists between this vein and other veins, if portal hypertension occurs, the direction of blood drainage in this vein may reverse, with blood draining from the portal venous system, through the plexus. Veins in the plexus may engorge and lead to varices. Esophageal varices often do not have symptoms until they rupture. A ruptured varix is considered a medical emergency, because varices can bleed a lot. A bleeding varix may cause a person to throw up blood, or may cause symptoms of hypovolemic shock. To deal with a ruptured varix, a band may be placed around the bleeding bood vessel, or a small amount of a clotting agent may be injected near the bleed. A surgeon may also try to use a small inflatable balloon to apply pressure to stop the wound. A person with a bleeding varice may also receive IV fluids in order to prevent hypovolemic shock from excess blood loss. ## Motility disorders Several disorders affect the motility of food as it travels down the esophagus. This can cause difficult swallowing, called dysphagia. Achalasia refers to a failure of the lower esophageal sphincter to relax properly, and generally develops later in life. This leads to progressive enlargement of the esophagus, and possibly eventual megaesophagus. A nutcracker esophagus refers to swallowing that can be extremely painful, and diffuse esophageal spasm refers to spasm of the esophagus that can be one cause of chest pain. Sclerosis of the esophagus, such as with systemic sclerosis or in CREST syndrome may cause hardening of the walls of the esophagus and interfere with peristalsis. ## Malformations Various structures may also constrict the esophagus. These esophageal strictures are usually benign and typically develop after a person has had reflux for many years. Other malformations may include esophageal webs (which can also be congenital) and damage to the esophagus by radiotherapy, corrosive ingestion, or eosinophilic esophagitis. A Schatzki ring is fibrosis at the gastro-esophageal junction. Strictures may also develop in chronic anemia, and Plummer-Vinson syndrome. ## Congenital malformation The esophagus fails to develop or there is an abnormal connection between the trachea and esophagus in about 1 in 3500 births. Conventional classification divides such connections into five types, based on whether the esophagus is a continuous tube or not, and which end of the esophagus (proximal, distal, both or neither) connects to the trachea. About half the time, these abnormalities occurs with additional abnormalities in other parts of the body, especially affecting the heart. # Imaging An X-ray of swallowed barium may be used to reveal the size and shape of the esophagus, and the presence of any masses. The esophagus may also be imaged using a flexible camera inserted into the esophagus, in a procedure called an endoscopy. If an endoscopy is used on the stomach, the camera will also have to pass through the esophagus. During an endoscopy, a biopsy may be taken. If cancer of the esophagus is being investigated, other methods, including a CT scan, may also be used. # History The word esophagus (British English: oesophagus) comes from Template:Lang-el (oisophagos), from "to carry" (oesin) and "to eat" (phagos). The Greek term oesophagus, from which the English term has been derived, has been documented in anatomical literature since at least the time of Hippocrates, who noted that "the oesophagus ... receives the greatest amount of what we consume." Its existence in other animals and its relationship with the stomach was documented by the Ancient Roman (philosopher) and physician Pliny the Elder, and the peristaltic contractions of the esophagus have been documented since at least the time of Galen. The first attempt at surgery on the esophagus focused in the neck, and was firstly conducted in dogs by Theodore Billroth in 1871, and then in people by Czerny in 1877. By 1908, an operation had been performed by Voeckler to remove the esophagus, and in 1933 the first surgical removal of parts of the lower esophagus, (to control esophageal cancer), had been conducted. The Nissen fundoplication, in which the stomach is wrapped around the lower esophageal sphincter in order to stimulate its function and control reflux, was first conducted by Rudolph Nissen in 1955. # Other animals ## Vertebrates In tetrapods, the pharynx is much shorter, and the esophagus correspondingly longer, than in fish. In the majority of vertebrates, the esophagus is simply a connecting tube, but in some birds, which regurgitate components to feed their young, it is extended towards the lower end to form a crop for storing food before it enters the true stomach. In ruminants, animals with four stomachs, a groove called the sulcus reticuli is often found in the esophagus, allowing milk to drain directly into the hind stomach, the abomasum. The esophagus of snakes is remarkable for the distension it undergoes when swallowing prey. In most fish, the esophagus is extremely short, primarily due to the length of the pharynx (which is associated with the gills). However, some fish, including lampreys, chimaeras, and lungfish, have no true stomach, so that the esophagus effectively runs from the pharynx directly to the intestine, and is therefore somewhat longer. In many vertebrates, the esophagus is lined by stratified squamous epithelia without glands. In fish, the esophagus is often lined with columnar epithelia, and in amphibians, sharks and rays, the esophageal epithelium is ciliated, helping to wash food along, in addition to the action of muscular peristalsis. In addition, in the bat Plecotus auritus, fish and some amphibians, glands secreting pepsinogen or hydrochloric acid have been found. The muscle of the esophagus in many mammals is striated initially, but then becomes smooth muscle in the caudal third or so. In the canine and ruminants, however, it is entirely striated to allow regurgitation to feed young (canines) or regurgitation to chew cud (ruminants). It is entirely smooth muscle in amphibians, reptiles and birds. Contrary to popular belief, a person would not be able to pass through the esophagus of a whale, which generally measure less than 10 cm in diameter, although in larger baleen whales may be up to ten inches when fully distended. ## Invertebrates A structure with the same name is often found in invertebrates, including molluscs and arthropods, connecting the oral cavity with the stomach. In the cephalopods, the brain often surrounds the esophagus. The mouth of gastropods opens into an esophagus, which connects to the stomach. Because of torsion, the esophagus usually passes around the stomach, and opens into its posterior portion, furthest from the mouth. In species that have undergone de-torsion, however, the esophagus may open into the anterior of the stomach, which is therefore reversed from the usual gastropod arrangement. In Tarebia granifera the brood pouch is above the esophagus. There is available an extensive rostrum on the anterior part of the esophagus in all carnivorous gastropods.	Esophagus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The esophagus (American English) or oesophagus (British English), commonly known as the foodpipe or gullet, is an organ in vertebrates which consists of a fibromuscular tube through which food passes, aided by peristaltic contractions, from the pharynx to the stomach. In humans, the esophagus is usually 18–25 centimeters (cm) long. During swallowing the epiglottis tilts backwards to prevent food from going down the larynx. The esophagus travels behind the trachea and heart, passes through the diaphragm and empties into the cardia of the stomach. The word esophagus derives from the Greek word oisophagos, which means "to carry to eat."[1] The wall of the esophagus from the lumen outwards consists of mucosa, sub-mucosa (connective tissue), layers of muscle fibers between layers of fibrous tissue, and an outer layer of connective tissue. The mucosa is a stratified squamous epithelium (multiple layers of cells topped by a layer of flat cells) which contrasts to the single layer of columnar cells of the stomach. The transition between these two type of epithelium is visible as a zig-zag line. Most of the muscle is smooth muscle although striated muscle predominates in its upper two thirds. It has two muscular rings or sphincters in its wall, one at the top and one at the bottom. The lower sphincter helps to prevent reflux of acidic stomach content. The esophagus has a rich blood supply and vascular drainage. Its smooth muscle is innervated by involuntary nerves (sympathetic nerves via the sympathetic trunk and parasympathetic nerves via the vagus nerve) and in addition voluntary nerves (lower motor neurons) are carried in the vagus nerve to innervate its striated muscle. The esophagus may be affected by gastric reflux, cancer, prominent dilated blood vessels called varices that can bleed heavily, tears, constrictions, and disorders of motility. Clinical investigations include X-rays using barium, endoscopy, and CT scans. # Structure The esophagus is one of the upper parts of the digestive system. At the mouth opening, it is continuous with the back of the oral cavity, passing downwards through the rear part of the mediastinum, through the diaphragm, and into the stomach. In humans, the esophagus generally starts around the level of the sixth cervical vertebra (C6) behind the cricoid cartilage, enters the diaphragm at about the level of the tenth thoracic vertebra (T10), and ends at the cardia of the stomach, at the level of the eleventh thoracic vertebra (T11).[2] The esophagus is usually about 25 cm (10 in) in length.[3] Many blood vessels serve the esophagus, with blood supply varying along its course. The cervical parts of the esophagus and the upper esophageal sphincter receive blood from inferior thyroid artery, the parts of the esophagus in the thorax from the bronchial arteries and branches directly from the thoracic aorta, and the lower parts of the esophagus and the lower esophageal sphincter (LES) receive blood from the left gastric artery and the left inferior phrenic artery.[4][5] The venous drainage also differs along the course of the esophagus. The upper and lower parts of the esophagus drain into the azygos and hemiazygos veins, and blood from the middle part drains into the left gastric vein. All these veins drain into the superior vena cava, with the exception of the left gastric vein, which is a branch of the portal vein.[4] Lymphatically, the upper third of the esophagus drains into the deep cervical lymph nodes, the middle into the superior and posterior mediastinal lymph nodes, and the lower esophagus into the gastric and celiac lymph nodes.[4] The esophagus is innervated by the vagus nerve and the cervical and thoracic sympathetic trunk.[4] The vagus nerve has a parasympathetic function, supplying the muscles of the esophagus and stimulating glandular contraction. Two sets of nerve fibres travel in the vagus nerve to supply the muscles. The upper striated muscle, and upper esophageal sphincter, are supplied by neurons with bodies in the nucleus ambiguus, whereas fibres that supply the smooth muscle and lower esophageal sphincter have bodies situated in the dorsal motor nucleus.[4] The vagus nerve plays the primary role in initiating peristalsis.[6] The sympathetic trunk has a sympathetic function. It may enhance the function of the vagus nerve, increasing peristalsis and glandular activity, and causing sphincter contraction. In addition, sympathetic activation may relax the muscle wall and cause blood vessel constriction.[4] Sensation along the esophagus is supplied by both nerves, with gross sensation being passed in the vagus nerve and pain passed up the sympathetic trunk.[2] The upper esophagus lies at the back of the mediastinum behind the trachea, and in front of the erector spinae muscles and the vertebral column. The lower esophagus lies behind the heart and curves in front of thoracic aorta. From the bifurcation of the trachea downwards, the esophagus passes behind the right pulmonary artery, left main bronchus, and left atrium. At this point it passes through the diaphragm.[2] The thoracic duct, which drains the majority of the body's lymph, passes behind the esophagus, curving from lying behind the esophagus on the right in the lower part of the esophagus, to lying behind the esophagus on the left in the upper esophagus. The esophagus also lies in front of parts of the hemiazygos veins and the intercostal veins on the right side. The vagus nerve divides and covers the esophagus in a plexus.[2] The esophagus has four points of constriction. When corrosive substances are ingested, or a solid object is swallowed, it is most likely to lodge and damage these four points. These constrictions are because of particular structures that compress on the esophagus. These constrictions are:[2] - At the start of the esophagus, where the pharynx joins the esophagus, behind the cricoid cartilage - Where it is crossed on the front by the aortic arch and the left main bronchus - Where it passes through the diaphragm ## Sphincters The esophagus is surrounded at the top and bottom by two muscular rings, known respectively as the upper esophageal sphincter and the lower esophageal sphincter.[2] These sphincters act to close the esophagus when food is not being swallowed. The esophageal sphincters are functional, but not anatomical sphincters, meaning that they are sections of the esophageal wall that act as a sphincter, but do not have distinct thickenings like other sphincters.[7] The upper esophageal sphincter surrounds the upper part of the esophagus. It consists of skeletal muscle, but is not under conscious control. Opening of the upper esophageal sphincter is triggered by the swallow reflex. The primary muscle of the upper esophageal sphincter is the cricopharyngeus portion of the inferior pharyngeal constrictor.[8] The lower esophageal sphincter surrounds the lower part of the esophagus. This sphincter surrounds the junction between the esophagus and the stomach.[7] ## Gastro-esophageal junction The gastro-esophageal junction (also known at the esophagogastic junction) is the junction between the esophagus and the stomach, and it is situated at the lower end of the esophagus.[9] The pink color of the esophageal mucosa contrasts to the a deeper red of the gastric mucosa,[4][10] and the mucosal transition can be seen as an irregular zig-zag line, which is often called the z-line.[11] Similarly, by direct vision of fresh specimens, grey-pink of the esophageal mucosa contrasts with the darker gastric mucosa,[12] but in embalmed cadavers a color contrast may not be apparent.[13] Histological examination reveals abrupt transition between the nonkeratinized stratified squamous epithelium of the esophagus and the simple columnar epithelium of the stomach.[13] Normally, the cardia of the stomach is immediately distal to the z-line[14] and the z-line coincides with the upper limit of the gastric folds of the cardia; however, when the anatomy of the mucosa is distorted in Barrets esophagus the true gastro-eshophageal junction can be identified by the upper limit of the gastric folds rather than the mucosal transition.[15] The functional location of LES is generally situated about 3 cm distal to the z-line.[4] ## Histology The human esophagus has a mucosa consisting of a tough stratified squamous epithelium without keratin, a smooth lamina propria, and a muscularis mucosa.[4] The epithelium of the esophagus has a relatively rapid turnover, and serves a protective function against the abrasive effects of food. In many animals the epithelium contains a layer of keratin, representing a coarser diet.[16] Protection is conferred by the secretion of mucus from glands.[17] There are two types of glands, with mucus-secreting esophageal glands being found in the submucosa, and esophageal cardiac glands, similar to cardiac glands of the stomach, located in the lamina propria and most frequent in the terminal part of the organ.[16][18] The submucosa also contains the submucosal plexus, a network of nerve cells part of the enteric nervous system.[16] The muscularis propria of the esophagus has two types of muscle. The upper third of the esophagus contains striated muscle and the lower third contain smooth muscle, with the middle third containing a mixture of both.[4] Muscle is arranged in two layers: one in which the muscle fibres run longitudinal to the esophagus, and the other in which the fibres encircle the esophagus. These are separated by the myenteric plexus, a tangled interpolation of nerve fibres involved in the secretion of mucus and peristalsis of the smooth muscle of the esophagus. The esophagus also has an adventitia, but not a serosa. This makes it distinct from many other structures in the gastrointestinal tract.[4] # Development The esophagus develops from the embryonic gut tube, an endodermal structure. Early in development, the human embryo has three layers and abuts an embryonic yolk sac. During the second week of embryological development, as the embryo grows, it begins to surround and envelop portions of this sac. The enveloped portions form the basis for the adult gastrointestinal tract. Sections of this gut begin to differentiate into the organs of the gastrointestinal tract, such as the esophagus, stomach, and intestines.[19] The sac is surrounded by a network of arteries called the vitelline plexus. Over time, these arteries consolitate into three main arteries that supply the developing gastrointestinal tract: the celiac artery, superior mesenteric artery, and inferior mesenteric artery. The areas supplied by these arteries are used to define the midgut, hindgut and foregut.[19] The esophagus develops as part of the foregut tube.[19] The innervation of the esophagus develops from the branchial arches.[2] # Function ## Swallowing In humans and other animals, food is ingested through the mouth. During swallowing, food passes from the mouth through the pharynx into the esophagus. The esophagus is thus one of the first components of the human digestive system and the human gastrointestinal tract. After food passes through the esophagus, it enters the stomach.[7] When food is being swallowed, the epiglottis moves backward to cover the larynx, preventing food from entering the trachea. At the same time, the upper esophageal sphincter relaxes, allowing a bolus of food to enter. Rhythmic contraction of the esophageal muscle called peristalsis pushes the food down the esophagus. These rhythmic contractions occur both as a reflex response to food that is in the mouth, and also as a response to the sensation of food within the esophagus itself. Along with the peristalsis, the lower esophageal sphincter relaxes.[7] ## Reducing gastric reflux The stomach generates strong acids, including hydrochloric acid (HCl), and enzymes to aid in food digestion. This digestive mixture is called gastric juice. Constriction of the upper and lower esophageal sphincters help to prevent reflux of gastric contents and juices into the esophagus, protecting the esophageal mucosa. In addition, the acute angle of His and the lower crura of the diaphragm helps this sphincteric action.[7][20] # Clinical significance The main conditions affecting the esophagus are described here. For a more complete list, see esophageal disease. ## Inflammation Inflammation of the esophagus is known as esophagitis. Reflux of gastric acids from the stomach, infection, substances ingested (for example, corrosives), some medications (such as bisphosphonates), food allergies, and can all lead to esophagitis. As of 2014[update] the cause of some forms of esophagitis, such as eosinophilic esophagitis, is not known. Esophagitis can cause painful swallowing and is usually treated by managing the cause of the esophagitis - such as managing reflux or treating infection.[3] ## Cancer Cancer of the esophagus may occur in two forms. If the cancer occurs in the squamous cells lining the esophagus, it is called a carcinoma. Such a cancer is more common in China and Iran. If the cancer occurs in the glands or columnar tissue of the esophagus, then the cancer is an adenocarcinoma. This is most common in Western countries in those with Barrett's esophagus, and occurs in the cuboidal cells.[3] In its early stages, esophageal cancer may not have any symptoms at all. When severe, esophageal cancer may eventually cause obstruction of the esophagus, making swallowing of any solid foods very difficult and causing weight loss. The progress of the cancer is staged using a system that measures how far into the esophageal wall the cancer has invaded, how many lymph nodes possess the cancer, and whether there are any metastases in different parts of the body. Esophageal cancer is often managed with radiotherapy, chemotherapy, and may also be managed by partial surgical removal of the esophagus. Inserting a stent into the esophagus, or inserting a nasogastric tube, may also be used to ensure that a person is able to digest enough food and water. As of 2014[update], the prognosis for esophageal cancer is still poor, so palliative therapy may also be a focus of treatment.[3] ## Barrett's esophagus Prolonged esophagitis, particularly from gastric reflux, is one factor thought to play a role in the development of Barrett's esophagus. In this condition, there is metaplasia of the lining of the lower esophagus, which changes from stratified squamous epithelia to simple columnar epithelia. Barrett's esophagus is thought to be one of the main contributors to the development of esophageal cancer.[3] ## Varices Esophageal varices refer to engorged blood vessels present within the esophageal walls. These blood vessels are engorged more than normal, and in the worst cases may partially obstruct the esophagus. These blood vessels develop as part of a collateral circulation that occurs to drain blood from the abdomen as a result of portal hypertension, usually as a result of liver diseases such as cirrhosis.[3] This collateral circulation occurs because the lower part of the esophagus drains into the left gastric vein, which is a branch of the portal vein. Because of the extensive venous plexus that exists between this vein and other veins, if portal hypertension occurs, the direction of blood drainage in this vein may reverse, with blood draining from the portal venous system, through the plexus. Veins in the plexus may engorge and lead to varices.[4][5] Esophageal varices often do not have symptoms until they rupture. A ruptured varix is considered a medical emergency, because varices can bleed a lot. A bleeding varix may cause a person to throw up blood, or may cause symptoms of hypovolemic shock. To deal with a ruptured varix, a band may be placed around the bleeding bood vessel, or a small amount of a clotting agent may be injected near the bleed. A surgeon may also try to use a small inflatable balloon to apply pressure to stop the wound. A person with a bleeding varice may also receive IV fluids in order to prevent hypovolemic shock from excess blood loss.[3] ## Motility disorders Several disorders affect the motility of food as it travels down the esophagus. This can cause difficult swallowing, called dysphagia. Achalasia refers to a failure of the lower esophageal sphincter to relax properly, and generally develops later in life. This leads to progressive enlargement of the esophagus, and possibly eventual megaesophagus. A nutcracker esophagus refers to swallowing that can be extremely painful, and diffuse esophageal spasm refers to spasm of the esophagus that can be one cause of chest pain. Sclerosis of the esophagus, such as with systemic sclerosis or in CREST syndrome may cause hardening of the walls of the esophagus and interfere with peristalsis.[3] ## Malformations Various structures may also constrict the esophagus. These esophageal strictures are usually benign and typically develop after a person has had reflux for many years. Other malformations may include esophageal webs (which can also be congenital) and damage to the esophagus by radiotherapy, corrosive ingestion, or eosinophilic esophagitis. A Schatzki ring is fibrosis at the gastro-esophageal junction. Strictures may also develop in chronic anemia, and Plummer-Vinson syndrome.[3] ## Congenital malformation The esophagus fails to develop or there is an abnormal connection between the trachea and esophagus in about 1 in 3500 births. Conventional classification divides such connections into five types, based on whether the esophagus is a continuous tube or not, and which end of the esophagus (proximal, distal, both or neither) connects to the trachea. About half the time, these abnormalities occurs with additional abnormalities in other parts of the body, especially affecting the heart.[21] # Imaging An X-ray of swallowed barium may be used to reveal the size and shape of the esophagus, and the presence of any masses. The esophagus may also be imaged using a flexible camera inserted into the esophagus, in a procedure called an endoscopy. If an endoscopy is used on the stomach, the camera will also have to pass through the esophagus. During an endoscopy, a biopsy may be taken. If cancer of the esophagus is being investigated, other methods, including a CT scan, may also be used.[3] # History The word esophagus (British English: oesophagus) comes from Template:Lang-el (oisophagos), from "to carry" (oesin) and "to eat" (phagos).[1] The Greek term oesophagus, from which the English term has been derived, has been documented in anatomical literature since at least the time of Hippocrates, who noted that "the oesophagus ... receives the greatest amount of what we consume." [22] Its existence in other animals and its relationship with the stomach was documented by the Ancient Roman (philosopher) and physician Pliny the Elder,[23] and the peristaltic contractions of the esophagus have been documented since at least the time of Galen.[24] The first attempt at surgery on the esophagus focused in the neck, and was firstly conducted in dogs by Theodore Billroth in 1871, and then in people by Czerny in 1877. By 1908, an operation had been performed by Voeckler to remove the esophagus, and in 1933 the first surgical removal of parts of the lower esophagus, (to control esophageal cancer), had been conducted.[25] The Nissen fundoplication, in which the stomach is wrapped around the lower esophageal sphincter in order to stimulate its function and control reflux, was first conducted by Rudolph Nissen in 1955.[25] # Other animals ## Vertebrates In tetrapods, the pharynx is much shorter, and the esophagus correspondingly longer, than in fish. In the majority of vertebrates, the esophagus is simply a connecting tube, but in some birds, which regurgitate components to feed their young, it is extended towards the lower end to form a crop for storing food before it enters the true stomach.[26][27] In ruminants, animals with four stomachs, a groove called the sulcus reticuli is often found in the esophagus, allowing milk to drain directly into the hind stomach, the abomasum.[28] The esophagus of snakes is remarkable for the distension it undergoes when swallowing prey.[29] In most fish, the esophagus is extremely short, primarily due to the length of the pharynx (which is associated with the gills). However, some fish, including lampreys, chimaeras, and lungfish, have no true stomach, so that the esophagus effectively runs from the pharynx directly to the intestine, and is therefore somewhat longer.[26] In many vertebrates, the esophagus is lined by stratified squamous epithelia without glands. In fish, the esophagus is often lined with columnar epithelia,[27] and in amphibians, sharks and rays, the esophageal epithelium is ciliated, helping to wash food along, in addition to the action of muscular peristalsis.[26] In addition, in the bat Plecotus auritus, fish and some amphibians, glands secreting pepsinogen or hydrochloric acid have been found.[27] The muscle of the esophagus in many mammals is striated initially, but then becomes smooth muscle in the caudal third or so. In the canine and ruminants, however, it is entirely striated to allow regurgitation to feed young (canines) or regurgitation to chew cud (ruminants). It is entirely smooth muscle in amphibians, reptiles and birds.[27] Contrary to popular belief,[30] a person would not be able to pass through the esophagus of a whale, which generally measure less than 10 cm in diameter, although in larger baleen whales may be up to ten inches when fully distended.[31] ## Invertebrates A structure with the same name is often found in invertebrates, including molluscs and arthropods, connecting the oral cavity with the stomach.[32] In the cephalopods, the brain often surrounds the esophagus.[33] The mouth of gastropods opens into an esophagus, which connects to the stomach. Because of torsion, the esophagus usually passes around the stomach, and opens into its posterior portion, furthest from the mouth. In species that have undergone de-torsion, however, the esophagus may open into the anterior of the stomach, which is therefore reversed from the usual gastropod arrangement.[34] In Tarebia granifera the brood pouch is above the esophagus.[35] There is available an extensive rostrum on the anterior part of the esophagus in all carnivorous gastropods.[36]	https://www.wikidoc.org/index.php/Esophageal_disorder
6c2aa5d6a277c66e511ede789f58de86d9e8cc46	wikidoc	Esotropia	Esotropia Esotropia is a form of strabismus where one or both of the eyes turn inward. Esotropia is often called "lazy eye" in error, as this term correctly refers to amblyopia. People with esotropia have "crossed eyes", and suffer from uncrossed diplopia. The most common type of esotropia occurs in approximately one to two percent of the population. Treatment options include glasses with prism lenses, orthoptics, and/or eye muscle surgery. While eye exercises are often useful for intermittent exotropia, they are less useful for intractable esotropia, as voluntary divergence is difficult to increase. # Accommodative esotropia Accommodative esotropia is often seen in patients with a moderate to large amount of hyperopia. The hyperope, in an attempt to "accommodate" or focus the eyes, converges the eyes as well, as convergence is associated with activation of the accommodation reflex. This is appropriately treated with hyperopic glasses to reduce accommodative convergence, and can just as effectively be treated with contact lenses. "Partly accommodative esotropia" is generally treated by glasses or contacts as well as eye muscle surgery. # Left or right eye, or both In esotropia, the patient often favors one eye. This will result in left esotropia or right esotropia, the directional name referring to the eye that turns. In this case, the turned eye almost always develops some degree of amblyopia. Just as often, the patient alternates between the two eyes, so that at one time, the right eye is fixating and the left eye is turned in, and the next moment, the left eye fixates and the right turns in. This is called alternating esotropia, and in this condition, it is common for neither eye to develop amblyopia, both eyes being capable of 20/20 corrected or uncorrected vision. It never happens, however, that both eyes turn in at the same time, as the patient will not be looking at anything if this happened. # Congenital esotropia Congenital esotropia, or infantile esotropia, is a variation that occurs very early in life, generally developing within the first three months of an infant's life. Children with congenital esotropia usually cross fixate, meaning that they use either eye to fixate with, and often show preference by fixating with the dominant eye. True congenital esotropia is usually best treated with early surgery (by age one year). Usually any associated amblyopia is treated by patching prior to surgical intervention. Oblique muscle dysfunction often accompanies congenital esotropia, and may require surgical treatment.	Esotropia Template:DiseaseDisorder infobox Esotropia is a form of strabismus where one or both of the eyes turn inward. Esotropia is often called "lazy eye" in error, as this term correctly refers to amblyopia. People with esotropia have "crossed eyes", and suffer from uncrossed diplopia. The most common type of esotropia occurs in approximately one to two percent of the population. Treatment options include glasses with prism lenses, orthoptics, and/or eye muscle surgery. While eye exercises are often useful for intermittent exotropia, they are less useful for intractable esotropia, as voluntary divergence is difficult to increase. # Accommodative esotropia Accommodative esotropia is often seen in patients with a moderate to large amount of hyperopia. The hyperope, in an attempt to "accommodate" or focus the eyes, converges the eyes as well, as convergence is associated with activation of the accommodation reflex. This is appropriately treated with hyperopic glasses to reduce accommodative convergence, and can just as effectively be treated with contact lenses. "Partly accommodative esotropia" is generally treated by glasses or contacts as well as eye muscle surgery. # Left or right eye, or both In esotropia, the patient often favors one eye. This will result in left esotropia or right esotropia, the directional name referring to the eye that turns. In this case, the turned eye almost always develops some degree of amblyopia. Just as often, the patient alternates between the two eyes, so that at one time, the right eye is fixating and the left eye is turned in, and the next moment, the left eye fixates and the right turns in. This is called alternating esotropia, and in this condition, it is common for neither eye to develop amblyopia, both eyes being capable of 20/20 corrected or uncorrected vision. It never happens, however, that both eyes turn in at the same time, as the patient will not be looking at anything if this happened. # Congenital esotropia Congenital esotropia, or infantile esotropia, is a variation that occurs very early in life, generally developing within the first three months of an infant's life. Children with congenital esotropia usually cross fixate, meaning that they use either eye to fixate with, and often show preference by fixating with the dominant eye. True congenital esotropia is usually best treated with early surgery (by age one year). Usually any associated amblyopia is treated by patching prior to surgical intervention. Oblique muscle dysfunction often accompanies congenital esotropia, and may require surgical treatment. # External links - What is Esotropia? All Types and Treatments - FAQs: Eye Muscle Surgery for Esotropia Template:WH Template:WS Template:Jb1	https://www.wikidoc.org/index.php/Esotropia
4810121db1275263d30a8fee8fc1ffdf2ac7103e	wikidoc	Estazolam	Estazolam # 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 Estazolam is a short or intermediate acting benzodiazepine that is FDA approved for the treatment of short-term management of insomnia. Common adverse reactions include somnolence, hypokinesia, dizziness, and ataxia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Estazolam is indicated for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. - Dosage: - The recommended initial dose for adults is 1 mg at bedtime - Some patients may need a 2 mg dose ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Estazolam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Estazolam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy in children under age 18 has not been established ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Estazolam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Estazolam in pediatric patients. # Contraindications Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression and also withdrawal phenomena following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. Estazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving estazolam she should be warned of the potential risk to the fetus and instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. Estazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair oxidative metabolism mediated by CYP3A # Warnings Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Because some of the important adverse effects of sedative-hypnotics appear to be dose-related, it is important to use the smallest possible effective dose, especially in the elderly. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. ### Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including estazolam. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with estazolam should not be rechallenged with the drug. Estazolam, like other benzodiazepines, has CNS depressant effects. For this reason, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle, after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of estazolam. Patients should also be cautioned about possible combined effects with alcohol and other CNS depressant drugs. As with all benzodiazepines, amnesia, paradoxical reactions (e.g., excitement, agitation, etc.), and other adverse behavioral effects may occur unpredictably. There have been reports of withdrawal signs and symptoms of the type associated with withdrawal from CNS depressant drugs following the rapid decrease or the abrupt discontinuation of benzodiazepines. ### Estazolam Interaction With Drugs That Inhibit Metabolism via Cytochrome P450 3A (CYP3A) The metabolism of estazolam to the major circulating metabolite 4-hydroxy-estazolam and the metabolism of other triazolobenzodiazepines is catalyzed by CYP3A. Consequently, estazolam should be avoided in patients receiving ketoconazole and itraconazole, which are very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser, but still significant degree, estazolam should be used only with caution and consideration of appropriate dosage reduction. The following are examples of drugs known to inhibit the metabolism of other related benzodiazepines, presumably through inhibition of CYP3A: nefazodone, fluvoxamine, cimetidine, diltiazem, isoniazide, and some macrolide antibiotics. While no in vivo drug-drug interaction studies were conducted between estazolam and inducers of CYP3A, compounds that are potent CYP3A inducers (such as carbamazepine, phenytoin, rifampin, and barbiturates) would be expected to decrease estazolam concentrations. # Adverse Reactions ## Clinical Trials Experience The table below enumerates adverse events that occurred at an incidence of 1% or greater among patients with insomnia who received estazolam in 7 night, placebo-controlled trials. Events reported by investigators were classified into standard dictionary (COSTART) terms to establish event frequencies. Event frequencies reported were not corrected for the occurrence of these events at baseline. The frequencies were obtained from data pooled across six studies: estazolam, N = 685; placebo, N = 433. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice in which patient characteristics and other factors differ from those that prevailed in these six clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials was conducted under a different set of conditions. However, the cited figures provide the physician with a basis of estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied. During clinical trials, some of which were not placebo-controlled, estazolam was administered to approximately 1300 patients. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, similar types of untoward events must be grouped into a smaller number of standardized event categories. In the tabulations that follow, a standard COSTART dictionary terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the 1277 individuals exposed to estazolam who experienced an event of the type cited on at least one occasion while receiving estazolam. All reported events are included except those already listed in the previous table, those COSTART terms too general to be informative, and those events where a drug cause was remote. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. It is important to emphasize that, although the events reported did occur during treatment with estazolam, they were not necessarily caused by it. - Body as a Whole - Infrequent: allergic reaction, chills, fever, neck pain, upper extremity pain - Rare: edema, jaw pain, swollen breast - Cardiovascular System - Infrequent: flushing, palpitation - Rare: arrhythmia, syncope - Digestive System - Frequent: constipation, dry mouth - Infrequent: decreased appetite, flatulence, gastritis, increased appetite, vomiting - Rare: enterocolitis, melena, ulceration of the mouth. - Endocrine System - Rare: thyroid nodule - Hematologic and Lymphatic System - Rare: leukopenia, purpura, swollen lymph nodes. - Metabolic/Nutritional Disorders - Infrequent: thirst - Rare: increased SGOT, weight gain, weight loss. - Musculoskeletal System - Infrequent: arthritis, muscle spasm, myalgia - Rare: arthralgia - Nervous System - Frequent: anxiety - Infrequent: agitation, amnesia, apathy, emotional lability, euphoria, hostility, paresthesia, seizure, sleep disorder, stupor, twitch - Rare: ataxia, circumoral paresthesia, decreased libido, decreased reflexes, hallucinations, neuritis, nystagmus, tremor. - Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during estazolam therapy or withdrawal and are of no known clinical significance. - Respiratory System - Infrequent: asthma, cough, dyspnea, rhinitis, sinusitis - Rare: epistaxis, hyperventilation, laryngitis. - Skin and Appendages - Infrequent: rash, sweating, urticaria - Rare: acne, dry skin - Special Senses - Infrequent: abnormal vision, ear pain, eye irritation, eye pain, eye swelling, perverse taste, photophobia, tinnitus - Rare: decreased hearing, diplopia, scotomata. - Urogenital System - Infrequent: frequent urination, menstrual cramps, urinary hesitancy, urinary urgency, vaginal discharge/itching - Rare: hematuria, nocturia, oliguria, penile discharge, urinary incontinence. ## Postmarketing Experience Voluntary reports of non-U.S. postmarketing experience with estazolam have included rare occurrences of photosensitivity, Stevens-Johnson syndrome and agranulocytosis. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to estazolam treatment has not been determined. # Drug Interactions If estazolam is given concomitantly with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of all agents. The action of the benzodiazepines may be potentiated by anticonvulsants, antihistamines, alcohol, barbiturates, monoamine oxidase inhibitors, narcotics, phenothiazines, psychotropic medications, or other drugs that produce CNS depression. Smokers have an increased clearance of benzodiazepines as compared to nonsmokers; this was seen in studies with estazolam. While no in vivo drug-drug interaction studies were conducted between estazolam and inducers of CYP3A, compounds that are potent CYP3A inhibitors (such as carbamazepine, phenytoin, rifampin, and barbiturates) would be expected to decrease estazolam concentrations. The metabolism of estazolam to the major circulating metabolite 4-hydroxy-estazolam and the metabolism of other triazolobenzodiazepines is catalyzed by CYP3A. Consequently, estazolam should be avoided in patients receiving ketoconazole and itraconazole, which are very potent inhibitors of CYP3A (see CONTRAINDICATIONS). With drugs inhibiting CYP3A to a lesser, but still significant degree, estazolam should be used only with caution and consideration of appropriate dosage reduction. The following are examples of drugs known to inhibit the metabolism of other related benzodiazepines, presumably through inhibition of CYP3A: nefazodone, fluvoxamine, cimetidine, diltiazem, isoniazide, and some macrolide antibiotics. A multiple-dose study was conducted to assess the effect of fluoxetine 20 mg BID on the pharmacokinetics of estazolam 2 mg QHS after seven days. The pharmacokinetics of estazolam (Cmax and AUC) were not affected during multiple-dose fluoxetine, suggesting no clinically significant pharmacokinetic interaction. At clinically relevant concentrations, in vitro studies indicate that estazolam (0.6µM) was not inhibitory towards the major cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. Therefore, based on these in vitro data, estazolam is very unlikely to inhibit the biotransformation of other drugs metabolized by these CYP isoforms. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression and also withdrawal phenomena following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. Estazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving estazolam she should be warned of the potential risk to the fetus and instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. The child born of a mother taking benzodiazepines may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has been reported in an infant born of a mother who received benzodiazepines during pregnancy. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Estazolam in women who are pregnant. ### Labor and Delivery Estazolam has no established use in labor or delivery. ### Nursing Mothers Human studies have not been conducted; however, studies in lactating rats indicate that estazolam and/or its metabolites are secreted in the milk. The use of estazolam in nursing mothers is not recommended. ### Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established. ### Geriatic Use Approximately 18% of individuals participating in the premarketing clinical trials of estazolam were 60 years of age or older. Overall, the adverse event profile did not differ substantively from that observed in younger individuals. Care should be exercised when prescribing benzodiazepines to small or debilitated elderly patients. ### Gender The gender-effect on the pharmacokinetics of estazolam has not been investigated. ### Race The influence of race on the pharmacokinetics of estazolam has not been studied. ### Renal Impairment There is no FDA guidance on the use of Estazolam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Estazolam in patients with hepatic impairment. ### Females of Reproductive Potential and Males Fertility in male and female rats was not affected by doses up to 30 times the usual recommended human dose. ### Immunocompromised Patients There is no FDA guidance one the use of Estazolam in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring Laboratory tests are not ordinarily required in otherwise healthy patients. When treatment with estazolam is protracted, periodic blood counts, urinalyses, and blood chemistry analyses are advisable. # IV Compatibility Estazolam tablets are a controlled substance in Schedule IV. # Overdosage As with other benzodiazepines, experience with estazolam indicates that manifestations of overdosage include somnolence, respiratory depression, confusion, impaired coordination, slurred speech, and ultimately, coma. Patients have recovered from overdosage as high as 40 mg. As in the management of intentional overdose with any drug, the possibility should be considered that multiple agents may have been taken. Gastric evacuation, either by the induction of emesis, lavage, or both, should be performed immediately. Maintenance of adequate ventilation is essential. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Fluids should be administered intravenously to maintain blood pressure and encourage diuresis. The value of dialysis in treatment of benzodiazepine overdose has not been determined. The physician may wish to consider contacting a Poison Control Center for up-to-date information on the management of hypnotic drug product overdose. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. # Pharmacology ## Mechanism of Action Estazolam is a benzodiazepine that acts as a CNS depressant and is used as a hypnotic agent ## Structure The structural formula is represented as follows: ## Pharmacodynamics Postulated relationship between elimination rate of benzodiazepine hypnotics and their profile of common untoward effects: The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. If half-lives are long, drug or metabolites may accumulate during periods of nightly administration and may be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be increased. In contrast, if half-lives are short, drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However, during nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics, namely, increased wakefulness during the last third of the night and increased daytime anxiety in selected patients. ## Pharmacokinetics Estazolam tablets have been found to be equivalent in absorption to an orally administered solution of estazolam. In healthy subjects who received up to three times the recommended dose of estazolam, peak estazolam plasma concentrations occurred within two hours after dosing (range 0.5 to 6.0 hours) and were proportional to the administered dose, suggesting linear pharmacokinetics over the dosage range tested. Independent of concentration, estazolam in plasma is 93% protein bound. Estazolam is extensively metabolized. Only two metabolites (1-oxo-estazolam & 4-hydroxy-estazolam) were detected in human plasma up to 18 hrs. The pharmacologic activity of estazolam is primarily from the parent drug. The elimination of the parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites that are eliminated largely in the urine both free and conjugated. In humans, greater than 70% of a single dose of estazolam was recovered in the urine as metabolites. Less than 5% of a 2 mg dose of estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces. The principal urinary excretion product is an unidentified metabolite, presumed to be a metabolic product of 4-hydroxy-estazolam, accounting for at least 27% of the administered dose. 4-hydroxy-estazolam is the major metabolite in plasma, with concentrations approaching 12% of those of the parent eight hours after administration. Urinary 4-hydroxy-estazolam and 1-oxo-estazolam account for 11.9% and 4.4% of the dose respectively. In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by cytochrome P450 3A (CYP3A). While 4-hydroxy-estazolam and the lesser metabolite, 1-oxo-estazolam, have some pharmacologic activity, their low potencies and low concentrations preclude any significant contribution to the hypnotic effect of estazolam. The range of estimates for the mean elimination half-life of estazolam varied from 10 to 24 hours. Radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. After 5 days, 87% of the administered radioactivity was excreted in human urine. Less than 4% of the dose was excreted unchanged. Eleven metabolites were found in urine. Four metabolites were identified as 1-oxo-estazolam, 4’-hydroxy-estazolam, 4-hydroxy-estazolam, and benzophenone, as free metabolites and glucuronides. The predominant metabolite in urine (17% of the administered dose) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam. ## Nonclinical Toxicology Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a dimunition of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Withdrawal symptoms similar to those noted with sedatives/hypnotics and alcohol have occurred following the abrupt discontinuation of drugs in the benzodiazepine class. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Although withdrawal symptoms are more commonly noted after the discontinuation of higher than therapeutic doses of benzodiazepines, a proportion of patients taking benzodiazepines chronically at therapeutic doses may become physically dependent on them. Available data, however, cannot provide a reliable estimate of the incidence of dependency or the relationship of the dependency to dose and duration of treatment. There is some evidence to suggest that gradual reduction of dosage will attenuate or eliminate some withdrawal phenomena. In most instances, withdrawal phenomena are relatively mild and transient; however, life-threatening events (e.g., seizures, delirium, etc.) have been reported. Gradual withdrawal is the preferred course for any patient taking benzodiazepines for a prolonged period. Patients with a history of seizures, regardless of their concomitant antiseizure drug therapy, should not be withdrawn abruptly from benzodiazepines. Individuals with a history of addiction to or abuse of drugs or alcohol should be under careful surveillance when receiving benzodiazepines because of the risk of habituation and dependence to such patients. Two-year carcinogenicity studies were conducted in mice and rats at dietary doses of 0.8, 3, and 10 mg/kg/day and 0.5, 2, and 10 mg/kg/day, respectively. Evidence of tumorigenicity was not observed in either study. Incidence of hyperplastic liver nodules increased in female mice given the mid- and high-dose levels. The significance of such nodules in mice is not known at this time. In vitro and in vivo mutagenicity tests including the Ames test, DNA repair in B. subtilis, in vivo cytogenetics in mice and rats, and the dominant lethal test in mice did not show a mutagenic potential for estazolam. # Clinical Studies Controlled Trials Supporting Efficacy: In three 7 night, double-blind, parallel-group trials comparing estazolam 1 mg and/or 2 mg with placebo in adult outpatients with chronic insomnia, estazolam 2 mg was consistently superior to placebo in subjective measures of sleep induction (latency) and sleep maintenance (duration, number of awakenings, depth and quality of sleep); estazolam 1 mg was similarly superior to placebo on all measures of sleep maintenance, however, it significantly improved sleep induction in only one of two studies. In a similarly designed trial comparing estazolam 0.5 mg and 1 mg with placebo in geriatric outpatients with chronic insomnia, only the 1 mg estazolam dose was consistently superior to placebo in sleep induction (latency) and in only one measure of sleep maintenance (i.e., duration of sleep). In a single-night, double-blind, parallel-group trial comparing estazolam 2 mg and placebo in patients admitted for elective surgery and requiring sleep medications, estazolam was superior to placebo in subjective measures of sleep induction and maintenance. In a 12 week, double-blind, parallel-group trial including a comparison of estazolam 2 mg and placebo in adult outpatients with chronic insomnia, estazolam was superior to placebo in subjective measures of sleep induction (latency) and maintenance (duration, number of awakenings, total wake time during sleep) at week 2, but produced consistent improvement over 12 weeks only for sleep duration and total wake time during sleep. Following withdrawal at week 12, rebound insomnia was seen at the first withdrawal week, but there was no difference between drug and placebo by the second withdrawal week in all parameters except latency, for which normalization did not occur until the fourth withdrawal week. Adult outpatients with chronic insomnia were evaluated in a sleep laboratory trial comparing four doses of estazolam (0.25, 0.5, 1 and 2 mg) and placebo, each administered for 2 nights in a crossover design. The higher estazolam doses were superior to placebo in most EEG measures of sleep induction and maintenance, especially at the 2 mg dose, but only for sleep duration in subjective measures of sleep. # How Supplied - Estazolam tablets 1 mg - Bottles of 100 - Estazolam tablets 2 mg - Bottles of 100 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. To assure the safe and effective use of estazolam, the following information and instructions should be given to patients: Inform your physician about any alcohol consumption and medicine you are taking now, including drugs you may buy without a prescription. Alcohol should not be used during treatment with hypnotics. Inform your physician if you are planning to become pregnant, if you are pregnant, or if you become pregnant while you are taking this medicine. You should not take this medicine if you are nursing, as the drug may be excreted in breast milk. Until you experience the way this medicine affects you, do not drive a car, operate potentially dangerous machinery, or engage in hazardous occupations requiring complete mental alertness after taking this medicine. Since benzodiazepines may produce psychological and physical dependence, you should not increase the dose before consulting your physician. In addition, since the abrupt discontinuation of estazolam may be associated with temporary sleep disturbances, you should consult your physician before abruptly discontinuing doses of 2 mg per night or more. # Precautions with Alcohol Alcohol-Estazolam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Prosom # Look-Alike Drug Names There is limited information regarding Estazolam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Estazolam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Estazolam is a short or intermediate acting benzodiazepine that is FDA approved for the treatment of short-term management of insomnia. Common adverse reactions include somnolence, hypokinesia, dizziness, and ataxia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Estazolam is indicated for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. - Dosage: - The recommended initial dose for adults is 1 mg at bedtime - Some patients may need a 2 mg dose ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Estazolam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Estazolam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy in children under age 18 has not been established ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Estazolam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Estazolam in pediatric patients. # Contraindications Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression and also withdrawal phenomena following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. Estazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving estazolam she should be warned of the potential risk to the fetus and instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. Estazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair oxidative metabolism mediated by CYP3A # Warnings Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Because some of the important adverse effects of sedative-hypnotics appear to be dose-related, it is important to use the smallest possible effective dose, especially in the elderly. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. ### Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including estazolam. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with estazolam should not be rechallenged with the drug. Estazolam, like other benzodiazepines, has CNS depressant effects. For this reason, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle, after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of estazolam. Patients should also be cautioned about possible combined effects with alcohol and other CNS depressant drugs. As with all benzodiazepines, amnesia, paradoxical reactions (e.g., excitement, agitation, etc.), and other adverse behavioral effects may occur unpredictably. There have been reports of withdrawal signs and symptoms of the type associated with withdrawal from CNS depressant drugs following the rapid decrease or the abrupt discontinuation of benzodiazepines. ### Estazolam Interaction With Drugs That Inhibit Metabolism via Cytochrome P450 3A (CYP3A) The metabolism of estazolam to the major circulating metabolite 4-hydroxy-estazolam and the metabolism of other triazolobenzodiazepines is catalyzed by CYP3A. Consequently, estazolam should be avoided in patients receiving ketoconazole and itraconazole, which are very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser, but still significant degree, estazolam should be used only with caution and consideration of appropriate dosage reduction. The following are examples of drugs known to inhibit the metabolism of other related benzodiazepines, presumably through inhibition of CYP3A: nefazodone, fluvoxamine, cimetidine, diltiazem, isoniazide, and some macrolide antibiotics. While no in vivo drug-drug interaction studies were conducted between estazolam and inducers of CYP3A, compounds that are potent CYP3A inducers (such as carbamazepine, phenytoin, rifampin, and barbiturates) would be expected to decrease estazolam concentrations. # Adverse Reactions ## Clinical Trials Experience The table below enumerates adverse events that occurred at an incidence of 1% or greater among patients with insomnia who received estazolam in 7 night, placebo-controlled trials. Events reported by investigators were classified into standard dictionary (COSTART) terms to establish event frequencies. Event frequencies reported were not corrected for the occurrence of these events at baseline. The frequencies were obtained from data pooled across six studies: estazolam, N = 685; placebo, N = 433. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice in which patient characteristics and other factors differ from those that prevailed in these six clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials was conducted under a different set of conditions. However, the cited figures provide the physician with a basis of estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied. During clinical trials, some of which were not placebo-controlled, estazolam was administered to approximately 1300 patients. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, similar types of untoward events must be grouped into a smaller number of standardized event categories. In the tabulations that follow, a standard COSTART dictionary terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the 1277 individuals exposed to estazolam who experienced an event of the type cited on at least one occasion while receiving estazolam. All reported events are included except those already listed in the previous table, those COSTART terms too general to be informative, and those events where a drug cause was remote. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. It is important to emphasize that, although the events reported did occur during treatment with estazolam, they were not necessarily caused by it. - Body as a Whole - Infrequent: allergic reaction, chills, fever, neck pain, upper extremity pain - Rare: edema, jaw pain, swollen breast - Cardiovascular System - Infrequent: flushing, palpitation - Rare: arrhythmia, syncope - Digestive System - Frequent: constipation, dry mouth - Infrequent: decreased appetite, flatulence, gastritis, increased appetite, vomiting - Rare: enterocolitis, melena, ulceration of the mouth. - Endocrine System - Rare: thyroid nodule - Hematologic and Lymphatic System - Rare: leukopenia, purpura, swollen lymph nodes. - Metabolic/Nutritional Disorders - Infrequent: thirst - Rare: increased SGOT, weight gain, weight loss. - Musculoskeletal System - Infrequent: arthritis, muscle spasm, myalgia - Rare: arthralgia - Nervous System - Frequent: anxiety - Infrequent: agitation, amnesia, apathy, emotional lability, euphoria, hostility, paresthesia, seizure, sleep disorder, stupor, twitch - Rare: ataxia, circumoral paresthesia, decreased libido, decreased reflexes, hallucinations, neuritis, nystagmus, tremor. - Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during estazolam therapy or withdrawal and are of no known clinical significance. - Respiratory System - Infrequent: asthma, cough, dyspnea, rhinitis, sinusitis - Rare: epistaxis, hyperventilation, laryngitis. - Skin and Appendages - Infrequent: rash, sweating, urticaria - Rare: acne, dry skin - Special Senses - Infrequent: abnormal vision, ear pain, eye irritation, eye pain, eye swelling, perverse taste, photophobia, tinnitus - Rare: decreased hearing, diplopia, scotomata. - Urogenital System - Infrequent: frequent urination, menstrual cramps, urinary hesitancy, urinary urgency, vaginal discharge/itching - Rare: hematuria, nocturia, oliguria, penile discharge, urinary incontinence. ## Postmarketing Experience Voluntary reports of non-U.S. postmarketing experience with estazolam have included rare occurrences of photosensitivity, Stevens-Johnson syndrome and agranulocytosis. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to estazolam treatment has not been determined. # Drug Interactions If estazolam is given concomitantly with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of all agents. The action of the benzodiazepines may be potentiated by anticonvulsants, antihistamines, alcohol, barbiturates, monoamine oxidase inhibitors, narcotics, phenothiazines, psychotropic medications, or other drugs that produce CNS depression. Smokers have an increased clearance of benzodiazepines as compared to nonsmokers; this was seen in studies with estazolam. While no in vivo drug-drug interaction studies were conducted between estazolam and inducers of CYP3A, compounds that are potent CYP3A inhibitors (such as carbamazepine, phenytoin, rifampin, and barbiturates) would be expected to decrease estazolam concentrations. The metabolism of estazolam to the major circulating metabolite 4-hydroxy-estazolam and the metabolism of other triazolobenzodiazepines is catalyzed by CYP3A. Consequently, estazolam should be avoided in patients receiving ketoconazole and itraconazole, which are very potent inhibitors of CYP3A (see CONTRAINDICATIONS). With drugs inhibiting CYP3A to a lesser, but still significant degree, estazolam should be used only with caution and consideration of appropriate dosage reduction. The following are examples of drugs known to inhibit the metabolism of other related benzodiazepines, presumably through inhibition of CYP3A: nefazodone, fluvoxamine, cimetidine, diltiazem, isoniazide, and some macrolide antibiotics. A multiple-dose study was conducted to assess the effect of fluoxetine 20 mg BID on the pharmacokinetics of estazolam 2 mg QHS after seven days. The pharmacokinetics of estazolam (Cmax and AUC) were not affected during multiple-dose fluoxetine, suggesting no clinically significant pharmacokinetic interaction. At clinically relevant concentrations, in vitro studies indicate that estazolam (0.6µM) was not inhibitory towards the major cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. Therefore, based on these in vitro data, estazolam is very unlikely to inhibit the biotransformation of other drugs metabolized by these CYP isoforms. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression and also withdrawal phenomena following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. Estazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving estazolam she should be warned of the potential risk to the fetus and instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. The child born of a mother taking benzodiazepines may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has been reported in an infant born of a mother who received benzodiazepines during pregnancy. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Estazolam in women who are pregnant. ### Labor and Delivery Estazolam has no established use in labor or delivery. ### Nursing Mothers Human studies have not been conducted; however, studies in lactating rats indicate that estazolam and/or its metabolites are secreted in the milk. The use of estazolam in nursing mothers is not recommended. ### Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established. ### Geriatic Use Approximately 18% of individuals participating in the premarketing clinical trials of estazolam were 60 years of age or older. Overall, the adverse event profile did not differ substantively from that observed in younger individuals. Care should be exercised when prescribing benzodiazepines to small or debilitated elderly patients. ### Gender The gender-effect on the pharmacokinetics of estazolam has not been investigated. ### Race The influence of race on the pharmacokinetics of estazolam has not been studied. ### Renal Impairment There is no FDA guidance on the use of Estazolam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Estazolam in patients with hepatic impairment. ### Females of Reproductive Potential and Males Fertility in male and female rats was not affected by doses up to 30 times the usual recommended human dose. ### Immunocompromised Patients There is no FDA guidance one the use of Estazolam in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring Laboratory tests are not ordinarily required in otherwise healthy patients. When treatment with estazolam is protracted, periodic blood counts, urinalyses, and blood chemistry analyses are advisable. # IV Compatibility Estazolam tablets are a controlled substance in Schedule IV. # Overdosage As with other benzodiazepines, experience with estazolam indicates that manifestations of overdosage include somnolence, respiratory depression, confusion, impaired coordination, slurred speech, and ultimately, coma. Patients have recovered from overdosage as high as 40 mg. As in the management of intentional overdose with any drug, the possibility should be considered that multiple agents may have been taken. Gastric evacuation, either by the induction of emesis, lavage, or both, should be performed immediately. Maintenance of adequate ventilation is essential. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Fluids should be administered intravenously to maintain blood pressure and encourage diuresis. The value of dialysis in treatment of benzodiazepine overdose has not been determined. The physician may wish to consider contacting a Poison Control Center for up-to-date information on the management of hypnotic drug product overdose. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. # Pharmacology ## Mechanism of Action Estazolam is a benzodiazepine that acts as a CNS depressant and is used as a hypnotic agent ## Structure The structural formula is represented as follows: ## Pharmacodynamics Postulated relationship between elimination rate of benzodiazepine hypnotics and their profile of common untoward effects: The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. If half-lives are long, drug or metabolites may accumulate during periods of nightly administration and may be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be increased. In contrast, if half-lives are short, drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However, during nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics, namely, increased wakefulness during the last third of the night and increased daytime anxiety in selected patients. ## Pharmacokinetics Estazolam tablets have been found to be equivalent in absorption to an orally administered solution of estazolam. In healthy subjects who received up to three times the recommended dose of estazolam, peak estazolam plasma concentrations occurred within two hours after dosing (range 0.5 to 6.0 hours) and were proportional to the administered dose, suggesting linear pharmacokinetics over the dosage range tested. Independent of concentration, estazolam in plasma is 93% protein bound. Estazolam is extensively metabolized. Only two metabolites (1-oxo-estazolam & 4-hydroxy-estazolam) were detected in human plasma up to 18 hrs. The pharmacologic activity of estazolam is primarily from the parent drug. The elimination of the parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites that are eliminated largely in the urine both free and conjugated. In humans, greater than 70% of a single dose of estazolam was recovered in the urine as metabolites. Less than 5% of a 2 mg dose of estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces. The principal urinary excretion product is an unidentified metabolite, presumed to be a metabolic product of 4-hydroxy-estazolam, accounting for at least 27% of the administered dose. 4-hydroxy-estazolam is the major metabolite in plasma, with concentrations approaching 12% of those of the parent eight hours after administration. Urinary 4-hydroxy-estazolam and 1-oxo-estazolam account for 11.9% and 4.4% of the dose respectively. In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by cytochrome P450 3A (CYP3A). While 4-hydroxy-estazolam and the lesser metabolite, 1-oxo-estazolam, have some pharmacologic activity, their low potencies and low concentrations preclude any significant contribution to the hypnotic effect of estazolam. The range of estimates for the mean elimination half-life of estazolam varied from 10 to 24 hours. Radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. After 5 days, 87% of the administered radioactivity was excreted in human urine. Less than 4% of the dose was excreted unchanged. Eleven metabolites were found in urine. Four metabolites were identified as 1-oxo-estazolam, 4’-hydroxy-estazolam, 4-hydroxy-estazolam, and benzophenone, as free metabolites and glucuronides. The predominant metabolite in urine (17% of the administered dose) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam. ## Nonclinical Toxicology Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a dimunition of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Withdrawal symptoms similar to those noted with sedatives/hypnotics and alcohol have occurred following the abrupt discontinuation of drugs in the benzodiazepine class. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Although withdrawal symptoms are more commonly noted after the discontinuation of higher than therapeutic doses of benzodiazepines, a proportion of patients taking benzodiazepines chronically at therapeutic doses may become physically dependent on them. Available data, however, cannot provide a reliable estimate of the incidence of dependency or the relationship of the dependency to dose and duration of treatment. There is some evidence to suggest that gradual reduction of dosage will attenuate or eliminate some withdrawal phenomena. In most instances, withdrawal phenomena are relatively mild and transient; however, life-threatening events (e.g., seizures, delirium, etc.) have been reported. Gradual withdrawal is the preferred course for any patient taking benzodiazepines for a prolonged period. Patients with a history of seizures, regardless of their concomitant antiseizure drug therapy, should not be withdrawn abruptly from benzodiazepines. Individuals with a history of addiction to or abuse of drugs or alcohol should be under careful surveillance when receiving benzodiazepines because of the risk of habituation and dependence to such patients. Two-year carcinogenicity studies were conducted in mice and rats at dietary doses of 0.8, 3, and 10 mg/kg/day and 0.5, 2, and 10 mg/kg/day, respectively. Evidence of tumorigenicity was not observed in either study. Incidence of hyperplastic liver nodules increased in female mice given the mid- and high-dose levels. The significance of such nodules in mice is not known at this time. In vitro and in vivo mutagenicity tests including the Ames test, DNA repair in B. subtilis, in vivo cytogenetics in mice and rats, and the dominant lethal test in mice did not show a mutagenic potential for estazolam. # Clinical Studies Controlled Trials Supporting Efficacy: In three 7 night, double-blind, parallel-group trials comparing estazolam 1 mg and/or 2 mg with placebo in adult outpatients with chronic insomnia, estazolam 2 mg was consistently superior to placebo in subjective measures of sleep induction (latency) and sleep maintenance (duration, number of awakenings, depth and quality of sleep); estazolam 1 mg was similarly superior to placebo on all measures of sleep maintenance, however, it significantly improved sleep induction in only one of two studies. In a similarly designed trial comparing estazolam 0.5 mg and 1 mg with placebo in geriatric outpatients with chronic insomnia, only the 1 mg estazolam dose was consistently superior to placebo in sleep induction (latency) and in only one measure of sleep maintenance (i.e., duration of sleep). In a single-night, double-blind, parallel-group trial comparing estazolam 2 mg and placebo in patients admitted for elective surgery and requiring sleep medications, estazolam was superior to placebo in subjective measures of sleep induction and maintenance. In a 12 week, double-blind, parallel-group trial including a comparison of estazolam 2 mg and placebo in adult outpatients with chronic insomnia, estazolam was superior to placebo in subjective measures of sleep induction (latency) and maintenance (duration, number of awakenings, total wake time during sleep) at week 2, but produced consistent improvement over 12 weeks only for sleep duration and total wake time during sleep. Following withdrawal at week 12, rebound insomnia was seen at the first withdrawal week, but there was no difference between drug and placebo by the second withdrawal week in all parameters except latency, for which normalization did not occur until the fourth withdrawal week. Adult outpatients with chronic insomnia were evaluated in a sleep laboratory trial comparing four doses of estazolam (0.25, 0.5, 1 and 2 mg) and placebo, each administered for 2 nights in a crossover design. The higher estazolam doses were superior to placebo in most EEG measures of sleep induction and maintenance, especially at the 2 mg dose, but only for sleep duration in subjective measures of sleep. # How Supplied - Estazolam tablets 1 mg - Bottles of 100 - Estazolam tablets 2 mg - Bottles of 100 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. To assure the safe and effective use of estazolam, the following information and instructions should be given to patients: Inform your physician about any alcohol consumption and medicine you are taking now, including drugs you may buy without a prescription. Alcohol should not be used during treatment with hypnotics. Inform your physician if you are planning to become pregnant, if you are pregnant, or if you become pregnant while you are taking this medicine. You should not take this medicine if you are nursing, as the drug may be excreted in breast milk. Until you experience the way this medicine affects you, do not drive a car, operate potentially dangerous machinery, or engage in hazardous occupations requiring complete mental alertness after taking this medicine. Since benzodiazepines may produce psychological and physical dependence, you should not increase the dose before consulting your physician. In addition, since the abrupt discontinuation of estazolam may be associated with temporary sleep disturbances, you should consult your physician before abruptly discontinuing doses of 2 mg per night or more. # Precautions with Alcohol Alcohol-Estazolam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Prosom [1] # Look-Alike Drug Names There is limited information regarding Estazolam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Estazolam
2e05de89299c4d115debf1bef74488ffd8788d89	wikidoc	Estratest	Estratest Estratest is hormone replacement therapy drug that combines esterified estrogens with methyltestosterone in one pill. # Indications Estratest is used to treat menopausal women who suffer from hot flashes but do not get relief from estrogen-only therapy # History Estratest was first marketed in the United States in 1965 by Reid-Provident Laboratories, which as 100% of Reid-Rowell, Inc. stock was acquired by the Belgian pharmaceutical company Solvay in 1986. There has been some controversy surrounding the drug in recent years as to its status with the FDA. Solvay is currently sponsoring a clinical trial of Estratest in the United States to determine whether the product is superior to treatment with esterified estrogens tablets # Dosage Estratest is sold in tablet form, with either 1.25 mg estrogens/2.5 mg methyltestosterone or 0.625 mg estrogens/1.25 mg methyltestosterone available. # Supply Estratest is supplied by Solvay. # Reference - August 2003 press release from the Prescription Access Litigation project .	Estratest Estratest is hormone replacement therapy drug that combines esterified estrogens with methyltestosterone in one pill. # Indications Estratest is used to treat menopausal women who suffer from hot flashes but do not get relief from estrogen-only therapy # History Estratest was first marketed in the United States in 1965 by Reid-Provident Laboratories, which as 100% of Reid-Rowell, Inc. stock was acquired by the Belgian pharmaceutical company Solvay in 1986. There has been some controversy surrounding the drug in recent years as to its status with the FDA. Solvay is currently sponsoring a clinical trial of Estratest in the United States to determine whether the product is superior to treatment with esterified estrogens tablets # Dosage Estratest is sold in tablet form, with either 1.25 mg estrogens/2.5 mg methyltestosterone or 0.625 mg estrogens/1.25 mg methyltestosterone available. # Supply Estratest is supplied by Solvay. # Reference - August 2003 press release from the Prescription Access Litigation project [1]. # External links - The product's web site - The clinical trial site Template:WS Template:WH	https://www.wikidoc.org/index.php/Estratest
c784ebc45e5e41b51fff3192d4e3a41cd6bb49b1	wikidoc	Ethocybin	Ethocybin Ethocybin (CEY-39; 4-phosphoryloxy-DET; 4-PO-DET) is a homologue of the mushroom alkaloid psilocybin, and a semi-synthetic psychedelic alkaloid of the tryptamine family. Effects of ethocybin are comparable to those of a shorter LSD or psilocybin, although intensity and duration vary depending on dosage, individual physiology, and set and setting. # Chemistry As with psilocybin and psilocin, ethocybin is may be prodrug that is converted into the pharmacologically active compound ethocin in the body by dephosphorylation. This chemical reaction takes place under strongly acidic conditions or enzymatically by phosphatases in the body. Albert Hofmann was the first to produce this chemical, soon after his discovery of psilocin and psilocybin. It was sold under the code name CEY-39. # Pharmacology As with psilocybin, ethocybin is rapidly dephosphorylated in the body to 4-HO-DET which then acts as a partial agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin (5-HT). # Medicine Ethocybin has been studied as a treatment for several disorders since the early 1960s, and numerous papers are devoted to this material. It's short-lived action was considered a virtue. # Effects Ethocybin is absorbed through the lining of the mouth and stomach. Effects begin 20-45 minutes after ingestion, and last from 2-4 hours depending on dose, species, and individual metabolism. The effects are somewhat shorter compared to psilocybin. # Pharmacology Ethocybin is probably metabolized mostly in the liver where it becomes ethocin, but is also broken down by the enzyme monoamine oxidase. Mental and physical tolerance to psilocybin builds and dissipates quickly. Taking ethocybin more than three or four times in a week (especially two days in a row) can result in diminished effects. Tolerance dissipates after a few days, so frequent users often keep doses spaced five to seven days apart to avoid the effect. # Legality Ethocybin is not controlled in the USA, but possession or sale may be considered illegal under the Federal Analog Act.	Ethocybin Ethocybin (CEY-39; 4-phosphoryloxy-DET; 4-PO-DET) is a homologue of the mushroom alkaloid psilocybin, and a semi-synthetic psychedelic alkaloid of the tryptamine family. Effects of ethocybin are comparable to those of a shorter LSD or psilocybin, although intensity and duration vary depending on dosage, individual physiology, and set and setting. # Chemistry As with psilocybin and psilocin, ethocybin is may be prodrug that is converted into the pharmacologically active compound ethocin in the body by dephosphorylation. This chemical reaction takes place under strongly acidic conditions or enzymatically by phosphatases in the body. Albert Hofmann was the first to produce this chemical, soon after his discovery of psilocin and psilocybin. It was sold under the code name CEY-39. # Pharmacology As with psilocybin, ethocybin is rapidly dephosphorylated in the body to 4-HO-DET which then acts as a partial agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin (5-HT). # Medicine Ethocybin has been studied as a treatment for several disorders since the early 1960s, and numerous papers are devoted to this material. It's short-lived action was considered a virtue. # Effects Ethocybin is absorbed through the lining of the mouth and stomach. Effects begin 20-45 minutes after ingestion, and last from 2-4 hours depending on dose, species, and individual metabolism. The effects are somewhat shorter compared to psilocybin. # Pharmacology Ethocybin is probably metabolized mostly in the liver where it becomes ethocin, but is also broken down by the enzyme monoamine oxidase. Mental and physical tolerance to psilocybin builds and dissipates quickly. Taking ethocybin more than three or four times in a week (especially two days in a row) can result in diminished effects. Tolerance dissipates after a few days, so frequent users often keep doses spaced five to seven days apart to avoid the effect. # Legality Ethocybin is not controlled in the USA, but possession or sale may be considered illegal under the Federal Analog Act.	https://www.wikidoc.org/index.php/Ethocybin
6d7121544895b353da3937d60347042fd8881932	wikidoc	Etorphine	Etorphine Etorphine (M99) is a semi-synthetic opioid possessing an analgesic potency approximately 1,000–3,000 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in the related plants Papaver orientale and Papaver bracteatum. It was later reproduced in 1963 by a research group at MacFarlan Smith in Gorgie, Edinburgh, led by Professor Kenneth Bentley. It can also be produced from thebaine. # Veterinary use Etorphine is available legally only for veterinary use and is strictly governed by law. It is often used to immobilize elephants and other large mammals. Diprenorphine (M5050), also known as Revivon, is an opioid receptor antagonist that can be administered in proportion to the amount of etorphine used (1.3 times) to reverse its effects. Veterinary-strength etorphine is fatal to humans. For this reason the package as supplied to vets always includes the human antidote as well as Etorphine. The human antidote is generally naloxone, not diprenorphine, and is always prepared prior to the preparation of etorphine to be immediately administered following accidental human exposure to etorphine. One of its main advantages is its speed of operation and, more importantly, the speed with which diprenorphine reverses the effects. The high incidence of side-effects, including severe cardiopulmonary depression, has caused etorphine to fall into disfavor in general veterinary practice. However, its high potency combined with the rapid action of both etorphine and its antagonist, diprenorphine, means that it has found a place for capture of large mammals such as rhinoceroses and elephant; under these circumstances both rapid onset and rapid recovery are very important characteristics. The high potency of etorphine means that sufficient etorphine can be administered to large wild mammals by projectile syringe (dart). Large Animal Immobilon is a combination of etorphine plus acepromazine maleate. An etorphine antidote Large Animal Revivon contains mainly diprenorphine for animals and a human-specific naloxone-based antidote, which should be prepared prior to the etorphine. A 5–15 mg dose is enough to immobilize an African elephant and a 2–4 mg dose is enough to immobilize a Black Rhino. # Pharmacology Etorphine is an agonist at μ, δ, and κ opioid receptors. It also has a weak affinity for the ORL1 nociceptin/orphanin FQ receptor. # Legal status In Hong Kong, Etorphine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. In the Netherlands, Etorphine is a list I drug of the Opium Law. It is used only for veterinary purposes in zoos to immobilize large animals. In the US, Etorphine is listed as a Schedule I drug with an ACSCN of 9056, although its hydrochloride salt is classified as Schedule II with an ACSCN of 9059. For both, the 2013 annual aggregate manufacturing quota for both was zero so presumably veterinary supplies of the hydrochloride are imported from Germany and/or the UK. In the UK, under the Misuse of Drugs Act 1971, Etorphine is controlled as a Class A substance. # Synthesis # In Popular Culture In the Showtime television series Dexter the lead character of the same name uses Etorphine to immobilize his victims. In the TV show "Lewis", Season 7, Episode 1, Etorphine is used by an assassin to kill two persons.	Etorphine Etorphine (M99) is a semi-synthetic opioid possessing an analgesic potency approximately 1,000–3,000 times that of morphine.[1] It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in the related plants Papaver orientale and Papaver bracteatum.[2] It was later reproduced in 1963 by a research group at MacFarlan Smith in Gorgie, Edinburgh, led by Professor Kenneth Bentley.[3] It can also be produced from thebaine.[citation needed] # Veterinary use Etorphine is available legally only for veterinary use and is strictly governed by law. It is often used to immobilize elephants and other large mammals. Diprenorphine (M5050), also known as Revivon, is an opioid receptor antagonist that can be administered in proportion to the amount of etorphine used (1.3 times) to reverse its effects. Veterinary-strength etorphine is fatal to humans. For this reason the package as supplied to vets always includes the human antidote as well as Etorphine. The human antidote is generally naloxone, not diprenorphine, and is always prepared prior to the preparation of etorphine to be immediately administered following accidental human exposure to etorphine. One of its main advantages is its speed of operation and, more importantly, the speed with which diprenorphine reverses the effects. The high incidence of side-effects, including severe cardiopulmonary depression, has caused etorphine to fall into disfavor in general veterinary practice. However, its high potency combined with the rapid action of both etorphine and its antagonist, diprenorphine, means that it has found a place for capture of large mammals such as rhinoceroses and elephant; under these circumstances both rapid onset and rapid recovery are very important characteristics. The high potency of etorphine means that sufficient etorphine can be administered to large wild mammals by projectile syringe (dart). Large Animal Immobilon is a combination of etorphine plus acepromazine maleate. An etorphine antidote Large Animal Revivon contains mainly diprenorphine for animals and a human-specific naloxone-based antidote, which should be prepared prior to the etorphine. A 5–15 mg dose is enough to immobilize an African elephant and a 2–4 mg dose is enough to immobilize a Black Rhino.[4] # Pharmacology Etorphine is an agonist at μ, δ, and κ opioid receptors. It also has a weak affinity for the ORL1 nociceptin/orphanin FQ receptor.[5] # Legal status In Hong Kong, Etorphine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. In the Netherlands, Etorphine is a list I drug of the Opium Law. It is used only for veterinary purposes in zoos to immobilize large animals. In the US, Etorphine is listed as a Schedule I drug with an ACSCN of 9056, although its hydrochloride salt is classified as Schedule II with an ACSCN of 9059. For both, the 2013 annual aggregate manufacturing quota for both was zero so presumably veterinary supplies of the hydrochloride are imported from Germany and/or the UK. In the UK, under the Misuse of Drugs Act 1971, Etorphine is controlled as a Class A substance. # Synthesis # In Popular Culture In the Showtime television series Dexter the lead character of the same name uses Etorphine to immobilize his victims. In the TV show "Lewis", Season 7, Episode 1, Etorphine is used by an assassin to kill two persons.	https://www.wikidoc.org/index.php/Etorphine
d16dbfb39e21eaaf484d2f294c04493e6326d733	wikidoc	Euphorbia	Euphorbia # Overview Euphorbia (spurge) is a very large and diverse genus of flowering plants in the spurge family (Euphorbiaceae). Sometimes in ordinary English, "euphorbia" is used to refer to the entire Euphorbiaceae family (as the type genus), not just to members of the genus. Some euphorbias are well known and widely commercially available, such as Poinsettias at Christmas. Some are commonly cultivated as ornamentals, or collected and highly valued for the aesthetic appearance of their unique floral structures, such as the Crown of Thorns plant. Euphorbias from the deserts of Southern Africa and Madagascar have evolved physical characteristics and forms similar to cacti of North and South America, so they (along with various other kinds of plants) are often incorrectly referred to as "cacti", although they are far from being related as plants, see below. Some are used as ornamentals in landscaping, because of beautiful or striking overall forms, and drought and heat tolerance. Botanists may be fascinated by the diversity or bizarreness of some of the floral structures, and by the range of growth forms and adaptations to such a wide range of habitats. Euphorbias range from tiny annual plants to large and long-lived trees. The genus has over or about 2,000 members, making it one of the largest genera of flowering plants. It also has one of the largest ranges of chromosome counts, along with Rumex and Senecio. Euphorbia antiquorum is the type species for the genus Euphorbia. It was first described by Carl Linnaeus in 1753 in Species Plantarum. The plants share the feature of having a poisonous, milky, white latex-like sap, and unusual and unique kind of floral structures. The genus may be described by properties of its members' gene sequences, or by the shape and form (morphology) of its heads of flowers. When viewed as a whole, the head of flowers looks like a single flower (a pseudanthium). It has a unique kind of pseudanthium, called a cyathium, where each flower in the head is reduced to its barest essential part needed for sexual reproduction. The individual flowers are either male or female, with the male flowers reduced to only the stamen, and the females to the pistil. These flowers have no sepals, petals, or other parts that are typical of flowers in other kinds of plants. Structures supporting the flower head and beneath that have evolved to attract pollinators with nectar, and with shapes and colors that function the way petals and other flower parts do in other flowers. It is the only genus of plants that has all three kinds of photosynthesis, CAM, C3, and C4. The genus can be found all over the world. The forms range from annual plants laying on the ground, to well developed tall trees. In deserts in Madagascar and southern Africa, convergent evolution has led to cactus-like forms where the plants occupy the same ecological niche as cacti do in deserts of North America and South America. The genus is primarily found in the tropical and subtropical regions of Africa and the Americas, but also in temperate zones worldwide. Succulent species originate mostly from Africa, the Americas and Madagascar. There exists a wide range of insular species. # Misidentification as cacti Among laypersons, Euphorbias are among the most commonly confused plant taxa with cacti, especially the stem succulents. Euphorbias secrete a sticky, milky-white fluid with latex, but cacti do not. Individual flowers of Euphorbias are usually tiny and nondescript (although structures around the individual flowers may not be), without petals and sepals, unlike cacti, which often have fantastically showy flowers. Euphorbias from desert habitats with growth forms similar to cacti have thorns, which are different from the spines of cacti. # Etymology The common name "spurge" derives from the Middle English/Old French espurge ("to purge"), due to the use of the plant's sap as a purgative. The botanical name Euphorbia derives from Euphorbos, the Greek physician of king Iuba (or Juba) II of Numidia (52–50 BC – 23 AD), who married the daughter of Anthony and Cleopatra. Juba was a prolific writer on various subjects, including natural history. Euphorbos wrote that one of the cactus-like Euphorbias (now called Euphorbia obtusifolia ssp. regis-jubae) which was used as a powerful laxative. In 12 B.C., Juba named this plant after his physician Euphorbos, as Augustus Caesar had dedicated a statue to the brother of Euphorbos, Antonius Musa, who was the personal physician of Augustus. In 1753, Botanist and taxonomist Carl Linnaeus assigned the name Euphorbia to the entire genus in the physician's honor. # Description The plants are annual or perennial herbs, woody shrubs or trees with a caustic, poisonous milky latex. The roots are fine or thick and fleshy or tuberous. Many species are more or less succulent, thorny or unarmed. The main stem and mostly also the side arms of the succulent species are thick and fleshy, 15–91 cm (6–36 inches) tall. The deciduous leaves may be opposite, alternate, or in whorls. In succulent species the leaves are mostly small and short-lived. The stipules are mostly small, partly transformed into spines or glands, or missing. ## Inflorescence and fruit Like all members of the family Euphorbiaceae, all spurges have unisexual flowers. In Euphorbia, flowers occur in a head, called the cyathium (plural cyathia). Each male or female flower in the cyathium head has only its essential sexual part, in males the stamen, and in females the pistil. The flowers do not have sepals, petals, or nectar to attract pollen, although other non-flower parts of the plant have an appearance and nectar glands with similar roles. Euphorbias are the only plants known to have this kind of flower head. Nectar glands and nectar that attract pollinators are held in the involucre, a cuplike part below and supporting the cyathium head. (The "involucre" in the Euphorbia genus is not to be confused with the "involucre" in Asteraceae family members, which is a collection of bracts called (phyllaries), which surround and encase the unopened flower head, then support the receptacle under it after the flower head opens.) The involucre is above and supported by bract-like modified leaf structures (usually in pairs) called cyathophylls, or cyathial leaves. The cyathophyll often has a superficial appearance of being petals of a flower. Euphorbia flowers are tiny, and the variation attracting different pollinators (and the human eye), with different forms and colors occurs, in the cyathium, involucre, cyathophyll, or additional parts such as glands that attached to these. The collection of many flowers may be shaped and arranged to appear collectively as a single individual flower, sometimes called a pseudanthium in Asteraceae, and also in Euphorbia. The majority of species are monoecious (bearing male and female flowers on the same plant), although some are dioecious with male and female flowers occurring on different plants. It is not unusual for the central cyathia of a cyme to be purely male, and for lateral cyathia to carry both sexes. Sometimes young plants or those growing under unfavorable conditions are male only, and only produce female flowers in the cyathia with maturity or as growing conditions improve. The female flowers reduced to a single pistil usually spit into 3 parts, often with 2 stigmas at each tip. male flowers often have anthers in 2's. Nectar glands usually occur in 5's, may be as few as one, and may be fused into a "U"-shape. The cyathophylls often occur in 2's, are leaf-like, and may be showy and brightly coloured and attractive to pollinators, or be reduced to barely visible tiny scales. The fruits are three (rarely two) compartment capsules, sometimes fleshy but almost always ripening to a woody container that then splits open (explosively, see explosive dehiscence). The seeds are 4-angled, oval or spherical, and in some species have a caruncle. ## Xerophytes and succulents In the genus Euphorbia, succulence in the species has often evolved divergently and to differing degrees. Sometimes it is difficult to decide, and it is a question of interpretation, whether or not a species is really succulent or "only" xerophytic. In some cases, especially with geophytes, plants closely related to the succulents are normal herbs. About 850 species are succulent in the strictest sense. If one includes slightly succulent and xerophytic species, this figure rises to about 1000, representing about 45% of all Euphorbia species. ## Irritants The milky sap of spurges (called "latex") evolved as a deterrent to herbivores. It is white and colorless when dry, except in E. abdelkuri, where it is yellow. The pressurized sap seeps from the slightest wound and congeals after a few minutes in air. The skin irritating and caustic effects are largely caused by varying amounts of diterpenes. Triterpenes such as betulin and corresponding esters are other major components of the latex. In contact with mucous membranes (eyes, nose, mouth), the latex can produce extremely painful inflammation. Therefore, spurges should be handled with caution and kept away from children and pets. Latex on skin should be washed off immediately and thoroughly. Congealed latex is insoluble in water, but can be removed with an emulsifier like milk or soap. A physician should be consulted if inflammation occurs, as severe eye damage including permanent blindness may result from exposure to the sap. When large succulent spurges in a greenhouse are cut, vapours can cause irritation to the eyes and throat several metres away. Precautions, including sufficient ventilation, are required. ## Uses Several spurges are grown as garden plants, among them Poinsettia (E. pulcherrima) and the succulent E. trigona. E. pekinensis (Template:Zh) is used in traditional Chinese medicine, where it is regarded as one of the 50 fundamental herbs. Several Euphorbia species are used as food plants by the larvae of some Lepidoptera (butterflies and moths), like the Spurge Hawk-moths (Hyles euphorbiae and Hyles tithymali), as well as the Giant Leopard Moth. Ingenol mebutate, a drug used to treat actinic keratosis, is a diterpenoid which is found in Euphorbia peplus. Euphorbia is often used as a hedging plant in many parts of Africa. # Systematics and taxonomy Euphorbia corresponds to what was its own former subtribe, Euphorbiinae. It has over 2000 species. Morphological description using the presence of a cyathium (see section above) is consistent with nuclear and chloroplast DNA sequence data in testing of about 10% of its members. This testing supports inclusion of formerly other genera as being best placed in this single genus, including Chamaesyce, Monadenium, Pedilanthus, and Poinsettia (E. pulcherrima). But genetic tests have shown that similar flower head structures or forms within the genus, might not mean close ancestry within the genus. The genetic data shows that within the genus, there may be convergent evolution of inflorescence structures from ancestral subunits that are not related. So using morphology within the genus becomes problematic for further subgeneric grouping. As stated on the Euphorbia Planetary Biodiversity Inventory project webpage - "Previous morphologically based delimitations of subgenera or sections within the genus should not be taken at face value. The genus is in fact rife with striking examples of morphological convergence in cyathial and vegetative features, which justifies a global approach to studying the genus to obtain a proper phylogenetic understanding of the whole group.... The bottom line is that a number of clades have been placed inside or outside of Euphorbia at different times... few of the subgeneric circumscriptions hold up under DNA sequence analysis." According to a 2002 publication on studies of DNA sequence data, most of the smaller "satellite genera" around the huge genus Euphorbia nest deep within the latter. Consequently these taxa, namely the never generally accepted genus Chamaesyce as well as the smaller genera Cubanthus, Elaeophorbia, Endadenium, Monadenium, Synadenium and Pedilanthus were transferred to Euphorbia. The entire subtribe Euphorbiinae now consists solely of the genus Euphorbia. ## Selected species See List of Euphorbia species for complete list. - Euphorbia albomarginata – rattlesnake weed, white-margined sandmat - Euphorbia amygdaloides – wood spurge - Euphorbia antisyphilitica – candelilla - Euphorbia balsamifera – sweet tabaiba (Canary Islands) - Euphorbia bulbispina - Euphorbia calyptrata - Euphorbia canariensis – cardón (Canary Islands) - Euphorbia caput-medusae - Medusa's head (South Africa) - Euphorbia characias - Mediterranean spurge - Euphorbia cotinifolia - Copper tree - Euphorbia cyparissias – cypress spurge - Euphorbia decidua - Euphorbia dendroides - tree spurge - Euphorbia echinus - Euphorbia elastica – palo amarillo - Euphorbia epithymoides – cushion spurge - Euphorbia esula – leafy spurge - Euphorbia falcata - Euphorbia franckiana - Euphorbia grantii – African milk bush - Euphorbia granulata - Euphorbia griffithii - Euphorbia guyoniana - Euphorbia helioscopia – sun spurge - Euphorbia heterophylla – painted euphorbia, desert poinsettia, fireplant, paint leaf, kaliko - Euphorbia hirta - Euphorbia horrida - African milk barrel - Euphorbia hypericifolia - "Inneuphe" diamond frost - Euphorbia ingens - candelabra tree - Euphorbia labatii - Euphorbia lactea – mottled spurge, frilled fan, elkhorn - Euphorbia lathyris – caper spurge, paper spurge, gopher spurge, gopher plant, mole plant - Euphorbia leuconeura – Madagascar jewel - Euphorbia maculata – spotted spurge, prostrate spurge - Euphorbia marginata – snow on the mountain - Euphorbia mammillaris - Euphorbia maritae - Euphorbia milii – crown-of-thorns, Christ plant - Euphorbia myrsinites – myrtle spurge, creeping spurge, donkey tail - Euphorbia neriifolia – Indian spurge tree - Euphorbia obesa - Euphorbia obtusifolia - Euphorbia paralias – sea spurge - Euphorbia pekinensis - Peking spurge - Euphorbia peplis – purple spurge - Euphorbia peplus – petty spurge - Euphorbia polychroma - bonfire - Euphorbia psammogeton – sand spurge - Euphorbia pulcherrima – poinsettia, Mexican flame leaf, Christmas star, winter rose, noche buena, lalupatae, pascua, Atatürk çiçeği (Turkish) - Euphorbia purpurea - Euphorbia resinifera – resin spurge - Euphorbia rigida – gopher spurge, upright myrtle spurge - Euphorbia serrata – serrated spurge, sawtooth spurge - Euphorbia terracina – Geraldton carnation weed - Euphorbia tirucalli – Indian tree spurge, milk bush, pencil tree, firestick - Euphorbia tithymaloides – devil's backbone, redbird cactus, cimora misha (Peru) - Euphorbia trigona – African milk tree, cathedral cactus, Abyssinian euphorbia - Euphorbia virosa - Euphorbia xanti - Baja spurge ## Subgenera The genus Euphorbia is one of the largest and most complex genera of flowering plants and several botanists have made unsuccessful attempts to subdivide the genus into numerous smaller genera. According to the recent phylogenetic studies, Euphorbia can be divided into 4 subgenera, each containing several not yet sufficiently studied sections and groups. Of these, Esula is the most basal. Chamaesyce and Euphorbia are probably sister taxa but very closely related to Rhizanthium. Extensive xeromorph adaptations in all probability evolved several times; it is not known if the common ancestor of the cactus-like Rhizanthium and Euphorbia lineages was xeromorphic—in which case a more normal morphology would have re-evolved namely in Chamaesyce—or whether extensive xeromorphism is entirely polyphyletic even to the level of the subgenera.	Euphorbia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] # Overview Euphorbia (spurge) is a very large and diverse genus of flowering plants in the spurge family (Euphorbiaceae). Sometimes in ordinary English, "euphorbia" is used to refer to the entire Euphorbiaceae family (as the type genus), not just to members of the genus.[1] Some euphorbias are well known and widely commercially available, such as Poinsettias at Christmas. Some are commonly cultivated as ornamentals, or collected and highly valued for the aesthetic appearance of their unique floral structures, such as the Crown of Thorns plant. Euphorbias from the deserts of Southern Africa and Madagascar have evolved physical characteristics and forms similar to cacti of North and South America, so they (along with various other kinds of plants) are often incorrectly referred to as "cacti",[2] although they are far from being related as plants, see below. Some are used as ornamentals in landscaping, because of beautiful or striking overall forms, and drought and heat tolerance.[3][4] Botanists may be fascinated by the diversity or bizarreness of some of the floral structures, and by the range of growth forms and adaptations to such a wide range of habitats. Euphorbias range from tiny annual plants to large and long-lived trees.[4] The genus has over[3] or about 2,000 members,[5] making it one of the largest genera of flowering plants.[6][7] It also has one of the largest ranges of chromosome counts, along with Rumex and Senecio.[6] Euphorbia antiquorum is the type species for the genus Euphorbia.[8] It was first described by Carl Linnaeus in 1753 in Species Plantarum. The plants share the feature of having a poisonous, milky, white latex-like sap, and unusual and unique kind of floral structures.[3] The genus may be described by properties of its members' gene sequences, or by the shape and form (morphology) of its heads of flowers. When viewed as a whole, the head of flowers looks like a single flower (a pseudanthium).[3] It has a unique kind of pseudanthium, called a cyathium, where each flower in the head is reduced to its barest essential part needed for sexual reproduction.[3] The individual flowers are either male or female, with the male flowers reduced to only the stamen, and the females to the pistil.[3] These flowers have no sepals, petals, or other parts that are typical of flowers in other kinds of plants.[3] Structures supporting the flower head and beneath that have evolved to attract pollinators with nectar, and with shapes and colors that function the way petals and other flower parts do in other flowers. It is the only genus of plants that has all three kinds of photosynthesis, CAM, C3, and C4.[3] The genus can be found all over the world.[3] The forms range from annual plants laying on the ground, to well developed tall trees.[3] In deserts in Madagascar and southern Africa, convergent evolution has led to cactus-like forms where the plants occupy the same ecological niche as cacti do in deserts of North America and South America.[3] The genus is primarily found in the tropical and subtropical regions of Africa and the Americas, but also in temperate zones worldwide.[citation needed] Succulent species originate mostly from Africa, the Americas and Madagascar.[citation needed] There exists a wide range[citation needed] of insular species.[citation needed] # Misidentification as cacti Among laypersons, Euphorbias are among the most commonly confused plant taxa with cacti, especially the stem succulents.[9] Euphorbias secrete a sticky, milky-white fluid with latex, but cacti do not.[9] Individual flowers of Euphorbias are usually tiny and nondescript (although structures around the individual flowers may not be), without petals and sepals, unlike cacti, which often have fantastically showy flowers.[9] Euphorbias from desert habitats with growth forms similar to cacti have thorns, which are different from the spines of cacti.[9] # Etymology The common name "spurge" derives from the Middle English/Old French espurge ("to purge"), due to the use of the plant's sap as a purgative. The botanical name Euphorbia derives from Euphorbos, the Greek physician of king Iuba (or Juba) II of Numidia (52–50 BC – 23 AD), who married the daughter of Anthony and Cleopatra.[10] Juba was a prolific writer on various subjects, including natural history. Euphorbos wrote that one of the cactus-like Euphorbias (now called Euphorbia obtusifolia ssp. regis-jubae) which was used as a powerful laxative.[10] In 12 B.C., Juba named this plant after his physician Euphorbos, as Augustus Caesar had dedicated a statue to the brother of Euphorbos, Antonius Musa, who was the personal physician of Augustus.[10] In 1753, Botanist and taxonomist Carl Linnaeus assigned the name Euphorbia to the entire genus in the physician's honor.[11] # Description The plants are annual or perennial herbs, woody shrubs or trees with a caustic, poisonous milky latex. The roots are fine or thick and fleshy or tuberous. Many species are more or less succulent, thorny or unarmed. The main stem and mostly also the side arms of the succulent species are thick and fleshy, 15–91 cm (6–36 inches) tall. The deciduous[citation needed] leaves may be opposite, alternate, or in whorls. In succulent species the leaves are mostly small and short-lived. The stipules are mostly small, partly transformed into spines or glands, or missing. ## Inflorescence and fruit Like all members of the family Euphorbiaceae, all spurges have unisexual flowers. In Euphorbia, flowers occur in a head, called the cyathium (plural cyathia). Each male or female flower in the cyathium head has only its essential sexual part, in males the stamen, and in females the pistil. The flowers do not have sepals, petals, or nectar to attract pollen, although other non-flower parts of the plant have an appearance and nectar glands with similar roles. Euphorbias are the only plants known to have this kind of flower head.[12] Nectar glands and nectar that attract pollinators are held in the involucre, a cuplike part below and supporting the cyathium head. (The "involucre" in the Euphorbia genus is not to be confused with the "involucre" in Asteraceae family members, which is a collection of bracts called (phyllaries), which surround and encase the unopened flower head, then support the receptacle under it after the flower head opens.) The involucre is above and supported by bract-like modified leaf structures (usually in pairs)[citation needed] called cyathophylls, or cyathial leaves. The cyathophyll often has a superficial appearance of being petals of a flower. Euphorbia flowers are tiny, and the variation attracting different pollinators (and the human eye), with different forms and colors occurs, in the cyathium, involucre, cyathophyll, or additional parts such as glands that attached to these. The collection of many flowers may be shaped and arranged to appear collectively as a single individual flower, sometimes called a pseudanthium in Asteraceae, and also in Euphorbia. The majority[citation needed] of species are monoecious (bearing male and female flowers on the same plant), although some are dioecious with male and female flowers occurring on different plants. It is not unusual for the central cyathia of a cyme[citation needed] to be purely male, and for lateral cyathia to carry both sexes. Sometimes young plants or those growing under unfavorable conditions are male only, and only produce female flowers in the cyathia with maturity or as growing conditions improve.[citation needed] The female flowers reduced to a single pistil usually spit into 3 parts,[citation needed] often with 2 stigmas at each tip.[citation needed] male flowers often have anthers in 2's.[citation needed] Nectar glands usually occur in 5's,[13] may be as few as one,[13] and may be fused into a "U"-shape.[12] The cyathophylls often occur in 2's,[citation needed] are leaf-like,[citation needed] and may be showy and brightly coloured and attractive to pollinators,[citation needed] or be reduced to barely visible tiny scales.[citation needed] The fruits are three[citation needed] (rarely two)[citation needed] compartment capsules, sometimes fleshy but almost always ripening to a woody[citation needed] container that then splits open (explosively, see explosive dehiscence). The seeds are 4-angled,[citation needed] oval or spherical,[citation needed] and in some species have a caruncle. ## Xerophytes and succulents In the genus Euphorbia, succulence in the species has often evolved divergently and to differing degrees. Sometimes it is difficult to decide, and it is a question of interpretation, whether or not a species is really succulent or "only" xerophytic. In some cases, especially with geophytes, plants closely related to the succulents are normal herbs. About 850 species are succulent in the strictest sense. If one includes slightly succulent and xerophytic species, this figure rises to about 1000, representing about 45% of all Euphorbia species. ## Irritants The milky sap of spurges (called "latex") evolved as a deterrent to herbivores. It is white and colorless when dry, except in E. abdelkuri, where it is yellow. The pressurized sap seeps from the slightest wound and congeals after a few minutes in air. The skin irritating and caustic effects are largely caused by varying amounts of diterpenes. Triterpenes such as betulin and corresponding esters are other major components of the latex.[14] In contact with mucous membranes (eyes, nose, mouth), the latex can produce extremely painful inflammation. Therefore, spurges should be handled with caution and kept away from children and pets. Latex on skin should be washed off immediately and thoroughly. Congealed latex is insoluble in water, but can be removed with an emulsifier like milk or soap. A physician should be consulted if inflammation occurs, as severe eye damage including permanent blindness may result from exposure to the sap.[15] When large succulent spurges in a greenhouse are cut, vapours can cause irritation to the eyes and throat several metres away. Precautions, including sufficient ventilation, are required. ## Uses Several spurges are grown as garden plants, among them Poinsettia (E. pulcherrima) and the succulent E. trigona. E. pekinensis (Template:Zh) is used in traditional Chinese medicine, where it is regarded as one of the 50 fundamental herbs. Several Euphorbia species are used as food plants by the larvae of some Lepidoptera (butterflies and moths), like the Spurge Hawk-moths (Hyles euphorbiae and Hyles tithymali), as well as the Giant Leopard Moth. Ingenol mebutate, a drug used to treat actinic keratosis, is a diterpenoid which is found in Euphorbia peplus. Euphorbia is often used as a hedging plant in many parts of Africa.[16] # Systematics and taxonomy Euphorbia corresponds to what was its own former subtribe, Euphorbiinae.[citation needed] It has over 2000 species.[3] Morphological description using the presence of a cyathium (see section above) is consistent with nuclear and chloroplast DNA sequence data in testing of about 10% of its members. This testing supports inclusion of formerly other genera as being best placed in this single genus, including Chamaesyce, Monadenium, Pedilanthus, and Poinsettia (E. pulcherrima). But genetic tests have shown that similar flower head structures or forms within the genus, might not mean close ancestry within the genus. The genetic data shows that within the genus, there may be convergent evolution of inflorescence structures from ancestral subunits that are not related. So using morphology within the genus becomes problematic for further subgeneric grouping. As stated on the Euphorbia Planetary Biodiversity Inventory project webpage[3] - "Previous morphologically based delimitations of subgenera or sections within the genus should not be taken at face value. The genus is in fact rife with striking examples of morphological convergence in cyathial and vegetative features, which justifies a global approach to studying the genus to obtain a proper phylogenetic understanding of the whole group.... The bottom line is that a number of clades have been placed inside or outside of Euphorbia at different times... few of the subgeneric circumscriptions hold up under DNA sequence analysis." According to a 2002 publication on studies of DNA sequence data,[17][18][19] most of the smaller "satellite genera" around the huge genus Euphorbia nest deep within the latter. Consequently these taxa, namely the never generally accepted genus Chamaesyce as well as the smaller genera Cubanthus,[20] Elaeophorbia, Endadenium, Monadenium, Synadenium and Pedilanthus were transferred to Euphorbia. The entire subtribe Euphorbiinae now consists solely of the genus Euphorbia. ## Selected species See List of Euphorbia species for complete list. - Euphorbia albomarginata – rattlesnake weed, white-margined sandmat - Euphorbia amygdaloides – wood spurge - Euphorbia antisyphilitica – candelilla - Euphorbia balsamifera – sweet tabaiba (Canary Islands)[21] - Euphorbia bulbispina - Euphorbia calyptrata - Euphorbia canariensis – cardón (Canary Islands)[22] - Euphorbia caput-medusae - Medusa's head (South Africa) - Euphorbia characias - Mediterranean spurge - Euphorbia cotinifolia - Copper tree - Euphorbia cyparissias – cypress spurge - Euphorbia decidua - Euphorbia dendroides - tree spurge - Euphorbia echinus - Euphorbia elastica – palo amarillo - Euphorbia epithymoides – cushion spurge - Euphorbia esula – leafy spurge - Euphorbia falcata - Euphorbia franckiana - Euphorbia grantii – African milk bush - Euphorbia granulata - Euphorbia griffithii - Euphorbia guyoniana - Euphorbia helioscopia – sun spurge - Euphorbia heterophylla – painted euphorbia, desert poinsettia, fireplant, paint leaf, kaliko - Euphorbia hirta - Euphorbia horrida - African milk barrel - Euphorbia hypericifolia - "Inneuphe" diamond frost - Euphorbia ingens - candelabra tree - Euphorbia labatii - Euphorbia lactea – mottled spurge, frilled fan, elkhorn - Euphorbia lathyris – caper spurge, paper spurge, gopher spurge, gopher plant, mole plant - Euphorbia leuconeura – Madagascar jewel - Euphorbia maculata – spotted spurge, prostrate spurge - Euphorbia marginata – snow on the mountain - Euphorbia mammillaris - Euphorbia maritae - Euphorbia milii – crown-of-thorns, Christ plant - Euphorbia myrsinites – myrtle spurge, creeping spurge, donkey tail - Euphorbia neriifolia – Indian spurge tree - Euphorbia obesa - Euphorbia obtusifolia - Euphorbia paralias – sea spurge - Euphorbia pekinensis - Peking spurge - Euphorbia peplis – purple spurge - Euphorbia peplus – petty spurge - Euphorbia polychroma - bonfire - Euphorbia psammogeton – sand spurge - Euphorbia pulcherrima – poinsettia, Mexican flame leaf, Christmas star, winter rose, noche buena, lalupatae, pascua, Atatürk çiçeği (Turkish) - Euphorbia purpurea - Euphorbia resinifera – resin spurge - Euphorbia rigida – gopher spurge, upright myrtle spurge - Euphorbia serrata – serrated spurge, sawtooth spurge - Euphorbia terracina – Geraldton carnation weed - Euphorbia tirucalli – Indian tree spurge, milk bush, pencil tree, firestick - Euphorbia tithymaloides – devil's backbone, redbird cactus, cimora misha (Peru) - Euphorbia trigona – African milk tree, cathedral cactus, Abyssinian euphorbia - Euphorbia virosa - Euphorbia xanti - Baja spurge ## Subgenera The genus Euphorbia is one of the largest and most complex genera of flowering plants and several botanists have made unsuccessful attempts to subdivide the genus into numerous smaller genera. According to the recent phylogenetic studies,[17][18][19] Euphorbia can be divided into 4 subgenera, each containing several not yet sufficiently studied sections and groups. Of these, Esula is the most basal. Chamaesyce and Euphorbia are probably sister taxa but very closely related to Rhizanthium. Extensive xeromorph adaptations in all probability evolved several times; it is not known if the common ancestor of the cactus-like Rhizanthium and Euphorbia lineages was xeromorphic—in which case a more normal morphology would have re-evolved namely in Chamaesyce—or whether extensive xeromorphism is entirely polyphyletic even to the level of the subgenera.	https://www.wikidoc.org/index.php/Euphorbia
8e71848652ee1529c14ae56217d634044e538221	wikidoc	Excipient	Excipient An excipient is an inactive substance used as a carrier for the active ingredients of a medication. In addition excipients can be used to aid the process by which a product is manufactured. In general, the active substances (such as aspirin) may not be easily administered and absorbed by the human body; they need to be put in some appropriate form. In such cases, the active substance is dissolved or mixed with an excipient. Excipients are also sometimes used to bulk up formulations with very potent active ingredients, to allow for convenient and accurate dosage. Depending on the route of administration, and form of medication, various excipients may be used. For oral administration, see Tablet and Capsule. For rectal administration see suppository. Once the active ingredient has been purified, it cannot stay in purified form for very long. In many cases it will denature, fall out of solution, or stick to the sides of the container. To stabilize the active ingredient, excipients are added to ensure that the active ingredient stays active, and is stable for a long enough period of time that the shelf-life of the product makes it competitive with other products. The formulation of these excipients in many cases is considered a trade secret. Pharmaceutical codes require that all ingredients in drugs, as well as their chemical decomposition products are identified and guaranteed to be safe. For this reason, excipients are only used when absolutely necessary and in the smallest amounts possible. # Types of excipients: ## Antiadherents Antiadherents are used to reduce the adhesion between the powder (granules) and the punch faces and thus prevent tablet sticking to the tablet punches. ## Binders Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength. Binders are usually starches, sugars, cellulose or modified cellulose such as hydroxypropyl cellulose, lactose, or sugar alcohols like xylitol, sorbitol or maltitol. Binders are classified according to their application: - Solution binders are dissolved in a solvent (for example water or alcohol and used in wet granulation processes. Examples are Gelatin, Cellulose, Cellulose derivatives, Polyvinyl pyrrolidone, Starch, Sucrose and Polyethylene glycol - Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula. Examples are Cellulose, Methyl cellulose, Polyvinyl pyrrolidone, Polyethylene glycol ## Coatings Tablet coatings protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose (plant fiber) film coating is used which is free of sugar and potential allergens. Occasionally, other coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides. ### Changing the dissolution rates of active species Enteric coatings or slow release coatings control the rate of drug release, or determine where the drug will be released in the digestive tract. ## Disintegrants Disintegrants expand and dissolve when wet causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption. Disintegrant types include: - Water uptake facilitators - Tablet rupture promoters They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, thereby facilitating dissolution. Examples of disintegrants include: starch, cellulose, crosslinked polyvinyl pyrrolidone, sodium starch glycolate, sodium carboxymethyl cellulosemethycellulose. ## Fillers/Diluents Fillers fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, the final product has the proper volume for patient handling. A good filler must be inert, compatible with the other components of the formulation, non-hygroscopic, soluble, relatively cheap, compactible, and preferably tasteless or pleasant tasting. Plant cellulose (pure plant filler) is a popular filler in tablets or hard gelatin capsules. Dibasic calcium phosphate is another popular tablet filler. A range of vegetable fats and oils can be used in soft gelatin capsules. Other examples of fillers include: lactose, sucrose, glucose, mannitol, sorbitol, and, calcium carbonate. ## Flavors and Colors Flavors and Colors are added to improve the taste or appearance of a formulation. Color consistency is important as it allows easy identification of a medication. ## Glidants Glidants are used to improve the flowability of the powder or granules or both. ## Lubricants Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and injection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. ## Preservatives Some typical preservatives used in pharmaceutical formulations are - antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium - the amino acids cysteine and methionine - citric acid and sodium citrate - synthetic preservatives like methyl paraben and propyl paraben. ## Sorbents Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by absorption) in a dry state. ## Sweeteners Sweeteners are added to make the ingredients more palatable, especially in chewable tablets such as antacid or liquids like cough syrup. Therefore, tooth decay is sometimes associated with cough syrup abuse. Sugar can be used to disguise unpleasant tastes or smells.	Excipient An excipient is an inactive substance used as a carrier for the active ingredients of a medication. In addition excipients can be used to aid the process by which a product is manufactured. In general, the active substances (such as aspirin) may not be easily administered and absorbed by the human body; they need to be put in some appropriate form. In such cases, the active substance is dissolved or mixed with an excipient. Excipients are also sometimes used to bulk up formulations with very potent active ingredients, to allow for convenient and accurate dosage. Depending on the route of administration, and form of medication, various excipients may be used. For oral administration, see Tablet and Capsule. For rectal administration see suppository. Once the active ingredient has been purified, it cannot stay in purified form for very long. In many cases it will denature, fall out of solution, or stick to the sides of the container. To stabilize the active ingredient, excipients are added to ensure that the active ingredient stays active, and is stable for a long enough period of time that the shelf-life of the product makes it competitive with other products. The formulation of these excipients in many cases is considered a trade secret. Pharmaceutical codes require that all ingredients in drugs, as well as their chemical decomposition products are identified and guaranteed to be safe. For this reason, excipients are only used when absolutely necessary and in the smallest amounts possible. # Types of excipients: ## Antiadherents Antiadherents are used to reduce the adhesion between the powder (granules) and the punch faces and thus prevent tablet sticking to the tablet punches. ## Binders Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength. Binders are usually starches, sugars, cellulose or modified cellulose such as hydroxypropyl cellulose, lactose, or sugar alcohols like xylitol, sorbitol or maltitol. Binders are classified according to their application: - Solution binders are dissolved in a solvent (for example water or alcohol and used in wet granulation processes. Examples are Gelatin, Cellulose, Cellulose derivatives, Polyvinyl pyrrolidone, Starch, Sucrose and Polyethylene glycol - Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula. Examples are Cellulose, Methyl cellulose, Polyvinyl pyrrolidone, Polyethylene glycol ## Coatings Tablet coatings protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose (plant fiber) film coating is used which is free of sugar and potential allergens. Occasionally, other coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides. ### Changing the dissolution rates of active species Enteric coatings or slow release coatings control the rate of drug release, or determine where the drug will be released in the digestive tract. ## Disintegrants Disintegrants expand and dissolve when wet causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption. Disintegrant types include: - Water uptake facilitators - Tablet rupture promoters They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, thereby facilitating dissolution. Examples of disintegrants include: starch, cellulose, crosslinked polyvinyl pyrrolidone, sodium starch glycolate, sodium carboxymethyl cellulosemethycellulose. ## Fillers/Diluents Fillers fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, the final product has the proper volume for patient handling. A good filler must be inert, compatible with the other components of the formulation, non-hygroscopic, soluble, relatively cheap, compactible, and preferably tasteless or pleasant tasting. Plant cellulose (pure plant filler) is a popular filler in tablets or hard gelatin capsules. Dibasic calcium phosphate is another popular tablet filler. A range of vegetable fats and oils can be used in soft gelatin capsules. Other examples of fillers include: lactose, sucrose, glucose, mannitol, sorbitol, and, calcium carbonate. ## Flavors and Colors Flavors and Colors are added to improve the taste or appearance of a formulation. Color consistency is important as it allows easy identification of a medication. ## Glidants Glidants are used to improve the flowability of the powder or granules or both. ## Lubricants Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and injection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. ## Preservatives Some typical preservatives used in pharmaceutical formulations are - antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium - the amino acids cysteine and methionine - citric acid and sodium citrate - synthetic preservatives like methyl paraben and propyl paraben. ## Sorbents Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by absorption) in a dry state. ## Sweeteners Sweeteners are added to make the ingredients more palatable, especially in chewable tablets such as antacid or liquids like cough syrup. Therefore, tooth decay is sometimes associated with cough syrup abuse. Sugar can be used to disguise unpleasant tastes or smells.	https://www.wikidoc.org/index.php/Excipient
ca803b3956b9f1564e1ab8980e9b3dd4b80254a9	wikidoc	Excretion	Excretion Steven C. Campbell, M.D., Ph.D. # Overview Excretion is the process of eliminating waste products of metabolism and other non-useful materials. It is an essential process in all forms of life. In single-celled organisms, waste products are discharged directly through the surface of the cell. Multicellular organisms utilize more complex excretory methods. Higher plants eliminate gases through the stomata, or pores, on the surface of leaves. Animals have special excretory organs. In humans the main organs of excretion are the kidneys and accessory urinary organs, through which urine is eliminated, and the large intestines, from which solid wastes are expelled. The skin and lungs also have excretory functions: the skin eliminates water and salts in sweat, and the lungs expel water vapor and carbon dioxide. # Specific examples Plants have been shown (by British biologist Brian J. Ford) to translocate wastes into leaves which are then shed. In this fashion, the leaf, in addition to acting as an energy-trapping structure, is also a plant's organ of excretion. Aquatic animals usually excrete ammonia directly into the external environment, as this compound has high solubility and there is ample water available for dilution. In terrestrial animals ammonia-like compounds are converted into other nitrogenous materials as there is less water in the environment and ammonia itself is toxic. In mammals, the two major excretory processes are the formation of urine in the kidneys and the formation of carbon dioxide (a human's abundant metabolic waste) molecules as a result of respiration, which is then exhaled from the lungs. These waste products are eliminated by urination and exhalation respectively. In urination, Hormone control over excretion occurs in the distal tubules of the kidneys as directed by the hypothalamus. Most mammals excrete nitrogenous wastes in the form of urea, an ancestral trait. Birds excrete their nitrogenous wastes as uric acid in the form of a paste. This is metabolically more expensive, but allows more efficient water retention and it can be stored more easily in the egg. Many avian species, especially seabirds, can also excrete salt via specialized nasal salt glands, the saline solution leaving through nostrils in the beak. Perspiration is another excretory process which removes salts and water, although the primary purpose is cooling. In insects, a system involving Malpighian tubules is utilized to excrete metabolic waste. Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines. The metabolic waste is then released from the body along with fecal stuffs. # Etymology Many people misuse the term excretion as a euphemism for defecation, and use excrement for feces, but this is medically inexact.	Excretion Template:Search infobox Steven C. Campbell, M.D., Ph.D. # Overview Excretion is the process of eliminating waste products of metabolism and other non-useful materials.[1] It is an essential process in all forms of life. In single-celled organisms, waste products are discharged directly through the surface of the cell. Multicellular organisms utilize more complex excretory methods. Higher plants eliminate gases through the stomata, or pores, on the surface of leaves. Animals have special excretory organs. In humans the main organs of excretion are the kidneys and accessory urinary organs, through which urine is eliminated,[2] and the large intestines, from which solid wastes are expelled. The skin and lungs also have excretory functions: the skin eliminates water and salts in sweat,[3] and the lungs expel water vapor and carbon dioxide. # Specific examples Plants have been shown (by British biologist Brian J. Ford) to translocate wastes into leaves which are then shed. In this fashion, the leaf, in addition to acting as an energy-trapping structure, is also a plant's organ of excretion. Aquatic animals usually excrete ammonia directly into the external environment, as this compound has high solubility and there is ample water available for dilution. In terrestrial animals ammonia-like compounds are converted into other nitrogenous materials as there is less water in the environment and ammonia itself is toxic. In mammals, the two major excretory processes are the formation of urine in the kidneys and the formation of carbon dioxide (a human's abundant metabolic waste) molecules as a result of respiration, which is then exhaled from the lungs. These waste products are eliminated by urination and exhalation respectively. In urination, Hormone control over excretion occurs in the distal tubules of the kidneys as directed by the hypothalamus. Most mammals excrete nitrogenous wastes in the form of urea, an ancestral trait. Birds excrete their nitrogenous wastes as uric acid in the form of a paste. This is metabolically more expensive, but allows more efficient water retention and it can be stored more easily in the egg. Many avian species, especially seabirds, can also excrete salt via specialized nasal salt glands, the saline solution leaving through nostrils in the beak. Perspiration is another excretory process which removes salts and water, although the primary purpose is cooling. In insects, a system involving Malpighian tubules is utilized to excrete metabolic waste. Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines. The metabolic waste is then released from the body along with fecal stuffs. # Etymology Many people misuse the term excretion as a euphemism for defecation, and use excrement for feces, but this is medically inexact.[1]	https://www.wikidoc.org/index.php/Excrete
2752bb39baf69b9f8a103514d68c8a2af0467a6b	wikidoc	Exogenous	Exogenous Exogenous (or exogeneous) (from the Greek words "exo" and "gen", meaning "outside" and "production") refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system. - In biology, "exogenous" refers to an action or object coming from the outside of a system. For example, an exogenous contrast agent in medical imaging refers to a liquid injected into the patient intravenously that enhances visibility of a pathology, such as a tumor. - In biology, an exogenous factor is any material that is present and active in an individual organism or living cell but that originated outside of that organism, as opposed to an endogenous factor. Exogenous factors in medicine include both pathogens and therapeutics. DNA introduced to cells via transfection or viral infection (transduction) is an exogenous factor. Carcinogens are exogenous factors. - Exogenous factors in medicine include both pathogens and therapeutics. - DNA introduced to cells via transfection or viral infection (transduction) is an exogenous factor. - Carcinogens are exogenous factors. - In attentional psychology, exogenous refers to attention being drawn without conscious intention (see Posner, 1980). An example of this would be attention drawn to a flashing light in the periphery of vision.	Exogenous Exogenous (or exogeneous) (from the Greek words "exo" and "gen", meaning "outside" and "production") refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system. - In biology, "exogenous" refers to an action or object coming from the outside of a system. For example, an exogenous contrast agent in medical imaging refers to a liquid injected into the patient intravenously that enhances visibility of a pathology, such as a tumor. - In biology, an exogenous factor is any material that is present and active in an individual organism or living cell but that originated outside of that organism, as opposed to an endogenous factor. Exogenous factors in medicine include both pathogens and therapeutics. DNA introduced to cells via transfection or viral infection (transduction) is an exogenous factor. Carcinogens are exogenous factors. - Exogenous factors in medicine include both pathogens and therapeutics. - DNA introduced to cells via transfection or viral infection (transduction) is an exogenous factor. - Carcinogens are exogenous factors. - In attentional psychology, exogenous refers to attention being drawn without conscious intention (see Posner, 1980). An example of this would be attention drawn to a flashing light in the periphery of vision.	https://www.wikidoc.org/index.php/Exogenous
536b1f2217d3679cf4aa5c714a2dccc698531559	wikidoc	Exophoria	Exophoria # Overview Exophoria is a form of heterophoria in which there is a tendency of the eyes to deviate outward. # Prevalence Exophoria is particularly common in infancy and childhood, and increases with age. # Cause Exophoria can be caused by several factors, which include: - Refractive errors - distance and near deviation approximately equal. - Divergence excess - exodeviation is more than 15 dioptres greater for distance than near deviation. - Convergence insufficiency - near exodeviation greater than distance deviation. These can be due to nerve, muscle, or congenital problems, or due to mechanical anomalies. Unlike exotropia, fusion is possible in this condition, causing diplopia to be uncommon.	Exophoria # Overview Exophoria is a form of heterophoria in which there is a tendency of the eyes to deviate outward. # Prevalence Exophoria is particularly common in infancy and childhood, and increases with age. # Cause Exophoria can be caused by several factors, which include: - Refractive errors - distance and near deviation approximately equal. - Divergence excess - exodeviation is more than 15 dioptres greater for distance than near deviation. - Convergence insufficiency - near exodeviation greater than distance deviation. These can be due to nerve, muscle, or congenital problems, or due to mechanical anomalies. Unlike exotropia, fusion is possible in this condition, causing diplopia to be uncommon. Template:WH Template:WS	https://www.wikidoc.org/index.php/Exophoria
a15ccde69d3b5e2887f819ab13d196153bee9ae5	wikidoc	Outer ear	Outer ear # Overview The outer ear is the external portion of the ear, which consists of the pinna, concha, and auditory meatus. It gathers sound energy and focuses it on the eardrum (tympanic membrane). One consequence of the configuration of the external ear is to selectively boost the sound pressure 30- to 100-fold for frequencies around 3000 Hz. This amplification makes humans most sensitive to frequencies in this range - and also explains why they are particulary prone to acoustical injury and hearing loss near this frequency. Most human speech sounds are also distributed in the bandwidth around 3 kHz. # Pinna, or auricle The visible part is called the pinna and functions to collect and focus sound waves. Many mammals can move the pinna (with the auriculares muscles) in order to focus their hearing in a certain direction in much the same way that they can turn their eyes. Most humans, unlike most other mammals, do not have this ability. # Ear canal, or external auditory meatus From the pinna the sound pressure waves move into the ear canal, a simple tube running to the middle ear. This tube amplifies frequencies in the range 3 kHz to 12 kHz. et:Väliskõrv no:Ytre øre sk:Vonkajšie ucho fi:Ulkokorva te:వెలుపలి చెవి	Outer ear Template:Infobox Anatomy # Overview The outer ear is the external portion of the ear, which consists of the pinna, concha, and auditory meatus. It gathers sound energy and focuses it on the eardrum (tympanic membrane). One consequence of the configuration of the external ear is to selectively boost the sound pressure 30- to 100-fold for frequencies around 3000 Hz. This amplification makes humans most sensitive to frequencies in this range - and also explains why they are particulary prone to acoustical injury and hearing loss near this frequency. Most human speech sounds are also distributed in the bandwidth around 3 kHz. # Pinna, or auricle The visible part is called the pinna and functions to collect and focus sound waves. Many mammals can move the pinna (with the auriculares muscles) in order to focus their hearing in a certain direction in much the same way that they can turn their eyes. Most humans, unlike most other mammals, do not have this ability. # Ear canal, or external auditory meatus From the pinna the sound pressure waves move into the ear canal, a simple tube running to the middle ear. This tube amplifies frequencies in the range 3 kHz to 12 kHz. Template:Auditory system et:Väliskõrv no:Ytre øre sk:Vonkajšie ucho fi:Ulkokorva te:వెలుపలి చెవి Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/External_ear
2f6b47ff885616c3f79600a8a2d8a26d58498e72	wikidoc	Sex organ	Sex organ # Overview A sex organ, or primary sexual characteristic, as narrowly defined, is any of those anatomical parts of the body which are involved in sexual reproduction and constitute the reproductive system in a complex organism; namely: - Male: testicles, penis, prepuce, scrotum, prostate, seminal vesicles, epididymis, Cowper's glands - Female: ovaries, clitoris, vulva, labia, Skene's gland, Bartholin's glands, vagina, cervix, uterus, Fallopian tube. The Latin term genitalia, sometimes anglicized as genitals and genital area, is used to describe the externally visible sex organs, known as primary genitalia or external genitalia: in males the penis and scrotum, in females the clitoris and vulva. The other, hidden sex organs are referred to as the secondary genitalia or internal genitalia. The most important of these are the gonads a pair of sex organs, specifically the testes in the male or the ovaries in the female. Gonads are the true sex organs, generating reproductive gametes containing inheritable DNA. They also produce most of the primary hormones that affect sexual development, and regulate other sexual organs and sexually differentiated behaviors. A more ambiguously defined term is erogenous zone, subjectively, any portion of the body that when stimulated produces erotic sensation, but always prominently including the genitalia. # Development In typical prenatal development, sexual organs originate from a common anlage anatomy during early gestation and differentiate into male or female variations. The SRY gene, usually located on the Y chromosome and encoding the testis determining factor, determines the direction of this differentiation. The absence of it allows the gonads to continue to develop into ovaries. Thereafter, the development of the internal reproductive organs and the external genitalia is determined by hormones produced by certain fetal gonads (ovaries or testes) and the cells' response to them. The initial appearance of the fetal genitalia (a few weeks after conception) looks basically feminine: a pair of "urogenital folds" with a small protuberance in the middle, and the urethra behind the protuberance. If the fetus has testes, and if the testes produce testosterone, and if the cells of the genitals respond to the testosterone, the outer urogenital folds swell and fuse in the midline to produce the scrotum; the protuberance grows larger and straighter to form the penis; the inner urogenital swellings grow, wrap around the penis, and fuse in the midline to form the penile urethra. Each sexual organ in one sex has a homologous counterpart in the other one. See a list of homologues of the human reproductive system. In a larger perspective, the whole process of sexual differentiation also includes development of secondary sexual characteristics such as patterns of pubic and facial hair and female breasts that emerge at puberty. Furthermore, differences in brain structure arises, affecting, but not absolutely determining, behavior. # Anatomical terms related to sex The following is a list of anatomical terms related to sex and sexuality: - areola - Bartholin's gland — breast — bulbospongiosus muscle — bulbourethral gland - cervix — Cleft of Venus — clitoris — common penile artery — corona glandis — corpora cavernosa — corpus cavernosum — corpus spongiosum — Cowper's glands — cremaster muscle - dartos muscle — ductus deferens - ejaculatory duct — endometrium — epididymis - Fallopian tube — foreskin — frenulum — frenulum preputii penis — frenulum labiorum pudendi — frenulum clitoridis — frenum — fundiform ligament - G-Spot — Gartner's duct — genital tubercle — genitofemoral nerve — glans — glans penis — Gräfenberg spot - hymen - internal pudendal artery — ischiocavernosus muscle - labium — labia majora — labia minora - mammae — mammary gland — meatus — mons pubis — mons veneris — Mullerian duct - nipple - ovary — ovum — oviducts - penis — perineum — prepuce — prostate — pubic hair — pubic symphysis — pubococcygeus muscle — pudendal nerve - raphe — ridged band - scrotum — seminal vesicles — semeniferous tubules — Skene's glands — spermatozoon — spermatic cord — sphincter urethrae membranaceae — splanchnic nerves - testes — testicle — tunica albuginea - urethra — urethral sponge — urogenital diaphragm — uterus - vas deferens — vagina	Sex organ Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A sex organ, or primary sexual characteristic, as narrowly defined, is any of those anatomical parts of the body which are involved in sexual reproduction and constitute the reproductive system in a complex organism; namely: - Male: testicles, penis, prepuce, scrotum, prostate, seminal vesicles, epididymis, Cowper's glands - Female: ovaries, clitoris, vulva, labia, Skene's gland, Bartholin's glands, vagina, cervix, uterus, Fallopian tube. The Latin term genitalia, sometimes anglicized as genitals and genital area, is used to describe the externally visible sex organs, known as primary genitalia or external genitalia: in males the penis and scrotum, in females the clitoris and vulva. The other, hidden sex organs are referred to as the secondary genitalia or internal genitalia. The most important of these are the gonads a pair of sex organs, specifically the testes in the male or the ovaries in the female. Gonads are the true sex organs, generating reproductive gametes containing inheritable DNA. They also produce most of the primary hormones that affect sexual development, and regulate other sexual organs and sexually differentiated behaviors. A more ambiguously defined term is erogenous zone, subjectively, any portion of the body that when stimulated produces erotic sensation, but always prominently including the genitalia. # Development In typical prenatal development, sexual organs originate from a common anlage anatomy during early gestation and differentiate into male or female variations. The SRY gene, usually located on the Y chromosome and encoding the testis determining factor, determines the direction of this differentiation. The absence of it allows the gonads to continue to develop into ovaries. Thereafter, the development of the internal reproductive organs and the external genitalia is determined by hormones produced by certain fetal gonads (ovaries or testes) and the cells' response to them. The initial appearance of the fetal genitalia (a few weeks after conception) looks basically feminine: a pair of "urogenital folds" with a small protuberance in the middle, and the urethra behind the protuberance. If the fetus has testes, and if the testes produce testosterone, and if the cells of the genitals respond to the testosterone, the outer urogenital folds swell and fuse in the midline to produce the scrotum; the protuberance grows larger and straighter to form the penis; the inner urogenital swellings grow, wrap around the penis, and fuse in the midline to form the penile urethra. Each sexual organ in one sex has a homologous counterpart in the other one. See a list of homologues of the human reproductive system. In a larger perspective, the whole process of sexual differentiation also includes development of secondary sexual characteristics such as patterns of pubic and facial hair and female breasts that emerge at puberty. Furthermore, differences in brain structure arises, affecting, but not absolutely determining, behavior. # Anatomical terms related to sex The following is a list of anatomical terms related to sex and sexuality: - areola - Bartholin's gland — breast — bulbospongiosus muscle — bulbourethral gland - cervix — Cleft of Venus — clitoris — common penile artery — corona glandis — corpora cavernosa — corpus cavernosum — corpus spongiosum — Cowper's glands — cremaster muscle - dartos muscle — ductus deferens - ejaculatory duct — endometrium — epididymis - Fallopian tube — foreskin — frenulum — frenulum preputii penis — frenulum labiorum pudendi — frenulum clitoridis — frenum — fundiform ligament - G-Spot — Gartner's duct — genital tubercle — genitofemoral nerve — glans — glans penis — Gräfenberg spot - hymen - internal pudendal artery — ischiocavernosus muscle - labium — labia majora — labia minora - mammae — mammary gland — meatus — mons pubis — mons veneris — Mullerian duct - nipple - ovary — ovum — oviducts - penis — perineum — prepuce — prostate — pubic hair — pubic symphysis — pubococcygeus muscle — pudendal nerve - raphe — ridged band - scrotum — seminal vesicles — semeniferous tubules — Skene's glands — spermatozoon — spermatic cord — sphincter urethrae membranaceae — splanchnic nerves - testes — testicle — tunica albuginea - urethra — urethral sponge — urogenital diaphragm — uterus - vas deferens — vagina Template:Human anatomical features Template:Organ systems Template:WikiDoc Sources	https://www.wikidoc.org/index.php/External_genitalia
c7d8e8305dfa87462e04cac621bc3b2085eecf28	wikidoc	Extractor	Extractor An (N,M,D,K,\epsilon) -extractor is a bipartite graph with N nodes on the left and M nodes on the right such that each node on the left has D neighbors (on the right), which has the added property that for any subset A of the left vertices of size at least K, the distribution on right vertices obtained by choosing a random node in A and then following a random edge to get a node x on the right side is \epsilon-close to the uniform distribution in terms of total variation distance. A disperser is a related graph. An equivalent way to view an extractor is as a bivariate function in the natural way. With this view it turns out that the extractor property is equivalent to: for any source of randomness X that gives n bits with min-entropy \log K, the distribution E(X,U_D) is \epsilon-close to U_M, where U_T denotes the uniform distribution on . Extractors are interesting when they can be constructed with small K,D,\epsilon relative to N and M is as close to KD (the total randomness in the input sources) as possible. Extractor functions were originally researched as a way to extract randomness from weakly random sources. Using the probabilistic method it is easy to show that extractor graphs with really good parameters exist. The challenge is to find explicit or polynomial time computable examples of such graphs with good parameters. Algorithms that compute extractor (and disperser) graphs have found many applications in computer science.	Extractor An <math>(N,M,D,K,\epsilon)</math> -extractor is a bipartite graph with <math>N</math> nodes on the left and <math>M</math> nodes on the right such that each node on the left has <math>D</math> neighbors (on the right), which has the added property that for any subset <math>A</math> of the left vertices of size at least <math>K</math>, the distribution on right vertices obtained by choosing a random node in <math>A</math> and then following a random edge to get a node x on the right side is <math>\epsilon</math>-close to the uniform distribution in terms of total variation distance. A disperser is a related graph. An equivalent way to view an extractor is as a bivariate function in the natural way. With this view it turns out that the extractor property is equivalent to: for any source of randomness <math>X</math> that gives <math>n</math> bits with min-entropy <math>\log K</math>, the distribution <math> E(X,U_D) </math> is <math>\epsilon</math>-close to <math>U_M</math>, where <math>U_T</math> denotes the uniform distribution on <math>[T]</math>. Extractors are interesting when they can be constructed with small <math>K,D,\epsilon</math> relative to <math>N</math> and <math>M</math> is as close to <math>KD</math> (the total randomness in the input sources) as possible. Extractor functions were originally researched as a way to extract randomness from weakly random sources. Using the probabilistic method it is easy to show that extractor graphs with really good parameters exist. The challenge is to find explicit or polynomial time computable examples of such graphs with good parameters. Algorithms that compute extractor (and disperser) graphs have found many applications in computer science.	https://www.wikidoc.org/index.php/Extractor
d5ac23c82d19ce7d7f7898422de8eb3a9e778ba8	wikidoc	Extrovert	Extrovert The trait of extraversion-introversion is a central dimension of human personality. Extraverts (also spelled extroverts) tend to be gregarious, assertive, and interested in seeking out excitement. Introverts, in contrast, tend to be more reserved, less outgoing, and less sociable. They are not necessarily loners but they tend to have smaller circles of friends and are less likely to thrive on making new social contacts. Introverts are less likely to seek stimulation from others because their own thoughts and imagination are stimulating enough. The terms introversion and extraversion were first popularized by Carl Jung. Virtually all comprehensive models of personality include these concepts. Examples include Jung's Analytical psychology, Eysenck's three-factor model, Cattell's 16 personality factors, the Big Five personality traits, the four temperaments, the Minnesota Multiphasic Personality Inventory, the Myers Briggs Type Indicator, and Socionics. Extraversion and introversion are generally understood as a single continuum. Thus, to be high on one is necessarily to be low on the other. That said, people fluctuate in their behavior all the time, and even extreme introverts and extraverts do not always act consistently. # Varieties ## Extraversion Extraversion is "the act, state, or habit of being predominantly concerned with and obtaining gratification from what is outside the self". Extraverts tend to enjoy human interactions and to be enthusiastic, talkative, assertive, and gregarious. They take pleasure in activities that involve large social gatherings, such as parties, community activities, public demonstrations, and business or political groups. Politics, teaching, sales, managing, and brokering are fields that favor extraversion. An extraverted person is likely to enjoy time spent with people and find less reward in time spent alone. They tend to be energized when around other people, and they are more prone to boredom when they are by themselves. ## Introversion Introversion is "the state of or tendency toward being wholly or predominantly concerned with and interested in one's own mental life". Introverts tend to be more reserved and less assertive in social situations. They often take pleasure in solitary activities such as reading, writing, drawing, and using computers. The archetypal artist, writer, sculptor, composer, and inventor are all highly introverted. An introvert is likely to enjoy time spent alone and find less reward in time spent with large groups of people, though they tend to enjoy interactions with close friends. They prefer to concentrate on a single activity at a time and like to observe situations before they participate. Introverts are easily overwhelmed by too much stimulation from social gatherings and engagement. They are more analytical before speaking. Introversion is not the same as shyness. Introverts choose solitary over social activities by preference, whereas shy people avoid social encounters out of fear. ## Ambiversion Although many people view being introverted or extraverted as a question with only two possible answers, most contemporary trait theories (e.g. the Big Five) measure levels of extraversion-introversion as part of a single, continuous dimension of personality, with some scores near one end, and others near the half-way mark. Ambiversion is a term used to describe people who fall more or less directly in the middle and exhibit tendencies of both groups. An ambivert is normally comfortable with groups and enjoys social interaction, but also relishes time alone and away from the crowd # Measurement Extraversion-introversion is normally measured by self-report. A questionnaire might ask if the test-taker agrees or disagrees with statements such as I am the life of the party or I think before I talk. Imagine a questionnaire consisting of ten "agree or disagree" statements. For the first five questions, agreement indicates a tendency towards extraversion, while for the last five questions, agreement indicates introversion. Five people take this questionnaire and answer as follows: In this example, John and Maria are extraverted, Sarah and David are introverted, and Marcus is neither. Self-report questionnaires have obvious limitations in that people may misrepresent themselves either intentionally or through lack of self-knowledge. It is also common to use peer report or observation. Another approach is to present test-takers with various sets of adjectives (for example: thoughtful, talkative, energetic, independent) and ask which describes them most and least. Psychological measures of this trait may break it down into subfactors including warmth, affiliation, positive affect, excitement seeking, and assertiveness/dominance seeking. # Causes ## Jungian theory According to Carl Jung, introversion and extraversion refer to the direction of psychic energy. If a person’s psychic energy usually flows outwards then he or she is an extravert, while if the energy usually flows inwards, the person is an introvert. Extraverts feel an increase of perceived energy when interacting with a large group of people, but a decrease of energy when left alone. Conversely, introverts feel an increase of energy when alone, but a decrease of energy when surrounded by a large group of people. Most modern psychologists consider theories of psychic energy to be obsolete. First, it is difficult to operationalize mental "energy" in ways that can be scientifically measured and tested. Second, more detailed explanations of extraversion and the brain have replaced Jung's rather speculative theories. Nevertheless, the concept is still in popular usage in the general sense of "feeling energized" in particular situations. Jung’s primary legacy in this area may be the popularizing of the terms introvert and extravert to refer to a particular dimension of personality. ## Eysenck's theory Hans Eysenck described extraversion-introversion as the degree to which a person is outgoing and interactive with other people. These behavioral differences are presumed to be the result of underlying differences in brain physiology. Extraverts seek excitement and social activity in an effort to heighten their arousal level, whereas introverts tend to avoid social situations in an effort to keep such arousal to a minimum. Eysenck designated extraversion as one of three major traits in his P-E-N model of personality, which also includes psychoticism and neuroticism. Eysenck originally suggested that extraversion was a combination of two major tendencies, impulsiveness and sociability. He later added several other more specific traits, namely liveliness, activity level, and excitability. These traits are further linked in his personality hierarchy to even more specific habitual responses, such as partying on the weekend. Eysenck compared this trait to the four temperaments of ancient medicine, with choleric and sanguine temperaments equating to extraversion, and melancholic and phlegmatic temperaments equating to introversion. ## Biological factors The relative importance of nature versus environment in determining the level of extraversion is controversial and the focus of many studies. Twin studies find a genetic component of 39% to 58%. In terms of the environmental component, the shared family environment appears to be far less important than individual environmental factors that are not shared between siblings. Eysenck proposed that extraversion was caused by variability in cortical arousal. He hypothesized that introverts are characterized by higher levels of activity than extraverts and so are chronically more cortically aroused than extraverts. The fact that extraverts require more external stimulation than introverts has been interpreted as evidence for this hypothesis. Other evidence of the "stimulation" hypothesis is that introverts salivate more than extraverts in response to a drop of lemon juice. Extraversion has been linked to higher sensitivity of the mesolimbic dopamine system to potentially rewarding stimuli. This in part explains the high levels of positive affect found in extraverts, since they will more intensely feel the excitement of a potential reward. One consequence of this is that extraverts can more easily learn the contingencies for positive reinforcement, since the reward itself is experienced as greater. One study found that introverts have more blood flow in the frontal lobes of their brain and the anterior or frontal thalamus, which are areas dealing with internal processing, such as planning and problem solving. Extraverts have more blood flow in the anterior cingulate gyrus, temporal lobes, and posterior thalamus, which are involved in sensory and emotional experience. This study and other research indicates that introversion-extraversion is related to individual differences in brain function. # Behavior Extraverts and introverts have a variety of behavioral differences. According to one study, extraverts tend to wear more decorative clothing, whereas introverts prefer practical, comfortable clothes. Extraverts are likely to prefer more upbeat, conventional, and energetic music than introverts. Personality also influences how people arrange their work areas. In general, extraverts decorate their offices more, keep their doors open, keep extra chairs nearby, and are more likely to put dishes of candy on their desks. These are attempts to invite co-workers and encourage interaction. Introverts, in contrast, decorate less and tend to arrange their workspace to discourage social interaction. Although extraverts and introverts have real personality and behavior differences, it is important to avoid pigeonholing or stereotyping by personality. Humans are complex and unique, and because extraversion varies along a continuum, they may have a mixture of both orientations. A person who acts introverted in one scenario may act extraverted in another, and people can learn to act “against type” in certain situations. Jung's theory states that when someone's primary function is extraverted, his secondary function is always introverted (and vice versa). # Mental health Acknowledging that introversion and extraversion are normal variants of behavior can help in self-acceptance and understanding of others. For example, an extravert can accept her introverted partner’s need for space, while an introvert can acknowledge his extraverted partner’s need for social interaction. Social psychologist David Myers found a correlation between extraversion and happiness; that is, more extraverted people reported higher levels of personal happiness. The causality is not clear, however. Extraversion may lead to greater happiness, happier people may become more extraverted, or there may be some other factor such as genetics that affects both. It is also possible that the results reflect biases in the survey itself. Another factor is that introversion is generally regarded as less healthy in Western culture. Also, according to Carl Jung, introverts acknowledge more readily their psychological needs and problems, whereas extraverts tend to be oblivious of them because they focus more on the outer world. On average, extraverts also have a somewhat higher self-esteem than introverts. As in the case of happiness, this may be due to inherent differences in the brain, or differential social treatment. Extraversion is perceived as socially desirable in Western culture, but it is not always an advantage. For example, extraverted youths are more likely to engage in delinquent behavior.Conversely, while introversion is perceived as less socially desirable, introversion is strongly associated with positive traits such as intelligence and "giftedness." For many years, researchers have found that introverts tend to be more successful in academic environments, which extraverts may find boring. Career counselors often use personality traits, along with other factors such as skill and interest, to advise their clients. Some careers such as computer programming may be more satisfying for an introverted temperament, while other areas such as sales may be more agreeable to the extraverted type. Although neither introversion nor extraversion is pathological, psychotherapists can take temperament into account when treating clients. Clients may respond better to different types of treatment depending on where they fall on the introversion/extraversion spectrum. Teachers can also consider temperament when dealing with their pupils, for example acknowledging that introverted children need more encouragement to speak in class while extraverted children may grow restless during long periods of quiet study. # Geography Researchers have found that people living in the midwestern states of North Dakota, South Dakota, Nebraska, Minnesota, Wisconsin, and Illinois score higher than the U.S. average on extraversion. Utah and the southeastern states of Florida and Georgia also score high on this personality trait. The most introverted states in the United States are Maryland, New Hampshire, Alaska, Washington, and Vermont. People who live in the northwestern states of Idaho, Montana, and Wyoming are also relatively introverted.	Extrovert The trait of extraversion-introversion is a central dimension of human personality. Extraverts (also spelled extroverts[1]) tend to be gregarious, assertive, and interested in seeking out excitement. Introverts, in contrast, tend to be more reserved, less outgoing, and less sociable. They are not necessarily loners but they tend to have smaller circles of friends and are less likely to thrive on making new social contacts. Introverts are less likely to seek stimulation from others because their own thoughts and imagination are stimulating enough. The terms introversion and extraversion were first popularized by Carl Jung.[2] Virtually all comprehensive models of personality include these concepts. Examples include Jung's Analytical psychology, Eysenck's three-factor model, Cattell's 16 personality factors, the Big Five personality traits, the four temperaments, the Minnesota Multiphasic Personality Inventory, the Myers Briggs Type Indicator, and Socionics. Extraversion and introversion are generally understood as a single continuum. Thus, to be high on one is necessarily to be low on the other. That said, people fluctuate in their behavior all the time, and even extreme introverts and extraverts do not always act consistently. # Varieties ## Extraversion Extraversion is "the act, state, or habit of being predominantly concerned with and obtaining gratification from what is outside the self".[3] Extraverts tend to enjoy human interactions and to be enthusiastic, talkative, assertive, and gregarious. They take pleasure in activities that involve large social gatherings, such as parties, community activities, public demonstrations, and business or political groups. Politics, teaching, sales, managing, and brokering are fields that favor extraversion. An extraverted person is likely to enjoy time spent with people and find less reward in time spent alone. They tend to be energized when around other people, and they are more prone to boredom when they are by themselves. ## Introversion Introversion is "the state of or tendency toward being wholly or predominantly concerned with and interested in one's own mental life".[3] Introverts tend to be more reserved and less assertive in social situations. They often take pleasure in solitary activities such as reading, writing, drawing, and using computers. The archetypal artist, writer, sculptor, composer, and inventor are all highly introverted. An introvert is likely to enjoy time spent alone and find less reward in time spent with large groups of people, though they tend to enjoy interactions with close friends. They prefer to concentrate on a single activity at a time and like to observe situations before they participate.[4] Introverts are easily overwhelmed by too much stimulation from social gatherings and engagement. They are more analytical before speaking.[5] Introversion is not the same as shyness. Introverts choose solitary over social activities by preference, whereas shy people avoid social encounters out of fear.[6] ## Ambiversion Although many people view being introverted or extraverted as a question with only two possible answers, most contemporary trait theories (e.g. the Big Five) measure levels of extraversion-introversion as part of a single, continuous dimension of personality, with some scores near one end, and others near the half-way mark.[7] Ambiversion is a term used to describe people who fall more or less directly in the middle and exhibit tendencies of both groups.[3][8] An ambivert is normally comfortable with groups and enjoys social interaction, but also relishes time alone and away from the crowd # Measurement Extraversion-introversion is normally measured by self-report. A questionnaire might ask if the test-taker agrees or disagrees with statements such as I am the life of the party or I think before I talk. Imagine a questionnaire consisting of ten "agree or disagree" statements. For the first five questions, agreement indicates a tendency towards extraversion, while for the last five questions, agreement indicates introversion. Five people take this questionnaire and answer as follows: In this example, John and Maria are extraverted, Sarah and David are introverted, and Marcus is neither. Self-report questionnaires have obvious limitations in that people may misrepresent themselves either intentionally or through lack of self-knowledge. It is also common to use peer report or observation. Another approach is to present test-takers with various sets of adjectives (for example: thoughtful, talkative, energetic, independent) and ask which describes them most and least. Psychological measures of this trait may break it down into subfactors including warmth, affiliation, positive affect, excitement seeking, and assertiveness/dominance seeking. # Causes ## Jungian theory According to Carl Jung, introversion and extraversion refer to the direction of psychic energy. If a person’s psychic energy usually flows outwards then he or she is an extravert, while if the energy usually flows inwards, the person is an introvert.[9] Extraverts feel an increase of perceived energy when interacting with a large group of people, but a decrease of energy when left alone. Conversely, introverts feel an increase of energy when alone, but a decrease of energy when surrounded by a large group of people. Most modern psychologists consider theories of psychic energy to be obsolete. First, it is difficult to operationalize mental "energy" in ways that can be scientifically measured and tested. Second, more detailed explanations of extraversion and the brain have replaced Jung's rather speculative theories.[10] Nevertheless, the concept is still in popular usage in the general sense of "feeling energized" in particular situations. Jung’s primary legacy in this area may be the popularizing of the terms introvert and extravert to refer to a particular dimension of personality. ## Eysenck's theory Hans Eysenck described extraversion-introversion as the degree to which a person is outgoing and interactive with other people. These behavioral differences are presumed to be the result of underlying differences in brain physiology.[11] Extraverts seek excitement and social activity in an effort to heighten their arousal level, whereas introverts tend to avoid social situations in an effort to keep such arousal to a minimum. Eysenck designated extraversion as one of three major traits in his P-E-N model of personality, which also includes psychoticism and neuroticism. Eysenck originally suggested that extraversion was a combination of two major tendencies, impulsiveness and sociability. He later added several other more specific traits, namely liveliness, activity level, and excitability. These traits are further linked in his personality hierarchy to even more specific habitual responses, such as partying on the weekend. Eysenck compared this trait to the four temperaments of ancient medicine, with choleric and sanguine temperaments equating to extraversion, and melancholic and phlegmatic temperaments equating to introversion.[12] ## Biological factors The relative importance of nature versus environment in determining the level of extraversion is controversial and the focus of many studies. Twin studies find a genetic component of 39% to 58%. In terms of the environmental component, the shared family environment appears to be far less important than individual environmental factors that are not shared between siblings.[13] Eysenck proposed that extraversion was caused by variability in cortical arousal. He hypothesized that introverts are characterized by higher levels of activity than extraverts and so are chronically more cortically aroused than extraverts. The fact that extraverts require more external stimulation than introverts has been interpreted as evidence for this hypothesis. Other evidence of the "stimulation" hypothesis is that introverts salivate more than extraverts in response to a drop of lemon juice.[14] Extraversion has been linked to higher sensitivity of the mesolimbic dopamine system to potentially rewarding stimuli.[15] This in part explains the high levels of positive affect found in extraverts, since they will more intensely feel the excitement of a potential reward. One consequence of this is that extraverts can more easily learn the contingencies for positive reinforcement, since the reward itself is experienced as greater. One study found that introverts have more blood flow in the frontal lobes of their brain and the anterior or frontal thalamus, which are areas dealing with internal processing, such as planning and problem solving. Extraverts have more blood flow in the anterior cingulate gyrus, temporal lobes, and posterior thalamus, which are involved in sensory and emotional experience.[16] This study and other research indicates that introversion-extraversion is related to individual differences in brain function. # Behavior Extraverts and introverts have a variety of behavioral differences. According to one study, extraverts tend to wear more decorative clothing, whereas introverts prefer practical, comfortable clothes.[17] Extraverts are likely to prefer more upbeat, conventional, and energetic music than introverts.[18] Personality also influences how people arrange their work areas. In general, extraverts decorate their offices more, keep their doors open, keep extra chairs nearby, and are more likely to put dishes of candy on their desks. These are attempts to invite co-workers and encourage interaction. Introverts, in contrast, decorate less and tend to arrange their workspace to discourage social interaction.[19] Although extraverts and introverts have real personality and behavior differences, it is important to avoid pigeonholing or stereotyping by personality. Humans are complex and unique, and because extraversion varies along a continuum, they may have a mixture of both orientations. A person who acts introverted in one scenario may act extraverted in another, and people can learn to act “against type” in certain situations. Jung's theory states that when someone's primary function is extraverted, his secondary function is always introverted (and vice versa).[2] # Mental health Acknowledging that introversion and extraversion are normal variants of behavior can help in self-acceptance and understanding of others. For example, an extravert can accept her introverted partner’s need for space, while an introvert can acknowledge his extraverted partner’s need for social interaction. Social psychologist David Myers found a correlation between extraversion and happiness; that is, more extraverted people reported higher levels of personal happiness.[20] The causality is not clear, however. Extraversion may lead to greater happiness, happier people may become more extraverted, or there may be some other factor such as genetics that affects both. It is also possible that the results reflect biases in the survey itself.[21] Another factor is that introversion is generally regarded as less healthy in Western culture. Also, according to Carl Jung, introverts acknowledge more readily their psychological needs and problems, whereas extraverts tend to be oblivious of them because they focus more on the outer world.[2] On average, extraverts also have a somewhat higher self-esteem than introverts. As in the case of happiness, this may be due to inherent differences in the brain, or differential social treatment. Extraversion is perceived as socially desirable in Western culture, but it is not always an advantage. For example, extraverted youths are more likely to engage in delinquent behavior.[22]Conversely, while introversion is perceived as less socially desirable, introversion is strongly associated with positive traits such as intelligence[23] and "giftedness."[24][25] For many years, researchers have found that introverts tend to be more successful in academic environments, which extraverts may find boring.[26] Career counselors often use personality traits, along with other factors such as skill and interest, to advise their clients.[27] Some careers such as computer programming may be more satisfying for an introverted temperament, while other areas such as sales may be more agreeable to the extraverted type. Although neither introversion nor extraversion is pathological, psychotherapists can take temperament into account when treating clients. Clients may respond better to different types of treatment depending on where they fall on the introversion/extraversion spectrum. Teachers can also consider temperament when dealing with their pupils, for example acknowledging that introverted children need more encouragement to speak in class while extraverted children may grow restless during long periods of quiet study. # Geography Researchers have found that people living in the midwestern states of North Dakota, South Dakota, Nebraska, Minnesota, Wisconsin, and Illinois score higher than the U.S. average on extraversion. Utah and the southeastern states of Florida and Georgia also score high on this personality trait. The most introverted states in the United States are Maryland, New Hampshire, Alaska, Washington, and Vermont. People who live in the northwestern states of Idaho, Montana, and Wyoming are also relatively introverted.[28]	https://www.wikidoc.org/index.php/Extrovert
959afff3117ad2edbb4712365820fab561b4a29c	wikidoc	Ezetimibe	Ezetimibe # 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 Ezetimibe is a dietary cholesterol absorption inhibitor that is FDA approved for the treatment of primary hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), homozygous sitosterolemia.. Common adverse reactions include diarrhea, arthralgia, myalgia, nasopharyngitis, sinusitis, upper respiratory infection.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Dosing Information - Recommended dosage: 10 mg PO qd - Ezetimibe can be administered with or without food. ### Concomitant Lipid-Lowering Therapy - Dosing information - Ezetimibe may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of Ezetimibe may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications. ### Coadministration with Bile Acid Sequestrants - Dosing information - Dosing of Ezetimibe should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ### Patients with Hepatic Impairment - Dosing information - No dosage adjustment is necessary in patients with mild hepatic impairment. ### Patients with Renal Impairment - Dosing information - No dosage adjustment is necessary in patients with renal impairment. When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring. ### Geriatric Patients - Dosing information - No dosage adjustment is necessary in geriatric patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Ezetimibe in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Ezetimibe in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Ezetimibe contains no information regarding Pediatric Indications and Dosage. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Ezetimibe in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Ezetimibe in pediatric patients. # Contraindications Ezetimibe is contraindicated in the following conditions: - The combination of Ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels. - Women who are pregnant or may become pregnant because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women. - Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. - If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy. - Nursing mothers-Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require Ezetimibe treatment in combination with a statin should be advised not to nurse their infants. - Patients with a known hypersensitivity to any component of this product. hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with Ezetimibe. # Warnings ### Use with statins or fenofibrate Concurrent administration of Ezetimibe with a specific statin or fenofibrate should be in accordance with the product labeling for that medication. ### Liver Enzymes - In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 × the upper limit of normal ) in hepatic transaminase levels was similar between Ezetimibe (0.5%) and placebo (0.3%). - In controlled clinical combination studies of Ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with Ezetimibe administered with statins and 0.4% for patients treated with statins alone. - These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. - When Ezetimibe is coadministered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. - Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of Ezetimibe and/or the statin. ### Myopathy/Rhabdomyolysis - In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with Ezetimibe compared with the relevant control arm (placebo or statin alone). - However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. - In clinical trials, the incidence of creatine phosphokinase (CPK) >10 × ULN was 0.2% for Ezetimibe vs. 0.1% for placebo, and 0.1% for Ezetimibe coadministered with a statin vs. 0.4% for statins alone. - Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. - In post-marketing experience with Ezetimibe, cases of myopathy and rhabdomyolysis have been reported. - Most patients who developed rhabdomyolysis were taking a statin prior to initiating Ezetimibe. - However, rhabdomyolysis has been reported with Ezetimibe monotherapy and with the addition of Ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. - Ezetimibe and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. - The presence of muscle symptoms and a CPK level >10 × the ULN indicates myopathy. ### Hepatic Impairment Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, Ezetimibe is not recommended in these patients. # Adverse Reactions ## Clinical Trials Experience The following serious adverse reactions are discussed in greater detail in other sections of the label: - Liver enzyme abnormalities - Rhabdomyolysis and myopathy Monotherapy Studies: In the Ezetimibe controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Ezetimibe and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe that led to treatment discontinuation and occurred at a rate greater than placebo were: - Arthralgia (0.3%) - Dizziness (0.2%) - Gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the Ezetimibe monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). Statin Coadministration Studies: In the Ezetimibe + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Ezetimibe + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: - Alanine aminotransferase increased (0.6%) - Myalgia (0.5%) - Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the Ezetimibe + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%). ## 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 clinical practice. ### Monotherapy In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9–86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥2% of patients treated with Ezetimibe and at an incidence greater than placebo in placebo-controlled studies of Ezetimibe, regardless of causality assessment, are shown in Table 1. ### Combination with a statin In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10–93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day concurrently with or added to on-going statin therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks). The incidence of consecutive increased transaminases (≥3 × ULN) was higher in patients receiving Ezetimibe administered with statins (1.3%) than in patients treated with statins alone (0.4%). Clinical adverse reactions reported in ≥2% of patients treated with Ezetimibe + statin and at an incidence greater than statin, regardless of causality assessment, are shown in Table 2. ### Combination with Fenofibrate - This clinical study involving 625 patients with mixed dyslipidemia (age range 20–76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated coadministration of Ezetimibe and Fenofibrate. - This study was not designed to compare treatment groups for infrequent events. - Incidence rates (95% CI) for clinically important elevations (≥3 × ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for Fenofibrate monotherapy (n=188) and Ezetimibe coadministered with Fenofibrate (n=183), respectively, adjusted for treatment exposure. - Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for Fenofibrate monotherapy and Ezetimibe coadministered with Fenofibrate, respectively. - The numbers of patients exposed to coadministration therapy as well as Fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. - There were no CPK elevations >10 × ULN in any of the treatment groups. ## Postmarketing Experience Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during post-approval use of Ezetimibe: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/Rhabdomyolysis; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis. # Drug Interactions ### Cyclosporine Caution should be exercised when using Ezetimibe and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe and cyclosporine. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe. ### Fibrates The efficacy and safety of coadministration of ezetimibe with fibrates other than fenofibrate have not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Coadministration of Ezetimibe with Fibrates other than fenofibrate is not recommended until use in patients is adequately studied. ### Fenofibrate If cholelithiasis is suspected in a patient receiving Ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered and the product labeling for fenofibrate. ### Cholestyramine Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. ### Coumarin Anticoagulants If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All statins are contraindicated in pregnant and nursing women. When Ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ezetimibe in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ezetimibe during labor and delivery. ### Nursing Mothers It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. ### Pediatric Use The effects of Ezetimibe coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe coadministered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161–351 mg/dL) in the Ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range: 149–336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered Ezetimibe and 40-mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6. From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the Ezetimibe coadministered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group. During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 × ULN) occurred in four (3%) individuals in the Ezetimibe coadministered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 × ULN) occurred in two (2%) individuals in the Ezetimibe coadministered with simvastatin group and in zero individuals in the simvastatin monotherapy group. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. Coadministration of Ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls. Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population less than 10 years of age are not available. ### Geriatic Use ### Monotherapy Studies Of the 2396 patients who received Ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. ### Statin Coadministration Studies Of the 11,308 patients who received Ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Ezetimibe with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ezetimibe with respect to specific racial populations. ### Renal Impairment When used as monotherapy, no dosage adjustment of Ezetimibe is necessary. In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of simvastatin exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with Ezetimibe in patients with moderate to severe renal impairment. ### Hepatic Impairment Ezetimibe is not recommended in patients with moderate to severe hepatic impairment. Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ezetimibe in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ezetimibe in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for ezetimibe contains no information regarding drug monitoring. # IV Compatibility FDA Package Insert for ezetimibe contains no information regarding IV Compatibility. # Overdosage In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In the event of an overdose, symptomatic and supportive measures should be employed. # Pharmacology ## Mechanism of Action Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, Ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients). The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol. Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants , fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate. ## Structure Ezetimibe (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)--4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4 and its structural formula is: Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF. ## Pharmacodynamics Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Ezetimibe with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established. ## Pharmacokinetics ### Absorption After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. ### Effect of Food on Oral Absorption Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as Ezetimibe 10-mg tablets. The Cmaxvalue of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe can be administered with or without food. ### Distribution Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. ### Metabolism and Excretion Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. ### Specific Populations Geriatric Patients: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects. Pediatric Patients: Gender: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) in women than in men. Race: Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects. Hepatic Impairment: After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, Ezetimibe is not recommended in these patients. Renal Impairment: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9). ## Nonclinical Toxicology Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Ezetimibe with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established. # Clinical Studies ## Primary hyperlipidemia Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy. ### Monotherapy In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C. ### Combination with statins In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either Ezetimibe or placebo in addition to their on-going statin. Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe were generally consistent across all statins. In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe or placebo was administered alone or with various doses of atorvastatin,simvastatin, pravastatin, or lovastatin. When all patients receiving Ezetimibe with a statin were compared to all those receiving the corresponding statin alone, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by Ezetimibe were generally consistent across all statins. ### Combination with fenofibrate In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe alone, 160-mg fenofibrate alone, or Ezetimibe and 160-mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks. Ezetimibe coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe coadministered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12). The changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above. ## Homozygous Familial Hypercholesterolemia (HoFH) A study was conducted to assess the efficacy of Ezetimibe in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), Ezetimibe administered with atorvastatin or simvastatin (40 mg), or Ezetimibe administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine, ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to Ezetimibe plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with Ezetimibe plus 80-mg atorvastatin or with Ezetimibe plus 80-mg simvastatin, LDL-C was reduced by 27%. ## Homozygous Sitosterolemia (Phytosterolemia) A study was conducted to assess the efficacy of Ezetimibe in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (more than 5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive Ezetimibe (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine, ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, Ezetimibe significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with Ezetimibe, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established. Reductions in sitosterol and campesterolwere consistent between patients taking Ezetimibe concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21). ### Limitations of Use The effect of Ezetimibe on cardiovascular morbidity and mortality has not been determined. # How Supplied No. 3861 — Tablets Ezetimibe, 10 mg, are white to off-white, capsule-shaped tablets debossed with "414" on one side. They are supplied as follows: NDC 66582-414-31 bottles of 30 NDC 66582-414-54 bottles of 90 NDC 66582-414-74 bottles of 500 NDC 66582-414-76 bottles of 5000 NDC 66582-414-28 unit dose packages of 100. ## Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). Protect from moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information See FDA-Approved Patient Labeling (Patient Information). Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. ## Muscle Pain All patients starting therapy with ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician. ## Liver Enzymes Liver tests should be performed when Ezetimibe is added to statin therapy and according to statin recommendations. ## Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Ezetimibe added to statin therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination Ezetimibe and statin therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination Ezetimibe and statin therapy and call their healthcare professional. ## Breastfeeding Women who are breastfeeding should be advised to not use Ezetimibe added to statin therapy. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals. # Precautions with Alcohol Alcohol-Ezetimibe 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 Ezetimibe Brand Names in the drug label. # Look-Alike Drug Names Ezetimibe - Zebeta Ezetimibe - Zestril # Drug Shortage Status # Price	Ezetimibe Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [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 Ezetimibe is a dietary cholesterol absorption inhibitor that is FDA approved for the treatment of primary hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), homozygous sitosterolemia.. Common adverse reactions include diarrhea, arthralgia, myalgia, nasopharyngitis, sinusitis, upper respiratory infection.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Dosing Information - Recommended dosage: 10 mg PO qd - Ezetimibe can be administered with or without food. ### Concomitant Lipid-Lowering Therapy - Dosing information - Ezetimibe may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of Ezetimibe may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications. ### Coadministration with Bile Acid Sequestrants - Dosing information - Dosing of Ezetimibe should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ### Patients with Hepatic Impairment - Dosing information - No dosage adjustment is necessary in patients with mild hepatic impairment. ### Patients with Renal Impairment - Dosing information - No dosage adjustment is necessary in patients with renal impairment. When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring. ### Geriatric Patients - Dosing information - No dosage adjustment is necessary in geriatric patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Ezetimibe in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Ezetimibe in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Ezetimibe contains no information regarding Pediatric Indications and Dosage. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Ezetimibe in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Ezetimibe in pediatric patients. # Contraindications Ezetimibe is contraindicated in the following conditions: - The combination of Ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels. - Women who are pregnant or may become pregnant because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women. - Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. - If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy. - Nursing mothers-Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require Ezetimibe treatment in combination with a statin should be advised not to nurse their infants. - Patients with a known hypersensitivity to any component of this product. hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with Ezetimibe. # Warnings ### Use with statins or fenofibrate Concurrent administration of Ezetimibe with a specific statin or fenofibrate should be in accordance with the product labeling for that medication. ### Liver Enzymes - In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 × the upper limit of normal [ULN]) in hepatic transaminase levels was similar between Ezetimibe (0.5%) and placebo (0.3%). - In controlled clinical combination studies of Ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with Ezetimibe administered with statins and 0.4% for patients treated with statins alone. - These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. - When Ezetimibe is coadministered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. - Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of Ezetimibe and/or the statin. ### Myopathy/Rhabdomyolysis - In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with Ezetimibe compared with the relevant control arm (placebo or statin alone). - However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. - In clinical trials, the incidence of creatine phosphokinase (CPK) >10 × ULN was 0.2% for Ezetimibe vs. 0.1% for placebo, and 0.1% for Ezetimibe coadministered with a statin vs. 0.4% for statins alone. - Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. - In post-marketing experience with Ezetimibe, cases of myopathy and rhabdomyolysis have been reported. - Most patients who developed rhabdomyolysis were taking a statin prior to initiating Ezetimibe. - However, rhabdomyolysis has been reported with Ezetimibe monotherapy and with the addition of Ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. - Ezetimibe and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. - The presence of muscle symptoms and a CPK level >10 × the ULN indicates myopathy. ### Hepatic Impairment Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, Ezetimibe is not recommended in these patients. # Adverse Reactions ## Clinical Trials Experience The following serious adverse reactions are discussed in greater detail in other sections of the label: - Liver enzyme abnormalities - Rhabdomyolysis and myopathy Monotherapy Studies: In the Ezetimibe controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Ezetimibe and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe that led to treatment discontinuation and occurred at a rate greater than placebo were: - Arthralgia (0.3%) - Dizziness (0.2%) - Gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the Ezetimibe monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). Statin Coadministration Studies: In the Ezetimibe + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Ezetimibe + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: - Alanine aminotransferase increased (0.6%) - Myalgia (0.5%) - Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the Ezetimibe + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%). ## 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 clinical practice. ### Monotherapy In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9–86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥2% of patients treated with Ezetimibe and at an incidence greater than placebo in placebo-controlled studies of Ezetimibe, regardless of causality assessment, are shown in Table 1. ### Combination with a statin In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10–93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day concurrently with or added to on-going statin therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks). The incidence of consecutive increased transaminases (≥3 × ULN) was higher in patients receiving Ezetimibe administered with statins (1.3%) than in patients treated with statins alone (0.4%). Clinical adverse reactions reported in ≥2% of patients treated with Ezetimibe + statin and at an incidence greater than statin, regardless of causality assessment, are shown in Table 2. ### Combination with Fenofibrate - This clinical study involving 625 patients with mixed dyslipidemia (age range 20–76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated coadministration of Ezetimibe and Fenofibrate. - This study was not designed to compare treatment groups for infrequent events. - Incidence rates (95% CI) for clinically important elevations (≥3 × ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for Fenofibrate monotherapy (n=188) and Ezetimibe coadministered with Fenofibrate (n=183), respectively, adjusted for treatment exposure. - Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for Fenofibrate monotherapy and Ezetimibe coadministered with Fenofibrate, respectively. - The numbers of patients exposed to coadministration therapy as well as Fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. - There were no CPK elevations >10 × ULN in any of the treatment groups. ## Postmarketing Experience Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during post-approval use of Ezetimibe: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/Rhabdomyolysis; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis. # Drug Interactions ### Cyclosporine Caution should be exercised when using Ezetimibe and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe and cyclosporine. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe. ### Fibrates The efficacy and safety of coadministration of ezetimibe with fibrates other than fenofibrate have not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Coadministration of Ezetimibe with Fibrates other than fenofibrate is not recommended until use in patients is adequately studied. ### Fenofibrate If cholelithiasis is suspected in a patient receiving Ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered and the product labeling for fenofibrate. ### Cholestyramine Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. ### Coumarin Anticoagulants If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All statins are contraindicated in pregnant and nursing women. When Ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ezetimibe in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ezetimibe during labor and delivery. ### Nursing Mothers It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. ### Pediatric Use The effects of Ezetimibe coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe coadministered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161–351 mg/dL) in the Ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range: 149–336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered Ezetimibe and 40-mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6. From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the Ezetimibe coadministered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group. During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 × ULN) occurred in four (3%) individuals in the Ezetimibe coadministered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 × ULN) occurred in two (2%) individuals in the Ezetimibe coadministered with simvastatin group and in zero individuals in the simvastatin monotherapy group. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. Coadministration of Ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls. Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population less than 10 years of age are not available. ### Geriatic Use ### Monotherapy Studies Of the 2396 patients who received Ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. ### Statin Coadministration Studies Of the 11,308 patients who received Ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Ezetimibe with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ezetimibe with respect to specific racial populations. ### Renal Impairment When used as monotherapy, no dosage adjustment of Ezetimibe is necessary. In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of simvastatin exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with Ezetimibe in patients with moderate to severe renal impairment. ### Hepatic Impairment Ezetimibe is not recommended in patients with moderate to severe hepatic impairment. Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ezetimibe in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ezetimibe in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for ezetimibe contains no information regarding drug monitoring. # IV Compatibility FDA Package Insert for ezetimibe contains no information regarding IV Compatibility. # Overdosage In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In the event of an overdose, symptomatic and supportive measures should be employed. # Pharmacology ## Mechanism of Action Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, Ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients). The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol. Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate. ## Structure Ezetimibe (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4 and its structural formula is: Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF. ## Pharmacodynamics Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Ezetimibe with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established. ## Pharmacokinetics ### Absorption After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. ### Effect of Food on Oral Absorption Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as Ezetimibe 10-mg tablets. The Cmaxvalue of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe can be administered with or without food. ### Distribution Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. ### Metabolism and Excretion Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. ### Specific Populations Geriatric Patients: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects. Pediatric Patients: Gender: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) in women than in men. Race: Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects. Hepatic Impairment: After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, Ezetimibe is not recommended in these patients. Renal Impairment: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9). ## Nonclinical Toxicology Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Ezetimibe with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established. # Clinical Studies ## Primary hyperlipidemia Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy. ### Monotherapy In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C. ### Combination with statins In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either Ezetimibe or placebo in addition to their on-going statin. Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe were generally consistent across all statins. In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe or placebo was administered alone or with various doses of atorvastatin,simvastatin, pravastatin, or lovastatin. When all patients receiving Ezetimibe with a statin were compared to all those receiving the corresponding statin alone, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by Ezetimibe were generally consistent across all statins. ### Combination with fenofibrate In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe alone, 160-mg fenofibrate alone, or Ezetimibe and 160-mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks. Ezetimibe coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe coadministered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12). The changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above. ## Homozygous Familial Hypercholesterolemia (HoFH) A study was conducted to assess the efficacy of Ezetimibe in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), Ezetimibe administered with atorvastatin or simvastatin (40 mg), or Ezetimibe administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine, ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to Ezetimibe plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with Ezetimibe plus 80-mg atorvastatin or with Ezetimibe plus 80-mg simvastatin, LDL-C was reduced by 27%. ## Homozygous Sitosterolemia (Phytosterolemia) A study was conducted to assess the efficacy of Ezetimibe in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (more than 5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive Ezetimibe (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine, ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, Ezetimibe significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with Ezetimibe, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established. Reductions in sitosterol and campesterolwere consistent between patients taking Ezetimibe concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21). ### Limitations of Use The effect of Ezetimibe on cardiovascular morbidity and mortality has not been determined. # How Supplied No. 3861 — Tablets Ezetimibe, 10 mg, are white to off-white, capsule-shaped tablets debossed with "414" on one side. They are supplied as follows: NDC 66582-414-31 bottles of 30 NDC 66582-414-54 bottles of 90 NDC 66582-414-74 bottles of 500 NDC 66582-414-76 bottles of 5000 NDC 66582-414-28 unit dose packages of 100. ## Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [USP Controlled Room Temperature.] Protect from moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information See FDA-Approved Patient Labeling (Patient Information). Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. ## Muscle Pain All patients starting therapy with ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician. ## Liver Enzymes Liver tests should be performed when Ezetimibe is added to statin therapy and according to statin recommendations. ## Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Ezetimibe added to statin therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination Ezetimibe and statin therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination Ezetimibe and statin therapy and call their healthcare professional. ## Breastfeeding Women who are breastfeeding should be advised to not use Ezetimibe added to statin therapy. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals. # Precautions with Alcohol Alcohol-Ezetimibe 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 Ezetimibe Brand Names in the drug label. # Look-Alike Drug Names Ezetimibe - Zebeta Ezetimibe - Zestril[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ezetimibe
010216b19ef8271cd20ec402b10836703a85857c	wikidoc	Ezogabine	Ezogabine # 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 Ezogabine is a potassium channel opener that is FDA approved for the treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, somnolence, fatigue, confusional state, vertigo, tremor, abnormal coordination, diplopia, disturbance in attention, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications - Ezogabine is indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity. ## Dosage ### Dosing Information - The initial dosage should be 100 mg 3 times daily (300 mg per day). The dosage should be increased gradually at weekly intervals by no more than 50 mg 3 times daily (increase in the daily dose of no more than 150 mg per day) up to a maintenance dosage of 200 mg to 400 mg 3 times daily (600 mg to 1,200 mg per day), based on individual patient response and tolerability. This information is summarized in Table 1 under Dosing in Specific Populations. In the controlled clinical trials, 400 mg 3 times daily showed limited evidence of additional improvement in seizure reduction, but an increase in adverse events and discontinuations, compared to the 300 mg 3 times daily dosage. The safety and efficacy of doses greater than 400 mg 3 times daily (1,200 mg per day) have not been examined in controlled trials. - Ezogabine should be given orally in 3 equally divided doses daily, with or without food. - Ezogabine Tablets should be swallowed whole. - If ezogabine is discontinued, the dosage should be gradually reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal. ### Dosing Considerations to Mitigate the Risk of Visual Adverse Reactions - Because ezogabine may cause retinal abnormalities with long-term use, patients who fail to show substantial clinical benefit after adequate titration should be discontinued from ezogabine. Testing of visual function should be done at baseline and every 6 months during therapy with ezogabine. Patients who cannot be monitored should usually not be treated with ezogabine. If retinal pigmentary abnormalities or vision changes are detected, ezogabine should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss. ### Dosing in Specific Populations - No adjustment in dosage is required for patients with mild renal or hepatic impairment (see Table 1). Dosage adjustment is required in geriatric and patients with moderate and greater renal or hepatic impairment (see Table 1). ### Dosage Forms and Strength - 50 mg, purple, round, film-coated tablets debossed with “RTG 50” on one side. - 200 mg, yellow, oblong, film-coated tablets debossed with “RTG-200” on one side. - 300 mg, green, oblong, film-coated tablets debossed with “RTG-300” on one side. - 400 mg, purple, oblong, film-coated tablets debossed with “RTG-400” on one side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ezogabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ezogabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and effectiveness of ezogabine in patients under 18 years of age have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ezogabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ezogabine in pediatric patients. # Contraindications - None. # Warnings ### Retinal Abnormalities and Potential Vision Loss - Ezogabine can cause abnormalities of the retina. The abnormalities seen in patients treated with ezogabine have funduscopic features similar to those seen in retinal pigment dystrophies that are known to result in damage to photoreceptors and vision loss. - The retinal abnormalities observed with ezogabine have been reported in patients who were originally enrolled in clinical trials with ezogabine and who have generally taken the drug for a long period of time in 2 ongoing extension studies. Approximately one third of the patients who had eye examinations performed after approximately 4 years of treatment were found to have retinal pigmentary abnormalities. However, an earlier onset cannot be ruled out, and it is possible that retinal abnormalities were present earlier in the course of exposure to ezogabine. Ezogabine causes skin, scleral, nail, and mucous membrane discoloration and it is not clear whether this discoloration is related to retinal abnormalities. Approximately 15% of patients with retinal pigmentary abnormalities had no such discoloration. - Funduscopic abnormalities have most commonly been described as perivascular pigmentation (bone spicule pattern) in the retinal periphery and/or as areas of focal retinal pigment epithelium clumping. Although some of the patients with retinal abnormalities have been found to have abnormal visual acuity, it is not possible to assess whether ezogabine caused their decreased visual acuity, as baseline assessments are not available for these patients. Two patients with retinal abnormalities have had more extensive diagnostic retinal evaluations. The results of these evaluations were consistent with a retinal dystrophy, including abnormalities in the electroretinogram and electrooculogram of both patients, with abnormal fluorescein angiography and diminished sensitivity on visual field testing in one patient. - The rate of progression of retinal abnormalities and the reversibility after drug discontinuation are unknown. - Because of the observed ophthalmologic adverse reactions, ezogabine should only be used in patients who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential vision loss. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from ezogabine. - Patients should have baseline ophthalmologic testing by an ophthalmic professional and follow-up testing every 6 months. The best method of detection of these abnormalities and the optimal frequency of periodic ophthalmologic monitoring are unknown. Patients who cannot be monitored should usually not be treated with ezogabine. The ophthalmologic monitoring program should include visual acuity testing and dilated fundus photography. Additional testing may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). If retinal pigmentary abnormalities or vision changes are detected, ezogabine should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss. ### Urinary Retention - Ezogabine caused Urinary Retention in clinical trials. Urinary retention was generally reported within the first 6 months of treatment, but was also observed later. Urinary retention was reported as an adverse event in 29 of 1,365 (approximately 2%) patients treated with ezogabine in the open-label and placebo-controlled epilepsy database. Of these 29 patients, 5 (17%) required catheterization, with post-voiding residuals of up to 1,500 mL. ezogabine was discontinued in 4 patients who required catheterization. Following discontinuation, these 4 patients were able to void spontaneously; however, 1 of the 4 patients continued intermittent self-catheterization. A fifth patient continued treatment with ezogabine and was able to void spontaneously after catheter removal. Hydronephrosis occurred in 2 patients, one of whom had associated renal function impairment that resolved upon discontinuation of ezogabine. Hydronephrosis was not reported in placebo patients. - In the placebo-controlled epilepsy trials, “Urinary Retention,” “urinary hesitation,” and “dysuria” were reported in 0.9%, 2.2%, and 2.3% of patients on ezogabine, respectively, and in 0.5%, 0.9%, and 0.7% of patients on placebo, respectively. - Because of the increased risk of Urinary Retention on ezogabine, urologic symptoms should be carefully monitored. Closer monitoring is recommended for patients who have other risk factors for urinary retention (e.g., benign prostatic hyperplasia ), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). In these patients, a comprehensive evaluation of urologic symptoms prior to and during treatment with ezogabine may be appropriate. ### Skin Discoloration - Ezogabine can cause skin discoloration. The skin discoloration is generally described as blue, but has also been described as grey-blue or brown. It is predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Discoloration of the palate, sclera, and conjunctiva has also been reported. - Approximately 10% of patients in long-term clinical trials developed skin discoloration, generally after 2 or more years of treatment and at higher doses (900 mg or greater) of ezogabine. Among patients in whom the status of both skin, nail, lip, or mucous membrane discoloration and retinal pigmentary abnormalities are reported, approximately a quarter of those with skin, nail, lip, or mucous membrane discoloration had concurrent retinal pigmentary abnormalities. - Information on the consequences, reversibility, time to onset, and pathophysiology of the skin abnormalities remains incomplete. The possibility of more extensive systemic involvement has not been excluded. If a patient develops skin discoloration, serious consideration should be given to changing to an alternate medication. ### Neuro-Psychiatric Symptoms - confusional state, psychotic symptoms, and Hallucinations were reported more frequently as adverse reactions in patients treated with ezogabine than in those treated with placebo in placebo-controlled epilepsy trials (see Table 2). Discontinuations resulting from these reactions were more common in the drug-treated group (see Table 2). These effects were dose-related and generally appeared within the first 8 weeks of treatment. Half of the patients in the controlled trials who discontinued ezogabine due to hallucinations or psychosis required hospitalization. Approximately two-thirds of patients with psychosis in controlled trials had no prior psychiatric history. The psychiatric symptoms in the vast majority of patients in both controlled and open-label trials resolved within 7 days of discontinuation of ezogabine. Rapid titration at greater than the recommended doses appeared to increase the risk of psychosis and hallucinations. ### Dizziness and Somnolence - Ezogabine causes dose-related increases in dizziness and somnolence. In placebo-controlled trials in patients with epilepsy, dizziness was reported in 23% of patients treated with ezogabine and 9% of patients treated with placebo. Somnolence was reported in 22% of patients treated with ezogabine and 12% of patients treated with placebo. In these trials 6% of patients on ezogabine and 1.2% on placebo discontinued treatment because of dizziness; 3% of patients on ezogabine and <1.0% on placebo discontinued because of somnolence. - Most of these adverse reactions were mild to moderate in intensity and occurred during the titration phase. For those patients continued on ezogabine, dizziness and somnolence appeared to diminish with continued use. ### QT Interval Effect - A study of cardiac conduction showed that ezogabine produced a mean 7.7-msec QT prolongation in healthy volunteers titrated to 400 mg 3 times daily. The QT-prolonging effect occurred within 3 hours. The QT interval should be monitored when ezogabine is prescribed with medicines known to increase QT interval and in patients with known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia. ### Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including ezogabine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive-therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval : 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis - The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications. - Anyone considering prescribing ezogabine or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Withdrawal Seizures - As with all AEDs, when ezogabine is discontinued, it should be withdrawn gradually when possible to minimize the potential of increased seizure frequency. The dosage of ezogabine should be reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and for varying durations, adverse reaction frequencies observed in the clinical trials of a drug cannot be directly compared with frequencies in the clinical trials of another drug and may not reflect the frequencies observed in practice. - Ezogabine was administered as adjunctive therapy to 1,365 patients with epilepsy in all controlled and uncontrolled clinical studies during the premarketing development. A total of 801 patients were treated for at least 6 months, 585 patients were treated for 1 year or longer, and 311 patients were treated for at least 2 years. - Adverse Reactions Leading to Discontinuation in All Controlled Clinical Studies: In the 3 randomized, double-blind, placebo-controlled studies, 199 of 813 patients (25%) receiving ezogabine and 45 of 427 patients (11%) receiving placebo discontinued treatment because of adverse reactions. The most common adverse reactions leading to withdrawal in patients receiving ezogabine were dizziness (6%), confusional state (4%), fatigue (3%), and somnolence (3%). - Common Adverse Reactions in All Controlled Clinical Studies: Overall, the most frequently reported adverse reactions in patients receiving ezogabine (≥4% and occurring approximately twice the placebo rate) were dizziness (23%), somnolence (22%), fatigue (15%), confusional state (9%), vertigo (8%), tremor (8%), abnormal coordination (7%), diplopia (7%), disturbance in attention (6%), memory impairment (6%), asthenia (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disorder (4%). In most cases the reactions were of mild or moderate intensity. - Table 4. Adverse Reaction Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients With Partial Onset seizures (Adverse reactions in at least 2% of patients treated with ezogabine in any treatment group and numerically more frequent than in the placebo group.) - Other adverse reactions reported in these 3 studies in <2% of patients treated with ezogabine and numerically greater than placebo were increased appetite, Hallucinations, myoclonus, peripheral edema, hypokinesia, dry mouth, dysphagia, hyperhydrosis, Urinary Retention, malaise, and increased liver enzymes. - Most of the adverse reactions appear to be dose related (especially those classified as psychiatric and nervous system symptoms), including dizziness, somnolence, confusional state, tremor, abnormal coordination, memory impairment, blurred vision, gait disturbance, aphasia, balance disorder, constipation, dysuria, and chromaturia. - Ezogabine was associated with dose-related weight gain, with mean weight increasing by 0.2 kg, 1.2 kg, 1.6 kg, and 2.7 kg in the placebo, 600 mg per day, 900 mg per day, and 1,200 mg per day groups, respectively. - Additional Adverse Reactions Observed During All Phase 2 and 3 Clinical Trials: Following is a list of adverse reactions reported by patients treated with ezogabine during all clinical trials: rash, nystagmus, dyspnea, leukopenia, muscle spasms, alopecia, nephrolithiasis, syncope, neutropenia, thrombocytopenia, euphoric mood, renal colic, coma, encephalopathy. - Comparison of Gender, Age, and Race: The overall adverse reaction profile of ezogabine was similar for females and males. - There are insufficient data to support meaningful analyses of adverse reactions by age or race. Approximately 86% of the population studied was Caucasian, and 0.8% of the population was older than 65 years. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience. # Drug Interactions ### Antiepileptic Drugs - The potentially significant interactions between ezogabine and concomitant AEDs are summarized in Table 5. ### Digoxin - Data from an in vitro study showed that the N-acetyl metabolite of ezogabine (NAMR) inhibited P-glycoprotein–mediated transport of digoxin in a concentration-dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of ezogabine at therapeutic doses may increase digoxin serum concentrations. Serum levels of digoxin should be monitored. ### Alcohol - Alcohol increased systemic exposure to ezogabine. Patients should be advised of possible worsening of ezogabine’s general dose-related adverse reactions if they take ezogabine with alcohol. ### Laboratory Tests - Ezogabine has been shown to interfere with clinical laboratory assays of both serum and urine bilirubin, which can result in falsely elevated readings. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. ezogabine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In animal studies, doses associated with maternal plasma exposures (AUC) to ezogabine and its major circulating metabolite, NAMR, similar to or below those expected in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day produced developmental toxicity when administered to pregnant rats and rabbits. The maximum doses evaluated were limited by maternal toxicity (acute neurotoxicity). - Treatment of pregnant rats with ezogabine (oral doses of up to 46 mg/kg/day) throughout organogenesis increased the incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rats (21 mg/kg/day) was associated with maternal plasma exposures (AUC) to ezogabine and NAMR less than those in humans at the MRHD. Treatment of pregnant rabbits with ezogabine (oral doses of up to 60 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rabbits (12 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD. - Administration of ezogabine (oral doses of up to 61.9 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased pre- and postnatal mortality, decreased body weight gain, and delayed reflex development in the offspring. The no-effect dose for pre- and postnatal developmental effects in rats (17.8 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD. - Pregnancy Registry: To provide information regarding the effects of in utero exposure to ezogabine, physicians are advised to recommend that pregnant patients taking ezogabine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website www.aedpregnancyregistry.org. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ezogabine in women who are pregnant. ### Labor and Delivery - The effects of ezogabine on labor and delivery in humans are unknown. ### Nursing Mothers - It is not known whether ezogabine is excreted in human milk. However, ezogabine and/or its metabolites are present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from ezogabine, 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 ezogabine in patients under 18 years of age have not been established. - In juvenile animal studies, increased sensitivity to acute neurotoxicity and urinary bladder toxicity was observed in young rats compared to adults. In studies in which rats were dosed starting on postnatal day 7, ezogabine-related mortality, clinical signs of neurotoxicity, and renal and urinary tract toxicities were observed at doses ≥2 mg/kg/day. The no-effect level was associated with plasma ezogabine exposures (AUC) less than those expected in human adults at the MRHD of 1,200 mg per day. In studies in which dosing began on postnatal day 28, acute central nervous system effects, but no apparent renal or urinary tract effects, were observed at doses of up to 30 mg/kg/day. These doses were associated with plasma ezogabine exposures less than those achieved clinically at the MRHD. ### Geriatic Use - There were insufficient numbers of elderly patients enrolled in partial-onset seizure controlled trials (n = 8 patients on ezogabine) to determine the safety and efficacy of ezogabine in this population. Dosage adjustment is recommended in patients aged 65 years and older. - Ezogabine may cause Urinary Retention. Elderly men with symptomatic BPH may be at increased risk for urinary retention. ### Gender There is no FDA guidance on the use of Ezogabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ezogabine with respect to specific racial populations. ### Renal Impairment - Dosage adjustment is recommended for patients with creatinine clearance <50 mL/min or patients with end-stage renal disease (ESRD) receiving dialysis treatments. ### Hepatic Impairment - No dosage adjustment is required for patients with mild hepatic impairment. - In patients with moderate or severe hepatic impairment, the initial and maintenance dosage of ezogabine should be reduced. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ezogabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ezogabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral. ### Monitoring - All patients taking ezogabine should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity and dilated fundus photography. - Closer monitoring is recommended for patients who have other risk factors for Urinary Retention (e.g., benign prostatic hyperplasia ), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). - Monitoring of cardiac rhythm and vital sign measurement is recommended in management of overdose. # IV Compatibility - There is limited information regarding IV Compatibility. # Overdosage ### Signs, Symptoms, and Laboratory Findings - There is limited experience of overdose with ezogabine. Total daily doses of ezogabine over 2,500 mg were reported during clinical trials. In addition to adverse reactions seen at therapeutic doses, symptoms reported with ezogabine overdose included agitation, aggressive behavior, and irritability. There were no reported sequelae. - In an abuse potential study, cardiac arrhythmia (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of receiving a single 900-mg dose of ezogabine. The arrhythmias spontaneously resolved and both volunteers recovered without sequelae. ### Management of Overdose - There is no specific antidote for overdose with ezogabine. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with ezogabine. # Pharmacology ## Mechanism of Action - The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents. ## Structure - The chemical name of ezogabine is N- carbamic acid ethyl ester, and it has the following structure: - The empirical formula is C16H18FN3O2, representing a molecular weight of 303.3. Ezogabine is a white to slightly colored, odorless, tasteless, crystalline powder. At room temperature, ezogabine is practically insoluble in aqueous media at pH values above 4, while the solubility is higher in polar organic solvents. At gastric pH, ezogabine is sparingly soluble in water (about 16 g/L). The pKa is approximately 3.7 (basic). - Ezogabine is supplied for oral administration as 50-mg, 200-mg, 300-mg, and 400-mg film-coated immediate-release tablets. Each tablet contains the labeled amount of ezogabine and the following inactive ingredients: carmine (50-mg and 400-mg tablets), croscarmellose sodium, FD&C Blue No. 2 (50-mg, 300-mg, and 400-mg tablets), hypromellose, iron oxide yellow (200‑mg and 300-mg tablets), lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum. ## Pharmacodynamics - The QTc prolongation risk of ezogabine was evaluated in healthy subjects. In a randomized, double-blind, active- and placebo-controlled parallel-group study, 120 healthy subjects (40 in each group) were administered ezogabine titrated up to the final dose of 400 mg 3 times daily, placebo, and placebo and moxifloxacin (on day 22). After 22 days of dosing, the maximum mean (upper 1-sided, 95% CI) increase of baseline- and placebo-adjusted QTc interval based on Fridericia correction method (QTcF) was 7.7 msec (11.9 msec) and was observed at 3 hours after dosing in subjects who achieved 1,200 mg per day. No effects on heart rate, PR, or QRS intervals were noted. - Patients who are prescribed ezogabine with medicines known to increase QT interval or who have known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia should be observed closely. ## Pharmacokinetics - The pharmacokinetic profile is approximately linear in daily doses between 600 mg and 1,200 mg in patients with epilepsy, with no unexpected accumulation following repeated administration. The pharmacokinetics of ezogabine are similar in healthy volunteers and patients with epilepsy. - Absorption: After both single and multiple oral doses, ezogabine is rapidly absorbed with median time to maximum plasma concentration (Tmax) values generally between 0.5 and 2 hours. Absolute oral bioavailability of ezogabine relative to an intravenous dose of ezogabine is approximately 60%. High-fat food does not affect the extent to which ezogabine is absorbed based on plasma AUC values, but it increases peak concentration (Cmax) by approximately 38% and delays Tmax by 0.75 hour. - Ezogabine can be taken with or without food. - Distribution: Data from in vitro studies indicate that ezogabine and NAMR are approximately 80% and 45% bound to plasma protein, respectively. Clinically significant interactions with other drugs through displacement from proteins are not anticipated. The steady-state volume of distribution of ezogabine is 2 to 3 L/kg following intravenous dosing, suggesting that ezogabine is well distributed in the body. - Metabolism: Ezogabine is extensively metabolized primarily via glucuronidation and acetylation in humans. A substantial fraction of the ezogabine dose is converted to inactive N-glucuronides, the predominant circulating metabolites in humans. Ezogabine is also metabolized to NAMR that is also subsequently glucuronidated. NAMR has antiepileptic activity, but it is less potent than ezogabine in animal seizure models. Additional minor metabolites of ezogabine are an N-glucoside of ezogabine and a cyclized metabolite believed to be formed from NAMR. In vitro studies using human biomaterials showed that the N-acetylation of ezogabine was primarily carried out by NAT2, while glucuronidation was primarily carried out by UGT1A4, with contributions by UGT1A1, UGT1A3, and UGT1A9. - In vitro studies showed no evidence of oxidative metabolism of ezogabine or NAMR by cytochrome P450 enzymes. Coadministration of ezogabine with medications that are inhibitors or inducers of cytochrome P450 enzymes is therefore unlikely to affect the pharmacokinetics of ezogabine or NAMR. - Elimination: Results of a mass balance study suggest that renal excretion is the major route of elimination for ezogabine and NAMR. About 85% of the dose was recovered in the urine, with the unchanged parent drug and NAMR accounting for 36% and 18% of the administered dose, respectively, and the total N-glucuronides of ezogabine and NAMR accounting for 24% of the administered dose. Approximately 14% of the radioactivity was recovered in the feces, with unchanged ezogabine accounting for 3% of the total dose. Average total recovery in both urine and feces within 240 hours after dosing is approximately 98%. - Ezogabine and its N-acetyl metabolite have similar elimination half-lives (t½) of 7 to 11 hours. The clearance of ezogabine following intravenous dosing was approximately 0.4 to 0.6 L/hr/kg. Ezogabine is actively secreted into the urine. - Specific Populations: Race: No study has been conducted to investigate the impact of race on pharmacokinetics of ezogabine. A population pharmacokinetic analysis comparing Caucasians and non-Caucasians (predominately African American and Hispanic patients) showed no significant pharmacokinetic difference. No adjustment of the ezogabine dose for race is recommended. - Gender: The impact of gender on the pharmacokinetics of ezogabine was examined following a single dose of ezogabine to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. The AUC values were approximately 20% higher in young females compared to young males and approximately 30% higher in elderly females compared to elderly males. The Cmax values were approximately 50% higher in young females compared to young males and approximately 100% higher in elderly females compared to elderly males. There was no gender difference in weight-normalized clearance. Overall, no adjustment of the dosage of ezogabine is recommended based on gender. - Pediatric Patients: The pharmacokinetics of ezogabine in pediatric patients have not been investigated. - Geriatric: The impact of age on the pharmacokinetics of ezogabine was examined following a single dose of ezogabine to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. Systemic exposure (AUC) of ezogabine was approximately 40% to 50% higher and terminal half-life was prolonged by approximately 30% in the elderly compared to the younger subjects. The peak concentration (Cmax) was similar to that observed in younger subjects. A dosage reduction in the elderly is recommended. - Renal Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of ezogabine in subjects with normal (CrCL >80 ml/min), mild (CrCL ≥50 to <80 mL/min), moderate (CrCL ≥30 to <50 mL/min), or severe renal impairment (CrCL <30 mL/min) (n = 6 in each cohort) and in subjects with ESRD requiring hemodialysis (n = 6). The ezogabine AUC was increased by approximately 30% in patients with mild renal impairment and doubled in patients with moderate impairment to ESRD (CrCL <50 mL/min) relative to healthy subjects. Similar increases in NAMR exposure were observed in the various degrees of renal impairment. The effect of hemodialysis on ezogabine clearance has not been established. Dosage reduction is recommended for patients with creatinine clearance <50 mL/min and for patients with ESRD receiving dialysis. - Hepatic Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of ezogabine in subjects with normal, mild (Child-Pugh score 5 to 6), moderate (Child-Pugh score 7 to 9), or severe hepatic (Child-Pugh score >9) impairment (n = 6 in each cohort). Relative to healthy subjects, ezogabine AUC was not affected by mild hepatic impairment, but was increased by approximately 50% in subjects with moderate hepatic impairment and doubled in subjects with severe hepatic impairment. There was an increase of approximately 30% in exposure to NAMR in patients with moderate to severe impairment. Dosage reduction is recommended for patients with moderate and severe hepatic impairment. - Drug Interactions: In vitro studies using human liver microsomes indicated that ezogabine does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. Inhibition of CYP2B6 by ezogabine has not been evaluated. In addition, in vitro studies in human primary hepatocytes showed that ezogabine and NAMR did not induce CYP1A2 or CYP3A4/5 activity. Therefore, ezogabine is unlikely to affect the pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through inhibition or induction mechanisms. - Ezogabine is neither a substrate nor an inhibitor of P-glycoprotein, an efflux transporter. NAMR is a P-glycoprotein inhibitor. Data from an in vitro study showed that NAMR inhibited P-glycoprotein–mediated transport of digoxin in a concentration-dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of ezogabine at therapeutic doses may increase digoxin serum concentration. - Interactions with Antiepileptic Drugs: The interactions between ezogabine and concomitant AEDs are summarized in Table 6. - Oral Contraceptives: In one study examining the potential interaction between ezogabine (150 mg 3 times daily for 3 days) and the combination oral contraceptive norgestrel/ethinyl estradiol (0.3 mg/0.03 mg) tablets in 20 healthy females, no significant alteration in the pharmacokinetics of either drug was observed. - In a second study examining the potential interaction of repeated ezogabine dosing (250 mg 3 times daily for 14 days) and the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg) tablets in 25 healthy females, no significant alteration in the pharmacokinetics of either drug was observed. - Alcohol: In a healthy volunteer study, the coadministration of ethanol 1g/kg (5 standard alcohol drinks) over 20 minutes and ezogabine (200 mg) resulted in an increase in the ezogabine Cmax and AUC by 23% and 37%, respectively. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: In a one-year neonatal mouse study of ezogabine (2 single-dose oral administrations of up to 96 mg/kg on postnatal days 8 and 15), a dose-related increase in the frequency of lung neoplasms (bronchioalveolar carcinoma and/or adenoma) was observed in treated males. No evidence of carcinogenicity was observed in rats following oral administration of ezogabine (oral gavage doses of up to 50 mg/kg/day) for 2 years. Plasma exposure (AUC) to ezogabine at the highest doses tested was less than that in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day. - Mutagenesis: Highly purified ezogabine was negative in the in vitro Ames assay, the in vitro Chinese hamster ovary (CHO) Hprt gene mutation assay, and the in vivo mouse micronucleus assay. Ezogabine was positive in the in vitro chromosomal aberration assay in human lymphocytes. The major circulating metabolite of ezogabine, NAMR, was negative in the in vitro Ames assay, but positive in the in vitro chromosomal aberration assay in CHO cells. - Impairment of Fertility: Ezogabine had no effect on fertility, general reproductive performance, or early embryonic development when administered to male and female rats at doses of up to 46.4 mg/kg/day (associated with a plasma ezogabine exposure less than that in humans at the MRHD) prior to and during mating, and continuing in females through gestation day 7. # Clinical Studies - The efficacy of ezogabine as adjunctive therapy in partial-onset seizures was established in 3 multicenter, randomized, double-blind, placebo-controlled studies in 1,239 adult patients. The primary endpoint consisted of the percent change in seizure frequency from baseline in the double-blind treatment phase. - Patients enrolled in the studies had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs, with or without concomitant vagus nerve stimulation. More than 75% of patients were taking 2 or more concomitant AEDs. During an 8-week baseline period, patients experienced at least 4 partial onset seizures per 28 days on average with no seizure-free period exceeding 3 to 4 weeks. Patients had a mean duration of epilepsy of 22 years. Across the 3 studies, the median baseline seizure frequency ranged from 8 to 12 seizures per month. The criteria for statistical significance was P<0.05. - Patients were randomized to the total daily maintenance dosages of 600 mg per day, 900 mg per day, or 1,200 mg per day, each administered in 3 equally divided doses. During the titration phase of all 3 studies, treatment was initiated at 300 mg per day (100 mg 3 times per day) and increased in weekly increments of 150 mg per day to the target maintenance dosage. - Figure 1 shows the median percent reduction in 28-day seizure frequency (baseline to double-blind phase) as compared with placebo across all 3 studies. A statistically significant effect was observed with ezogabine at doses of 600 mg per day (Study 1), at 900 mg per day (Studies 1 and 3), and at 1,200 mg per day (Studies 2 and 3). Figure 1. Median Percent Reduction From Baseline in seizure Frequency per 28 Days by Dose - Figure 2 shows changes from baseline in the 28-day total partial seizure frequency by category for patients treated with ezogabine and placebo in an integrated analysis across the 3 clinical trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in five categories. - Figure 2. Proportion of Patients by Category of Seizure Response for ezogabine and Placebo Across All Three Double-blind Trials # How Supplied - Ezogabine is supplied as film-coated immediate-release tablets for oral administration containing 50 mg, 200 mg, 300 mg, or 400 mg of ezogabine in the following packs: - 50-mg Tablets: purple, round, film-coated tablets debossed with “RTG 50” on one side in bottles of 90 tablets with desiccant (NDC 0173-0810-59). - 200-mg Tablets: yellow, oblong, film-coated tablets debossed with “RTG-200” on one side in bottles of 90 tablets with desiccant (NDC 0173-0812-59). - 300-mg Tablets: green, oblong, film-coated tablets debossed with “RTG-300” on one side in bottles of 90 tablets with desiccant (NDC 0173-0813-59). - 400-mg Tablets: purple, oblong, film-coated tablets debossed with “RTG-400” on one side in bottles of 90 tablets with desiccant (NDC 0173-0814-59). ## Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Retinal Abnormalities and Potential Vision Loss - Inform patients of the risk of retinal abnormalities and possible risk of vision loss, which may be permanent. All patients taking ezogabine should participate in baseline and periodic ophthalmologic monitoring of vision by an ophthalmic professional. Inform patients that if they suspect any vision changes, they should notify their physician immediately. ### Urinary Retention - Patients should be informed that ezogabine can cause Urinary Retention (including urinary hesitation and dysuria). If patients experience any symptoms of urinary retention, inability to urinate, and/or pain with urination, they should be instructed to seek immediate medical assistance. For patients who cannot reliably report symptoms of urinary retention (for example, patients with cognitive impairment), urologic consultation may be helpful. ### Skin Discoloration - Inform patients that ezogabine can cause discoloration of nails, lips, skin, palate, and parts of the eye and that it is not known if the discoloration is reversible upon drug discontinuation. Most skin discoloration has been reported after at least 2 years of treatment with ezogabine, but may happen earlier. Inform patients that the possibility of more extensive systemic involvement has not been excluded. Instruct patients to notify their physician if they develop skin discoloration. ### Psychiatric Symptoms - Patients should be informed that ezogabine can cause psychiatric symptoms such as confusional state, disorientation, hallucinations, and other symptoms of psychosis. Patients and their caregivers should be instructed to notify their physicians if they experience psychotic symptoms. ### Central Nervous System Effects - Patients should be informed that ezogabine may cause dizziness, somnolence, memory impairment, abnormal coordination/balance, disturbance in attention, and ophthalmological effects such as diplopia or blurred vision. Patients taking ezogabine should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with ezogabine. ### Suicidal Thinking and Behavior - Patients, their caregivers, and families should be informed that AEDs, including ezogabine, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Pregnancy - Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant. - Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry collects information about the safety of AEDs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. # Precautions with Alcohol - Alcohol-Ezogabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - POTIGA® # Look-Alike Drug Names There is limited information regarding Look-Alike Drug Names. # Drug Shortage Status # Price	Ezogabine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, 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 Ezogabine is a potassium channel opener that is FDA approved for the treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, somnolence, fatigue, confusional state, vertigo, tremor, abnormal coordination, diplopia, disturbance in attention, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications - Ezogabine is indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity. ## Dosage ### Dosing Information - The initial dosage should be 100 mg 3 times daily (300 mg per day). The dosage should be increased gradually at weekly intervals by no more than 50 mg 3 times daily (increase in the daily dose of no more than 150 mg per day) up to a maintenance dosage of 200 mg to 400 mg 3 times daily (600 mg to 1,200 mg per day), based on individual patient response and tolerability. This information is summarized in Table 1 under Dosing in Specific Populations. In the controlled clinical trials, 400 mg 3 times daily showed limited evidence of additional improvement in seizure reduction, but an increase in adverse events and discontinuations, compared to the 300 mg 3 times daily dosage. The safety and efficacy of doses greater than 400 mg 3 times daily (1,200 mg per day) have not been examined in controlled trials. - Ezogabine should be given orally in 3 equally divided doses daily, with or without food. - Ezogabine Tablets should be swallowed whole. - If ezogabine is discontinued, the dosage should be gradually reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal. ### Dosing Considerations to Mitigate the Risk of Visual Adverse Reactions - Because ezogabine may cause retinal abnormalities with long-term use, patients who fail to show substantial clinical benefit after adequate titration should be discontinued from ezogabine. Testing of visual function should be done at baseline and every 6 months during therapy with ezogabine. Patients who cannot be monitored should usually not be treated with ezogabine. If retinal pigmentary abnormalities or vision changes are detected, ezogabine should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss. ### Dosing in Specific Populations - No adjustment in dosage is required for patients with mild renal or hepatic impairment (see Table 1). Dosage adjustment is required in geriatric and patients with moderate and greater renal or hepatic impairment (see Table 1). ### Dosage Forms and Strength - 50 mg, purple, round, film-coated tablets debossed with “RTG 50” on one side. - 200 mg, yellow, oblong, film-coated tablets debossed with “RTG-200” on one side. - 300 mg, green, oblong, film-coated tablets debossed with “RTG-300” on one side. - 400 mg, purple, oblong, film-coated tablets debossed with “RTG-400” on one side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ezogabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ezogabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and effectiveness of ezogabine in patients under 18 years of age have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ezogabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ezogabine in pediatric patients. # Contraindications - None. # Warnings ### Retinal Abnormalities and Potential Vision Loss - Ezogabine can cause abnormalities of the retina. The abnormalities seen in patients treated with ezogabine have funduscopic features similar to those seen in retinal pigment dystrophies that are known to result in damage to photoreceptors and vision loss. - The retinal abnormalities observed with ezogabine have been reported in patients who were originally enrolled in clinical trials with ezogabine and who have generally taken the drug for a long period of time in 2 ongoing extension studies. Approximately one third of the patients who had eye examinations performed after approximately 4 years of treatment were found to have retinal pigmentary abnormalities. However, an earlier onset cannot be ruled out, and it is possible that retinal abnormalities were present earlier in the course of exposure to ezogabine. Ezogabine causes skin, scleral, nail, and mucous membrane discoloration and it is not clear whether this discoloration is related to retinal abnormalities. Approximately 15% of patients with retinal pigmentary abnormalities had no such discoloration. - Funduscopic abnormalities have most commonly been described as perivascular pigmentation (bone spicule pattern) in the retinal periphery and/or as areas of focal retinal pigment epithelium clumping. Although some of the patients with retinal abnormalities have been found to have abnormal visual acuity, it is not possible to assess whether ezogabine caused their decreased visual acuity, as baseline assessments are not available for these patients. Two patients with retinal abnormalities have had more extensive diagnostic retinal evaluations. The results of these evaluations were consistent with a retinal dystrophy, including abnormalities in the electroretinogram and electrooculogram of both patients, with abnormal fluorescein angiography and diminished sensitivity on visual field testing in one patient. - The rate of progression of retinal abnormalities and the reversibility after drug discontinuation are unknown. - Because of the observed ophthalmologic adverse reactions, ezogabine should only be used in patients who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential vision loss. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from ezogabine. - Patients should have baseline ophthalmologic testing by an ophthalmic professional and follow-up testing every 6 months. The best method of detection of these abnormalities and the optimal frequency of periodic ophthalmologic monitoring are unknown. Patients who cannot be monitored should usually not be treated with ezogabine. The ophthalmologic monitoring program should include visual acuity testing and dilated fundus photography. Additional testing may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). If retinal pigmentary abnormalities or vision changes are detected, ezogabine should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss. ### Urinary Retention - Ezogabine caused Urinary Retention in clinical trials. Urinary retention was generally reported within the first 6 months of treatment, but was also observed later. Urinary retention was reported as an adverse event in 29 of 1,365 (approximately 2%) patients treated with ezogabine in the open-label and placebo-controlled epilepsy database. Of these 29 patients, 5 (17%) required catheterization, with post-voiding residuals of up to 1,500 mL. ezogabine was discontinued in 4 patients who required catheterization. Following discontinuation, these 4 patients were able to void spontaneously; however, 1 of the 4 patients continued intermittent self-catheterization. A fifth patient continued treatment with ezogabine and was able to void spontaneously after catheter removal. Hydronephrosis occurred in 2 patients, one of whom had associated renal function impairment that resolved upon discontinuation of ezogabine. Hydronephrosis was not reported in placebo patients. - In the placebo-controlled epilepsy trials, “Urinary Retention,” “urinary hesitation,” and “dysuria” were reported in 0.9%, 2.2%, and 2.3% of patients on ezogabine, respectively, and in 0.5%, 0.9%, and 0.7% of patients on placebo, respectively. - Because of the increased risk of Urinary Retention on ezogabine, urologic symptoms should be carefully monitored. Closer monitoring is recommended for patients who have other risk factors for urinary retention (e.g., benign prostatic hyperplasia [BPH]), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). In these patients, a comprehensive evaluation of urologic symptoms prior to and during treatment with ezogabine may be appropriate. ### Skin Discoloration - Ezogabine can cause skin discoloration. The skin discoloration is generally described as blue, but has also been described as grey-blue or brown. It is predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Discoloration of the palate, sclera, and conjunctiva has also been reported. - Approximately 10% of patients in long-term clinical trials developed skin discoloration, generally after 2 or more years of treatment and at higher doses (900 mg or greater) of ezogabine. Among patients in whom the status of both skin, nail, lip, or mucous membrane discoloration and retinal pigmentary abnormalities are reported, approximately a quarter of those with skin, nail, lip, or mucous membrane discoloration had concurrent retinal pigmentary abnormalities. - Information on the consequences, reversibility, time to onset, and pathophysiology of the skin abnormalities remains incomplete. The possibility of more extensive systemic involvement has not been excluded. If a patient develops skin discoloration, serious consideration should be given to changing to an alternate medication. ### Neuro-Psychiatric Symptoms - confusional state, psychotic symptoms, and Hallucinations were reported more frequently as adverse reactions in patients treated with ezogabine than in those treated with placebo in placebo-controlled epilepsy trials (see Table 2). Discontinuations resulting from these reactions were more common in the drug-treated group (see Table 2). These effects were dose-related and generally appeared within the first 8 weeks of treatment. Half of the patients in the controlled trials who discontinued ezogabine due to hallucinations or psychosis required hospitalization. Approximately two-thirds of patients with psychosis in controlled trials had no prior psychiatric history. The psychiatric symptoms in the vast majority of patients in both controlled and open-label trials resolved within 7 days of discontinuation of ezogabine. Rapid titration at greater than the recommended doses appeared to increase the risk of psychosis and hallucinations. ### Dizziness and Somnolence - Ezogabine causes dose-related increases in dizziness and somnolence. In placebo-controlled trials in patients with epilepsy, dizziness was reported in 23% of patients treated with ezogabine and 9% of patients treated with placebo. Somnolence was reported in 22% of patients treated with ezogabine and 12% of patients treated with placebo. In these trials 6% of patients on ezogabine and 1.2% on placebo discontinued treatment because of dizziness; 3% of patients on ezogabine and <1.0% on placebo discontinued because of somnolence. - Most of these adverse reactions were mild to moderate in intensity and occurred during the titration phase. For those patients continued on ezogabine, dizziness and somnolence appeared to diminish with continued use. ### QT Interval Effect - A study of cardiac conduction showed that ezogabine produced a mean 7.7-msec QT prolongation in healthy volunteers titrated to 400 mg 3 times daily. The QT-prolonging effect occurred within 3 hours. The QT interval should be monitored when ezogabine is prescribed with medicines known to increase QT interval and in patients with known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia. ### Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including ezogabine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive-therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis - The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications. - Anyone considering prescribing ezogabine or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Withdrawal Seizures - As with all AEDs, when ezogabine is discontinued, it should be withdrawn gradually when possible to minimize the potential of increased seizure frequency. The dosage of ezogabine should be reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and for varying durations, adverse reaction frequencies observed in the clinical trials of a drug cannot be directly compared with frequencies in the clinical trials of another drug and may not reflect the frequencies observed in practice. - Ezogabine was administered as adjunctive therapy to 1,365 patients with epilepsy in all controlled and uncontrolled clinical studies during the premarketing development. A total of 801 patients were treated for at least 6 months, 585 patients were treated for 1 year or longer, and 311 patients were treated for at least 2 years. - Adverse Reactions Leading to Discontinuation in All Controlled Clinical Studies: In the 3 randomized, double-blind, placebo-controlled studies, 199 of 813 patients (25%) receiving ezogabine and 45 of 427 patients (11%) receiving placebo discontinued treatment because of adverse reactions. The most common adverse reactions leading to withdrawal in patients receiving ezogabine were dizziness (6%), confusional state (4%), fatigue (3%), and somnolence (3%). - Common Adverse Reactions in All Controlled Clinical Studies: Overall, the most frequently reported adverse reactions in patients receiving ezogabine (≥4% and occurring approximately twice the placebo rate) were dizziness (23%), somnolence (22%), fatigue (15%), confusional state (9%), vertigo (8%), tremor (8%), abnormal coordination (7%), diplopia (7%), disturbance in attention (6%), memory impairment (6%), asthenia (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disorder (4%). In most cases the reactions were of mild or moderate intensity. - Table 4. Adverse Reaction Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients With Partial Onset seizures (Adverse reactions in at least 2% of patients treated with ezogabine in any treatment group and numerically more frequent than in the placebo group.) - Other adverse reactions reported in these 3 studies in <2% of patients treated with ezogabine and numerically greater than placebo were increased appetite, Hallucinations, myoclonus, peripheral edema, hypokinesia, dry mouth, dysphagia, hyperhydrosis, Urinary Retention, malaise, and increased liver enzymes. - Most of the adverse reactions appear to be dose related (especially those classified as psychiatric and nervous system symptoms), including dizziness, somnolence, confusional state, tremor, abnormal coordination, memory impairment, blurred vision, gait disturbance, aphasia, balance disorder, constipation, dysuria, and chromaturia. - Ezogabine was associated with dose-related weight gain, with mean weight increasing by 0.2 kg, 1.2 kg, 1.6 kg, and 2.7 kg in the placebo, 600 mg per day, 900 mg per day, and 1,200 mg per day groups, respectively. - Additional Adverse Reactions Observed During All Phase 2 and 3 Clinical Trials: Following is a list of adverse reactions reported by patients treated with ezogabine during all clinical trials: rash, nystagmus, dyspnea, leukopenia, muscle spasms, alopecia, nephrolithiasis, syncope, neutropenia, thrombocytopenia, euphoric mood, renal colic, coma, encephalopathy. - Comparison of Gender, Age, and Race: The overall adverse reaction profile of ezogabine was similar for females and males. - There are insufficient data to support meaningful analyses of adverse reactions by age or race. Approximately 86% of the population studied was Caucasian, and 0.8% of the population was older than 65 years. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience. # Drug Interactions ### Antiepileptic Drugs - The potentially significant interactions between ezogabine and concomitant AEDs are summarized in Table 5. ### Digoxin - Data from an in vitro study showed that the N-acetyl metabolite of ezogabine (NAMR) inhibited P-glycoprotein–mediated transport of digoxin in a concentration-dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of ezogabine at therapeutic doses may increase digoxin serum concentrations. Serum levels of digoxin should be monitored. ### Alcohol - Alcohol increased systemic exposure to ezogabine. Patients should be advised of possible worsening of ezogabine’s general dose-related adverse reactions if they take ezogabine with alcohol. ### Laboratory Tests - Ezogabine has been shown to interfere with clinical laboratory assays of both serum and urine bilirubin, which can result in falsely elevated readings. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. ezogabine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In animal studies, doses associated with maternal plasma exposures (AUC) to ezogabine and its major circulating metabolite, NAMR, similar to or below those expected in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day produced developmental toxicity when administered to pregnant rats and rabbits. The maximum doses evaluated were limited by maternal toxicity (acute neurotoxicity). - Treatment of pregnant rats with ezogabine (oral doses of up to 46 mg/kg/day) throughout organogenesis increased the incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rats (21 mg/kg/day) was associated with maternal plasma exposures (AUC) to ezogabine and NAMR less than those in humans at the MRHD. Treatment of pregnant rabbits with ezogabine (oral doses of up to 60 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rabbits (12 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD. - Administration of ezogabine (oral doses of up to 61.9 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased pre- and postnatal mortality, decreased body weight gain, and delayed reflex development in the offspring. The no-effect dose for pre- and postnatal developmental effects in rats (17.8 mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR less than those in humans at the MRHD. - Pregnancy Registry: To provide information regarding the effects of in utero exposure to ezogabine, physicians are advised to recommend that pregnant patients taking ezogabine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website www.aedpregnancyregistry.org. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ezogabine in women who are pregnant. ### Labor and Delivery - The effects of ezogabine on labor and delivery in humans are unknown. ### Nursing Mothers - It is not known whether ezogabine is excreted in human milk. However, ezogabine and/or its metabolites are present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from ezogabine, 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 ezogabine in patients under 18 years of age have not been established. - In juvenile animal studies, increased sensitivity to acute neurotoxicity and urinary bladder toxicity was observed in young rats compared to adults. In studies in which rats were dosed starting on postnatal day 7, ezogabine-related mortality, clinical signs of neurotoxicity, and renal and urinary tract toxicities were observed at doses ≥2 mg/kg/day. The no-effect level was associated with plasma ezogabine exposures (AUC) less than those expected in human adults at the MRHD of 1,200 mg per day. In studies in which dosing began on postnatal day 28, acute central nervous system effects, but no apparent renal or urinary tract effects, were observed at doses of up to 30 mg/kg/day. These doses were associated with plasma ezogabine exposures less than those achieved clinically at the MRHD. ### Geriatic Use - There were insufficient numbers of elderly patients enrolled in partial-onset seizure controlled trials (n = 8 patients on ezogabine) to determine the safety and efficacy of ezogabine in this population. Dosage adjustment is recommended in patients aged 65 years and older. - Ezogabine may cause Urinary Retention. Elderly men with symptomatic BPH may be at increased risk for urinary retention. ### Gender There is no FDA guidance on the use of Ezogabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ezogabine with respect to specific racial populations. ### Renal Impairment - Dosage adjustment is recommended for patients with creatinine clearance <50 mL/min or patients with end-stage renal disease (ESRD) receiving dialysis treatments. ### Hepatic Impairment - No dosage adjustment is required for patients with mild hepatic impairment. - In patients with moderate or severe hepatic impairment, the initial and maintenance dosage of ezogabine should be reduced. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ezogabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ezogabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral. ### Monitoring - All patients taking ezogabine should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity and dilated fundus photography. - Closer monitoring is recommended for patients who have other risk factors for Urinary Retention (e.g., benign prostatic hyperplasia [BPH]), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). - Monitoring of cardiac rhythm and vital sign measurement is recommended in management of overdose. # IV Compatibility - There is limited information regarding IV Compatibility. # Overdosage ### Signs, Symptoms, and Laboratory Findings - There is limited experience of overdose with ezogabine. Total daily doses of ezogabine over 2,500 mg were reported during clinical trials. In addition to adverse reactions seen at therapeutic doses, symptoms reported with ezogabine overdose included agitation, aggressive behavior, and irritability. There were no reported sequelae. - In an abuse potential study, cardiac arrhythmia (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of receiving a single 900-mg dose of ezogabine. The arrhythmias spontaneously resolved and both volunteers recovered without sequelae. ### Management of Overdose - There is no specific antidote for overdose with ezogabine. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with ezogabine. # Pharmacology ## Mechanism of Action - The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents. ## Structure - The chemical name of ezogabine is N-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester, and it has the following structure: - The empirical formula is C16H18FN3O2, representing a molecular weight of 303.3. Ezogabine is a white to slightly colored, odorless, tasteless, crystalline powder. At room temperature, ezogabine is practically insoluble in aqueous media at pH values above 4, while the solubility is higher in polar organic solvents. At gastric pH, ezogabine is sparingly soluble in water (about 16 g/L). The pKa is approximately 3.7 (basic). - Ezogabine is supplied for oral administration as 50-mg, 200-mg, 300-mg, and 400-mg film-coated immediate-release tablets. Each tablet contains the labeled amount of ezogabine and the following inactive ingredients: carmine (50-mg and 400-mg tablets), croscarmellose sodium, FD&C Blue No. 2 (50-mg, 300-mg, and 400-mg tablets), hypromellose, iron oxide yellow (200‑mg and 300-mg tablets), lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum. ## Pharmacodynamics - The QTc prolongation risk of ezogabine was evaluated in healthy subjects. In a randomized, double-blind, active- and placebo-controlled parallel-group study, 120 healthy subjects (40 in each group) were administered ezogabine titrated up to the final dose of 400 mg 3 times daily, placebo, and placebo and moxifloxacin (on day 22). After 22 days of dosing, the maximum mean (upper 1-sided, 95% CI) increase of baseline- and placebo-adjusted QTc interval based on Fridericia correction method (QTcF) was 7.7 msec (11.9 msec) and was observed at 3 hours after dosing in subjects who achieved 1,200 mg per day. No effects on heart rate, PR, or QRS intervals were noted. - Patients who are prescribed ezogabine with medicines known to increase QT interval or who have known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia should be observed closely. ## Pharmacokinetics - The pharmacokinetic profile is approximately linear in daily doses between 600 mg and 1,200 mg in patients with epilepsy, with no unexpected accumulation following repeated administration. The pharmacokinetics of ezogabine are similar in healthy volunteers and patients with epilepsy. - Absorption: After both single and multiple oral doses, ezogabine is rapidly absorbed with median time to maximum plasma concentration (Tmax) values generally between 0.5 and 2 hours. Absolute oral bioavailability of ezogabine relative to an intravenous dose of ezogabine is approximately 60%. High-fat food does not affect the extent to which ezogabine is absorbed based on plasma AUC values, but it increases peak concentration (Cmax) by approximately 38% and delays Tmax by 0.75 hour. - Ezogabine can be taken with or without food. - Distribution: Data from in vitro studies indicate that ezogabine and NAMR are approximately 80% and 45% bound to plasma protein, respectively. Clinically significant interactions with other drugs through displacement from proteins are not anticipated. The steady-state volume of distribution of ezogabine is 2 to 3 L/kg following intravenous dosing, suggesting that ezogabine is well distributed in the body. - Metabolism: Ezogabine is extensively metabolized primarily via glucuronidation and acetylation in humans. A substantial fraction of the ezogabine dose is converted to inactive N-glucuronides, the predominant circulating metabolites in humans. Ezogabine is also metabolized to NAMR that is also subsequently glucuronidated. NAMR has antiepileptic activity, but it is less potent than ezogabine in animal seizure models. Additional minor metabolites of ezogabine are an N-glucoside of ezogabine and a cyclized metabolite believed to be formed from NAMR. In vitro studies using human biomaterials showed that the N-acetylation of ezogabine was primarily carried out by NAT2, while glucuronidation was primarily carried out by UGT1A4, with contributions by UGT1A1, UGT1A3, and UGT1A9. - In vitro studies showed no evidence of oxidative metabolism of ezogabine or NAMR by cytochrome P450 enzymes. Coadministration of ezogabine with medications that are inhibitors or inducers of cytochrome P450 enzymes is therefore unlikely to affect the pharmacokinetics of ezogabine or NAMR. - Elimination: Results of a mass balance study suggest that renal excretion is the major route of elimination for ezogabine and NAMR. About 85% of the dose was recovered in the urine, with the unchanged parent drug and NAMR accounting for 36% and 18% of the administered dose, respectively, and the total N-glucuronides of ezogabine and NAMR accounting for 24% of the administered dose. Approximately 14% of the radioactivity was recovered in the feces, with unchanged ezogabine accounting for 3% of the total dose. Average total recovery in both urine and feces within 240 hours after dosing is approximately 98%. - Ezogabine and its N-acetyl metabolite have similar elimination half-lives (t½) of 7 to 11 hours. The clearance of ezogabine following intravenous dosing was approximately 0.4 to 0.6 L/hr/kg. Ezogabine is actively secreted into the urine. - Specific Populations: Race: No study has been conducted to investigate the impact of race on pharmacokinetics of ezogabine. A population pharmacokinetic analysis comparing Caucasians and non-Caucasians (predominately African American and Hispanic patients) showed no significant pharmacokinetic difference. No adjustment of the ezogabine dose for race is recommended. - Gender: The impact of gender on the pharmacokinetics of ezogabine was examined following a single dose of ezogabine to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. The AUC values were approximately 20% higher in young females compared to young males and approximately 30% higher in elderly females compared to elderly males. The Cmax values were approximately 50% higher in young females compared to young males and approximately 100% higher in elderly females compared to elderly males. There was no gender difference in weight-normalized clearance. Overall, no adjustment of the dosage of ezogabine is recommended based on gender. - Pediatric Patients: The pharmacokinetics of ezogabine in pediatric patients have not been investigated. - Geriatric: The impact of age on the pharmacokinetics of ezogabine was examined following a single dose of ezogabine to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. Systemic exposure (AUC) of ezogabine was approximately 40% to 50% higher and terminal half-life was prolonged by approximately 30% in the elderly compared to the younger subjects. The peak concentration (Cmax) was similar to that observed in younger subjects. A dosage reduction in the elderly is recommended. - Renal Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of ezogabine in subjects with normal (CrCL >80 ml/min), mild (CrCL ≥50 to <80 mL/min), moderate (CrCL ≥30 to <50 mL/min), or severe renal impairment (CrCL <30 mL/min) (n = 6 in each cohort) and in subjects with ESRD requiring hemodialysis (n = 6). The ezogabine AUC was increased by approximately 30% in patients with mild renal impairment and doubled in patients with moderate impairment to ESRD (CrCL <50 mL/min) relative to healthy subjects. Similar increases in NAMR exposure were observed in the various degrees of renal impairment. The effect of hemodialysis on ezogabine clearance has not been established. Dosage reduction is recommended for patients with creatinine clearance <50 mL/min and for patients with ESRD receiving dialysis. - Hepatic Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of ezogabine in subjects with normal, mild (Child-Pugh score 5 to 6), moderate (Child-Pugh score 7 to 9), or severe hepatic (Child-Pugh score >9) impairment (n = 6 in each cohort). Relative to healthy subjects, ezogabine AUC was not affected by mild hepatic impairment, but was increased by approximately 50% in subjects with moderate hepatic impairment and doubled in subjects with severe hepatic impairment. There was an increase of approximately 30% in exposure to NAMR in patients with moderate to severe impairment. Dosage reduction is recommended for patients with moderate and severe hepatic impairment. - Drug Interactions: In vitro studies using human liver microsomes indicated that ezogabine does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. Inhibition of CYP2B6 by ezogabine has not been evaluated. In addition, in vitro studies in human primary hepatocytes showed that ezogabine and NAMR did not induce CYP1A2 or CYP3A4/5 activity. Therefore, ezogabine is unlikely to affect the pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through inhibition or induction mechanisms. - Ezogabine is neither a substrate nor an inhibitor of P-glycoprotein, an efflux transporter. NAMR is a P-glycoprotein inhibitor. Data from an in vitro study showed that NAMR inhibited P-glycoprotein–mediated transport of digoxin in a concentration-dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of ezogabine at therapeutic doses may increase digoxin serum concentration. - Interactions with Antiepileptic Drugs: The interactions between ezogabine and concomitant AEDs are summarized in Table 6. - Oral Contraceptives: In one study examining the potential interaction between ezogabine (150 mg 3 times daily for 3 days) and the combination oral contraceptive norgestrel/ethinyl estradiol (0.3 mg/0.03 mg) tablets in 20 healthy females, no significant alteration in the pharmacokinetics of either drug was observed. - In a second study examining the potential interaction of repeated ezogabine dosing (250 mg 3 times daily for 14 days) and the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg) tablets in 25 healthy females, no significant alteration in the pharmacokinetics of either drug was observed. - Alcohol: In a healthy volunteer study, the coadministration of ethanol 1g/kg (5 standard alcohol drinks) over 20 minutes and ezogabine (200 mg) resulted in an increase in the ezogabine Cmax and AUC by 23% and 37%, respectively. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: In a one-year neonatal mouse study of ezogabine (2 single-dose oral administrations of up to 96 mg/kg on postnatal days 8 and 15), a dose-related increase in the frequency of lung neoplasms (bronchioalveolar carcinoma and/or adenoma) was observed in treated males. No evidence of carcinogenicity was observed in rats following oral administration of ezogabine (oral gavage doses of up to 50 mg/kg/day) for 2 years. Plasma exposure (AUC) to ezogabine at the highest doses tested was less than that in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day. - Mutagenesis: Highly purified ezogabine was negative in the in vitro Ames assay, the in vitro Chinese hamster ovary (CHO) Hprt gene mutation assay, and the in vivo mouse micronucleus assay. Ezogabine was positive in the in vitro chromosomal aberration assay in human lymphocytes. The major circulating metabolite of ezogabine, NAMR, was negative in the in vitro Ames assay, but positive in the in vitro chromosomal aberration assay in CHO cells. - Impairment of Fertility: Ezogabine had no effect on fertility, general reproductive performance, or early embryonic development when administered to male and female rats at doses of up to 46.4 mg/kg/day (associated with a plasma ezogabine exposure [AUC] less than that in humans at the MRHD) prior to and during mating, and continuing in females through gestation day 7. # Clinical Studies - The efficacy of ezogabine as adjunctive therapy in partial-onset seizures was established in 3 multicenter, randomized, double-blind, placebo-controlled studies in 1,239 adult patients. The primary endpoint consisted of the percent change in seizure frequency from baseline in the double-blind treatment phase. - Patients enrolled in the studies had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs, with or without concomitant vagus nerve stimulation. More than 75% of patients were taking 2 or more concomitant AEDs. During an 8-week baseline period, patients experienced at least 4 partial onset seizures per 28 days on average with no seizure-free period exceeding 3 to 4 weeks. Patients had a mean duration of epilepsy of 22 years. Across the 3 studies, the median baseline seizure frequency ranged from 8 to 12 seizures per month. The criteria for statistical significance was P<0.05. - Patients were randomized to the total daily maintenance dosages of 600 mg per day, 900 mg per day, or 1,200 mg per day, each administered in 3 equally divided doses. During the titration phase of all 3 studies, treatment was initiated at 300 mg per day (100 mg 3 times per day) and increased in weekly increments of 150 mg per day to the target maintenance dosage. - Figure 1 shows the median percent reduction in 28-day seizure frequency (baseline to double-blind phase) as compared with placebo across all 3 studies. A statistically significant effect was observed with ezogabine at doses of 600 mg per day (Study 1), at 900 mg per day (Studies 1 and 3), and at 1,200 mg per day (Studies 2 and 3). Figure 1. Median Percent Reduction From Baseline in seizure Frequency per 28 Days by Dose - Figure 2 shows changes from baseline in the 28-day total partial seizure frequency by category for patients treated with ezogabine and placebo in an integrated analysis across the 3 clinical trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in five categories. - Figure 2. Proportion of Patients by Category of Seizure Response for ezogabine and Placebo Across All Three Double-blind Trials # How Supplied - Ezogabine is supplied as film-coated immediate-release tablets for oral administration containing 50 mg, 200 mg, 300 mg, or 400 mg of ezogabine in the following packs: - 50-mg Tablets: purple, round, film-coated tablets debossed with “RTG 50” on one side in bottles of 90 tablets with desiccant (NDC 0173-0810-59). - 200-mg Tablets: yellow, oblong, film-coated tablets debossed with “RTG-200” on one side in bottles of 90 tablets with desiccant (NDC 0173-0812-59). - 300-mg Tablets: green, oblong, film-coated tablets debossed with “RTG-300” on one side in bottles of 90 tablets with desiccant (NDC 0173-0813-59). - 400-mg Tablets: purple, oblong, film-coated tablets debossed with “RTG-400” on one side in bottles of 90 tablets with desiccant (NDC 0173-0814-59). ## Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature.] # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Retinal Abnormalities and Potential Vision Loss - Inform patients of the risk of retinal abnormalities and possible risk of vision loss, which may be permanent. All patients taking ezogabine should participate in baseline and periodic ophthalmologic monitoring of vision by an ophthalmic professional. Inform patients that if they suspect any vision changes, they should notify their physician immediately. ### Urinary Retention - Patients should be informed that ezogabine can cause Urinary Retention (including urinary hesitation and dysuria). If patients experience any symptoms of urinary retention, inability to urinate, and/or pain with urination, they should be instructed to seek immediate medical assistance. For patients who cannot reliably report symptoms of urinary retention (for example, patients with cognitive impairment), urologic consultation may be helpful. ### Skin Discoloration - Inform patients that ezogabine can cause discoloration of nails, lips, skin, palate, and parts of the eye and that it is not known if the discoloration is reversible upon drug discontinuation. Most skin discoloration has been reported after at least 2 years of treatment with ezogabine, but may happen earlier. Inform patients that the possibility of more extensive systemic involvement has not been excluded. Instruct patients to notify their physician if they develop skin discoloration. ### Psychiatric Symptoms - Patients should be informed that ezogabine can cause psychiatric symptoms such as confusional state, disorientation, hallucinations, and other symptoms of psychosis. Patients and their caregivers should be instructed to notify their physicians if they experience psychotic symptoms. ### Central Nervous System Effects - Patients should be informed that ezogabine may cause dizziness, somnolence, memory impairment, abnormal coordination/balance, disturbance in attention, and ophthalmological effects such as diplopia or blurred vision. Patients taking ezogabine should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with ezogabine. ### Suicidal Thinking and Behavior - Patients, their caregivers, and families should be informed that AEDs, including ezogabine, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Pregnancy - Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant. - Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry collects information about the safety of AEDs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. # Precautions with Alcohol - Alcohol-Ezogabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - POTIGA®[2] # Look-Alike Drug Names There is limited information regarding Look-Alike Drug Names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ezogabine
cef116b792e4c8331fe8c660c27d07e01957dba0	wikidoc	F-plasmid	F-plasmid # Overview The Fertility factor (also known as F factor or sex factor) is a bacterial DNA sequence that allows a bacterium to produce a sex pilus necessary for conjugation. It contains 20 tra (for "transfer") genes and a number of other genetic sequences responsible for incompatibility, replication, and other functions. The F factor is an episome and can exist as an independent plasmid or integrate into the bacterial cell's genome. There are several names for the possible states: - Hfr bacteria possess F factor integrated into the bacterial genome. - F+ bacteria possess F factor as a plasmid independent of the bacterial genome. The F plasmid contains only F factor DNA and no DNA from the bacterial genome. - F' (F-prime) bacteria possess an F plasmid that also includes some DNA taken from the bacterial genome. - F- bacteria do not contain F factor. When an F+ cell conjugates with an F− cell, the result is two F+ cells, both capable of transmitting the plasmid further by conjugation. In the case of Hfr, the result are two Hfr cells. When F-prime plasmids are transferred to a recipient bacterial cell, they carry pieces of the donor's DNA that can become important in recombination. Bioengineers have created F plasmids that can contain inserted foreign DNA; this is called a fosmid. de:F-Plasmid	F-plasmid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Fertility factor (also known as F factor or sex factor) is a bacterial DNA sequence that allows a bacterium to produce a sex pilus necessary for conjugation. It contains 20 tra (for "transfer") genes and a number of other genetic sequences responsible for incompatibility, replication, and other functions. The F factor is an episome and can exist as an independent plasmid or integrate into the bacterial cell's genome. There are several names for the possible states: - Hfr bacteria possess F factor integrated into the bacterial genome. - F+ bacteria possess F factor as a plasmid independent of the bacterial genome. The F plasmid contains only F factor DNA and no DNA from the bacterial genome. - F' (F-prime) bacteria possess an F plasmid that also includes some DNA taken from the bacterial genome. - F- bacteria do not contain F factor. When an F+ cell conjugates with an F− cell, the result is two F+ cells, both capable of transmitting the plasmid further by conjugation. In the case of Hfr, the result are two Hfr cells. When F-prime plasmids are transferred to a recipient bacterial cell, they carry pieces of the donor's DNA that can become important in recombination. Bioengineers have created F plasmids that can contain inserted foreign DNA; this is called a fosmid. de:F-Plasmid Template:WikiDoc Sources	https://www.wikidoc.org/index.php/F-plasmid
866a7423c332b0300d4127e8d842aa743d808a57	wikidoc	FMRFamide	FMRFamide FMRFamide (Phe-Met-Arg-Phe-NH2) is a neuropeptide from a broad family of FMRFamide-related peptides (FaRPs) all sharing an -RFamide sequence at their C-terminus. First identified in Hard clam Mercenaria mercenaria it is thought to play an important role in cardiac activity regulation. In Mercenaria mercenaria, FMRFamide has been isolated and demonstrated to increase both the force and frequency of the heartbeat through a biochemical pathway that is thought to involve the increase of cytoplasmic cAMP in the ventricular region (Higgins et al., 1978). FMRFamide is an important neuropeptide in several phyla such as Insecta, Nematoda, Mollusca and Annelida. It is the most abundant neuropeptide in endocrine cells of insect alimentary tracts along with allatostatin and tachykinin families, however the neuropeptide’s function is not known. Generally, the neuropeptide is encoded by several genes such as flp-1 through flp-22 in C. elegans. The common precursor of the FaRPs is modified to yield many different neuropeptides all having the same FMRFamide sequence. Moreover, these peptides are not functionally redundant . In invertebrates, the FMFRamide-related peptides are known to affect heart rate, blood pressure, gut motility, feeding behaviour and reproduction. In vertebrates such as mice, they are known to affect opioid receptors resulting in elicitation of naloxone-sensitive antinociception and reduction of morphine-induced antinociception .	FMRFamide FMRFamide (Phe-Met-Arg-Phe-NH2) is a neuropeptide from a broad family of FMRFamide-related peptides (FaRPs) all sharing an -RFamide sequence at their C-terminus. First identified in Hard clam Mercenaria mercenaria it is thought to play an important role in cardiac activity regulation. In Mercenaria mercenaria, FMRFamide has been isolated and demonstrated to increase both the force and frequency of the heartbeat through a biochemical pathway that is thought to involve the increase of cytoplasmic cAMP in the ventricular region (Higgins et al., 1978). FMRFamide is an important neuropeptide in several phyla such as Insecta, Nematoda, Mollusca and Annelida[1]. It is the most abundant neuropeptide in endocrine cells of insect alimentary tracts along with allatostatin and tachykinin families, however the neuropeptide’s function is not known. Generally, the neuropeptide is encoded by several genes such as flp-1 through flp-22 in C. elegans. The common precursor of the FaRPs is modified to yield many different neuropeptides all having the same FMRFamide sequence. Moreover, these peptides are not functionally redundant [2]. In invertebrates, the FMFRamide-related peptides are known to affect heart rate, blood pressure, gut motility, feeding behaviour and reproduction. In vertebrates such as mice, they are known to affect opioid receptors resulting in elicitation of naloxone-sensitive antinociception and reduction of morphine-induced antinociception [3].	https://www.wikidoc.org/index.php/FMRFamide
cc46f58470cc32227225a5dd88ab4ce8419584cf	wikidoc	Face time	Face time # Overview Face time is interaction or contact between two or more people at the same time and physical location. Face time therefore occurs in "real life" or "meatspace" and contrasts primarily with interaction or contact which occurs over distance (eg. via telephone) and/or electronically (eg. via email, instant messaging, e-commerce, or computer simulations). The term was originally a colloquialism but has entered the vernacular with the increasing number of people throughout the world who commonly and extensively rely on telecommunications and the internet for personal and business communication. "Face time" was a primary theme in Douglas Coupland's novel Microserfs. # Characteristics of face time Face time is important for its unique characteristics of eye contact and touch. Various simulations that serve as an alternative to face time do not have these features (yet). Quality time is the idea of surrounding oneself with others of value, while having low obligations and being oriented towards fun (see Anthropological theories of value). This sort of behaviour is possible in non-face time situations like chat rooms, but it is widely felt that fun in a chat room does not qualify as quality time. The reasons for this are complicated (see loneliness). One explanation is that touch between humans is a fundamental of emotion well-being. Another explanation is that direct eye contact is critical to guarantee honesty. (see lying) ## Factors increasing face time - Software is being developed to encourage conversation at coffee shops in which laptops are obstacle to face time. (see toothing) - singles bars, dance clubs - The rise of the Service economy - collectivist cultures like China - An increasing amount of intellectuals like Esther Dyson and Nicholas Negroponte studying the effects of technology in society. ## Factors decreasing face time - Face time alternatives are more efficient (see Microsoft's business culture). - The importance of the mass media. - cybersex # Applications in culture - It applies to high-paced offices, like a newsroom. - Can be used to describe direct time on television. - Also has a variant of "Deface Time" - when a boss is around in real life to catch a worker being unproductive. - Can apply to lobbyists, who value face-time for more effective persuasion. - Can apply to student time with teachers or professors	Face time Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Face time is interaction or contact between two or more people at the same time and physical location. Face time therefore occurs in "real life" or "meatspace" and contrasts primarily with interaction or contact which occurs over distance (eg. via telephone) and/or electronically (eg. via email, instant messaging, e-commerce, or computer simulations). The term was originally a colloquialism but has entered the vernacular with the increasing number of people throughout the world who commonly and extensively rely on telecommunications and the internet for personal and business communication. "Face time" was a primary theme in Douglas Coupland's novel Microserfs. # Characteristics of face time Face time is important for its unique characteristics of eye contact and touch. Various simulations that serve as an alternative to face time do not have these features (yet). Quality time is the idea of surrounding oneself with others of value, while having low obligations and being oriented towards fun (see Anthropological theories of value). This sort of behaviour is possible in non-face time situations like chat rooms, but it is widely felt that fun in a chat room does not qualify as quality time. The reasons for this are complicated (see loneliness). One explanation is that touch between humans is a fundamental of emotion well-being.[2] Another explanation is that direct eye contact is critical to guarantee honesty.[3] (see lying) ## Factors increasing face time - Software is being developed to encourage conversation at coffee shops in which laptops are obstacle to face time. (see toothing) - singles bars, dance clubs - The rise of the Service economy - collectivist cultures like China - An increasing amount of intellectuals like Esther Dyson and Nicholas Negroponte studying the effects of technology in society. ## Factors decreasing face time - Face time alternatives are more efficient (see Microsoft's business culture). - The importance of the mass media. - cybersex # Applications in culture - It applies to high-paced offices, like a newsroom.[4] - Can be used to describe direct time on television. - Also has a variant of "Deface Time" - when a boss is around in real life to catch a worker being unproductive.[5] - Can apply to lobbyists, who value face-time for more effective persuasion.[6] - Can apply to student time with teachers or professors [7]	https://www.wikidoc.org/index.php/Face_time
296e48ce5d43268132abdaed90464fa011ddcb02	wikidoc	Protein S	Protein S Protein S (also known as S-Protein) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene. # History Protein S is named for Seattle, Washington, where it was originally discovered and purified. # Structure Protein S is partly homologous to other vitamin K-dependent plasma coagulation proteins, such as protein C and factors VII, IX, and X. Similar to them, it has a Gla domain and several EGF-like domains (four rather than two), but no serine protease domain. Instead, there is a large C-terminus domain that is homologous to plasma steroid hormone-binding proteins such as sex hormone-binding globulin and corticosteroid-binding globulin. It may play a role in the protein functions as either a cofactor for activated protein C (APC) or in binding C4BP. Additionally, protein S has a peptide between the Gla domain and the EGF-like domain, that is cleaved by thrombin. The Gla and EGF-like domains stay connected after the cleavage by a disulfide bond. However, protein S loses its function as an APC cofactor following either this cleavage or binding C4BP. # Function The best characterized function of Protein S is its role in the anti coagulation pathway, where it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity. Protein S can bind to negatively charged phospholipids via the carboxylated Gla domain. This property allows Protein S to function in the removal of cells which are undergoing apoptosis. Apoptosis is a form of cell death that is used by the body to remove unwanted or damaged cells from tissues. Cells, which are apoptotic (i.e. in the process of apoptosis), no longer actively manage the distribution of phospholipids in their outer membrane and hence begin to display negatively charged phospholipids, such as phosphatidyl serine, on the cell surface. In healthy cells, an ATP (Adenosine triphosphate)-dependent enzyme removes these from the outer leaflet of the cell membrane. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S can bind to the negatively charged phospholipids and function as a bridging molecule between the apoptotic cell and the phagocyte. The bridging property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring. Protein S also binds to the nascent complement complex C5,6,7 and prevents this complex from inserting into a membrane. This function prevents the inappropriate activation of the complement system, which would cause uncontrolled systemic inflammation. In fact, Protein S was first discovered in 1977 in this role and it is named after the membrane site that it occupies in the complex. # Pathology Mutations in the PROS1 gene can lead to Protein S deficiency which is a rare blood disorder which can lead to an increased risk of thrombosis. # Interactions Protein S has been shown to interact with Factor V.	Protein S Protein S (also known as S-Protein) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene.[1][2] # History Protein S is named for Seattle, Washington, where it was originally discovered and purified.[3] # Structure Protein S is partly homologous to other vitamin K-dependent plasma coagulation proteins, such as protein C and factors VII, IX, and X. Similar to them, it has a Gla domain and several EGF-like domains (four rather than two), but no serine protease domain. Instead, there is a large C-terminus domain that is homologous to plasma steroid hormone-binding proteins such as sex hormone-binding globulin and corticosteroid-binding globulin. It may play a role in the protein functions as either a cofactor for activated protein C (APC) or in binding C4BP.[4][5] Additionally, protein S has a peptide between the Gla domain and the EGF-like domain, that is cleaved by thrombin. The Gla and EGF-like domains stay connected after the cleavage by a disulfide bond. However, protein S loses its function as an APC cofactor following either this cleavage or binding C4BP.[6] # Function The best characterized function of Protein S is its role in the anti coagulation pathway, where it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity.[7] Protein S can bind to negatively charged phospholipids via the carboxylated Gla domain. This property allows Protein S to function in the removal of cells which are undergoing apoptosis. Apoptosis is a form of cell death that is used by the body to remove unwanted or damaged cells from tissues. Cells, which are apoptotic (i.e. in the process of apoptosis), no longer actively manage the distribution of phospholipids in their outer membrane and hence begin to display negatively charged phospholipids, such as phosphatidyl serine, on the cell surface. In healthy cells, an ATP (Adenosine triphosphate)-dependent enzyme removes these from the outer leaflet of the cell membrane. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S can bind to the negatively charged phospholipids and function as a bridging molecule between the apoptotic cell and the phagocyte. The bridging property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring. Protein S also binds to the nascent complement complex C5,6,7 and prevents this complex from inserting into a membrane. This function prevents the inappropriate activation of the complement system, which would cause uncontrolled systemic inflammation. In fact, Protein S was first discovered in 1977 in this role and it is named after the membrane site that it occupies in the complex.[8] # Pathology Mutations in the PROS1 gene can lead to Protein S deficiency which is a rare blood disorder which can lead to an increased risk of thrombosis.[9][10] # Interactions Protein S has been shown to interact with Factor V.[11][12]	https://www.wikidoc.org/index.php/Factor_S
9aa899a23e54a22dfa96897ca2cda0d0a8d826dc	wikidoc	Factor XI	Factor XI Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene. # Function Factor XI (FXI) is produced by the liver and circulates as a homo-dimer in its inactive form. The plasma half-life of FXI is approximately 52 hours. The zymogen factor is activated into factor XIa by factor XIIa (FXIIa), thrombin, and FXIa itself; due to its activation by FXIIa, FXI is a member of the "contact pathway" (which includes HMWK, prekallikrein, factor XII, factor XI, and factor IX). Factor XIa activates factor IX by selectively cleaving arg-ala and arg-val peptide bonds. Factor IXa, in turn, forms a complex with Factor VIIIa (FIXa-FVIIIa) and activates factor X. Inhibitors of factor XIa include protein Z-dependent protease inhibitor (ZPI, a member of the serine protease inhibitor/serpin class of proteins), which is independent of protein Z (its action on factor X, however, is protein Z-dependent, hence its name). # Structure Although synthesized as a single polypeptide chain, FXI circulates as a homodimer. Every chain has a relative molecular mass of approximately 80000. Typical plasma concentrations of FXI are 5 μg/mL, corresponding to a plasma concentration (of FXI dimers) of approximately 30 nM. The FXI gene is 23kb in length, has 15 exons, and is found on chromosome 4q32-35. Factor XI consists of four apple domains, that create a disk-like platform around the base of a fifth, catalytic serine protease domain. One contains a binding site for thrombin, another for high molecular weight kininogen, a third one for factor IX, heparin and glycoprotein Ib and the fourth is implicated in forming the factor XI homodimer, including a cysteine residue that creates a disulfide bond. In the homodimer, the apple domains create two disk-like platforms connected together at an angle, with the catalytic domains sticking out at each side of the dimer. Activation by thrombin or factor XIIa is achieved by cleavage of Arg369-Ile370 peptide bonds on both subunits of the dimer. This results in a partial detachment of the catalytic domain from the disk-like apple domains, still linked to the fourth domain with a disulfide bond, but now farther from the third domain. This is thought that this exposes the factor IX binding site of the third apple domain, allowing factor XI's protease activity on it. # Role in disease Deficiency of factor XI causes the rare hemophilia C; this mainly occurs in Ashkenazi Jews and is believed to affect approximately 8% of that population. Less commonly, hemophilia C can be found in Jews of Iraqi ancestry and in Israeli Arabs. The condition has been described in other populations at around 1% of cases. It is an autosomal recessive disorder. There is little spontaneous bleeding, but surgical procedures may cause excessive blood loss, and prophylaxis is required. Low levels of factor XI also occur in many other disease states, including Noonan syndrome. High levels of factor XI have been implicated in thrombosis, although it is uncertain what determines these levels and how serious the procoagulant state is.	Factor XI Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene.[1][2][3][4] # Function Factor XI (FXI) is produced by the liver and circulates as a homo-dimer in its inactive form.[5] The plasma half-life of FXI is approximately 52 hours. The zymogen factor is activated into factor XIa by factor XIIa (FXIIa), thrombin, and FXIa itself; due to its activation by FXIIa, FXI is a member of the "contact pathway" (which includes HMWK, prekallikrein, factor XII, factor XI, and factor IX).[6] Factor XIa activates factor IX by selectively cleaving arg-ala and arg-val peptide bonds. Factor IXa, in turn, forms a complex with Factor VIIIa (FIXa-FVIIIa) and activates factor X. Inhibitors of factor XIa include protein Z-dependent protease inhibitor (ZPI, a member of the serine protease inhibitor/serpin class of proteins), which is independent of protein Z (its action on factor X, however, is protein Z-dependent, hence its name). # Structure Although synthesized as a single polypeptide chain, FXI circulates as a homodimer. Every chain has a relative molecular mass of approximately 80000. Typical plasma concentrations of FXI are 5 μg/mL, corresponding to a plasma concentration (of FXI dimers) of approximately 30 nM. The FXI gene is 23kb in length, has 15 exons, and is found on chromosome 4q32-35.[2][3] Factor XI consists of four apple domains, that create a disk-like platform around the base of a fifth, catalytic serine protease domain. One contains a binding site for thrombin, another for high molecular weight kininogen, a third one for factor IX, heparin and glycoprotein Ib and the fourth is implicated in forming the factor XI homodimer, including a cysteine residue that creates a disulfide bond. In the homodimer, the apple domains create two disk-like platforms connected together at an angle, with the catalytic domains sticking out at each side of the dimer. Activation by thrombin or factor XIIa is achieved by cleavage of Arg369-Ile370 peptide bonds on both subunits of the dimer. This results in a partial detachment of the catalytic domain from the disk-like apple domains, still linked to the fourth domain with a disulfide bond, but now farther from the third domain. This is thought that this exposes the factor IX binding site of the third apple domain, allowing factor XI's protease activity on it. [7] # Role in disease Deficiency of factor XI causes the rare hemophilia C; this mainly occurs in Ashkenazi Jews and is believed to affect approximately 8% of that population. Less commonly, hemophilia C can be found in Jews of Iraqi ancestry and in Israeli Arabs. The condition has been described in other populations at around 1% of cases. It is an autosomal recessive disorder. There is little spontaneous bleeding, but surgical procedures may cause excessive blood loss, and prophylaxis is required.[8] Low levels of factor XI also occur in many other disease states, including Noonan syndrome. High levels of factor XI have been implicated in thrombosis, although it is uncertain what determines these levels and how serious the procoagulant state is.	https://www.wikidoc.org/index.php/Factor_XI
e377fdcae67b7ce7f8878ff51087e0c0cf14a166	wikidoc	Fair coin	Fair coin # Overview In probability theory and statistics, a sequence of independent Bernoulli trials with probability 1/2 of success on each trial is metaphorically called a fair coin. One for which the probability is not 1/2 is called a biased or unfair coin. # Fair results from a biased coin If a cheater has altered a coin to prefer one side over another (a biased coin), surprisingly the coin can still be used for fair results by changing the game slightly. John von Neumann gave the following procedure: - Toss the coin twice. - If the results match, start over, forgetting both results. - If the results differ, use the first result, forgetting the second. The reason this process produces a fair result is that the probability of getting heads and then tails must be the same as the probability of getting tails and then heads, as the coin is not changing its bias between flips and the two flips are independent. By excluding the events of two heads and two tails by repeating the procedure, the coin flipper is left with the only two remaining outcomes having equivalent probability. This procedure only works if the tosses are paired properly; if part of a pair is reused in another pair, the fairness may be ruined. Some coins have been alleged to be unfair when spun on a table, but the results have not been substantiated or are not significant.	Fair coin # Overview In probability theory and statistics, a sequence of independent Bernoulli trials with probability 1/2 of success on each trial is metaphorically called a fair coin. One for which the probability is not 1/2 is called a biased or unfair coin. # Fair results from a biased coin If a cheater has altered a coin to prefer one side over another (a biased coin), surprisingly the coin can still be used for fair results by changing the game slightly. John von Neumann gave the following procedure: - Toss the coin twice. - If the results match, start over, forgetting both results. - If the results differ, use the first result, forgetting the second. The reason this process produces a fair result is that the probability of getting heads and then tails must be the same as the probability of getting tails and then heads, as the coin is not changing its bias between flips and the two flips are independent. By excluding the events of two heads and two tails by repeating the procedure, the coin flipper is left with the only two remaining outcomes having equivalent probability. This procedure only works if the tosses are paired properly; if part of a pair is reused in another pair, the fairness may be ruined. Some coins have been alleged to be unfair when spun on a table, but the results have not been substantiated or are not significant.[1]	https://www.wikidoc.org/index.php/Fair_coin
ebd4b3149a1f49678adc1bf65165a695300bc416	wikidoc	Farnesene	Farnesene The term farnesene refers to a set of closely related chemical compounds which are sesquiterpenes. α-Farnesene and β-farnesene are isomers, differing by the location of one double bond. α-Farnesene is 3,7,11-trimethyl-1,3,6,10-dodecatetraene and β-farnesene is 7,11-dimethyl-3-methylene-1,6,10-dodecatriene. The alpha form can exist as four stereoisomers that differ about the geometry of two of its three internal double bonds (the E and Z stereoisomers of the third internal double bond are identical). The beta form can exist as two stereoisomers about the geometry of its central double bond. α-(E,E)-Farnesene is the most common isomer. It is found the coating of apples, and other fruits, and its oxidation by air produces compounds that are damaging to the fruit. It produces a characteristic green apple odour. The oxidation products result in injury to cell membranes which eventually result in cell death in the outermost cell layers of the fruit, resulting in a storage disorder known as scald. α-(Z,E)-Farnesene has been isolated from the oil of perilla. Both isomers are also insect pheremones. β-Farnesene has one naturally occurring isomer. The (E)-isomer is a constituent of various essential oils. It is also released by aphids as an alarm pheromone upon death to warn away other aphids. Several plants, including the wild potato have been shown to synthesize this pheromone as a natural insect repellent.	Farnesene The term farnesene refers to a set of closely related chemical compounds which are sesquiterpenes. α-Farnesene and β-farnesene are isomers, differing by the location of one double bond. α-Farnesene is 3,7,11-trimethyl-1,3,6,10-dodecatetraene and β-farnesene is 7,11-dimethyl-3-methylene-1,6,10-dodecatriene. The alpha form can exist as four stereoisomers that differ about the geometry of two of its three internal double bonds (the E and Z stereoisomers of the third internal double bond are identical). The beta form can exist as two stereoisomers about the geometry of its central double bond. α-(E,E)-Farnesene is the most common isomer. It is found the coating of apples, and other fruits, and its oxidation by air produces compounds that are damaging to the fruit. It produces a characteristic green apple odour. The oxidation products result in injury to cell membranes which eventually result in cell death in the outermost cell layers of the fruit, resulting in a storage disorder known as scald. α-(Z,E)-Farnesene has been isolated from the oil of perilla. Both isomers are also insect pheremones. β-Farnesene has one naturally occurring isomer. The (E)-isomer is a constituent of various essential oils. It is also released by aphids as an alarm pheromone upon death to warn away other aphids. Several plants, including the wild potato have been shown to synthesize this pheromone as a natural insect repellent.	https://www.wikidoc.org/index.php/Farnesene
23b7bf3cf2344febbcfd07f800e9f5ae0efd712a	wikidoc	Faropenem	Faropenem # Overview Faropenem is an orally-active beta-lactam antibiotic belonging to the penem group. It is the first orally-active penem antibiotic. Faropenem was developed by Daiichi Asubio Pharma, which markets it in two forms. - The sodium salt faropenem sodium, available under the trade name Farom, has been marketed in Japan since 1997. (Template:PubChem) - The prodrug form faropenem medoxomil (also known as faropenem daloxate) has been licensed from Daiichi Asubio Pharma by Replidyne, which plans to market it in conjunction with Forest Pharmaceuticals. The trade name proposed for the product was Orapem but company officials recently announced that this name was rejected by the FDA. (Q1 06 Investor Conf Call)(Template:PubChem) The company also stated their hope to have the product available for commercial sale months before the 2007 influenza season. # Clinical use Faropenem has yet to receive marketing approval in the United States, and was submitted for consideration by the United States Food and Drug Administration (FDA) on 20 December 2005. The new drug application (NDA) dossier submitted included four proposed indications: - acute bacterial sinusitis - community acquired pneumonia - acute exacerbations of chronic bronchitis - uncomplicated skin and skin structure infections	Faropenem Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Faropenem is an orally-active beta-lactam antibiotic belonging to the penem group. It is the first orally-active penem antibiotic. Faropenem was developed by Daiichi Asubio Pharma, which markets it in two forms. - The sodium salt faropenem sodium, available under the trade name Farom, has been marketed in Japan since 1997. (Template:PubChem) - The prodrug form faropenem medoxomil (also known as faropenem daloxate) has been licensed from Daiichi Asubio Pharma by Replidyne, which plans to market it in conjunction with Forest Pharmaceuticals. The trade name proposed for the product was Orapem but company officials recently announced that this name was rejected by the FDA. (Q1 06 Investor Conf Call)(Template:PubChem) The company also stated their hope to have the product available for commercial sale months before the 2007 influenza season. # Clinical use Faropenem has yet to receive marketing approval in the United States, and was submitted for consideration by the United States Food and Drug Administration (FDA) on 20 December 2005. The new drug application (NDA) dossier submitted included four proposed indications: - acute bacterial sinusitis - community acquired pneumonia - acute exacerbations of chronic bronchitis - uncomplicated skin and skin structure infections # External links - Replidyne website - Daiichi Asubio Pharma products page Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Faropenem
519b1c2b75b43b5a0e9c5b12f24ffa6d40d28da4	wikidoc	Fecal fat	Fecal fat # Overview In medicine, a fecal fat test is a diagnostic test for fat malabsorption conditions (also referred to as steatorrhea). # Background In the small intestine, dietary fat (primarily triglycerides) is digested by enzymes such as pancreatic lipase into smaller molecules which can be absorbed through the wall of the small intestine and enter the circulation for metabolism and storage. As fat is a valuable nutrient, human feces normally contain very little undigested fat. However, a number of diseases of the pancreas and gastrointestinal tract are characterized by fat malabsorption. Examples of such diseases are: - disorders of exocrine pancreatic function, such as chronic pancreatitis, cystic fibrosis and Shwachman-Diamond syndrome (these are characterized by deficiency of pancreatic digestive enzymes) - celiac disease (in which the fat malabsorption in severe cases due to inflammatory damage to the integrity of the intestinal lining) - short bowel syndrome (in which much of the small intestine has had to be surgically removed and the remaining portion cannot completely absorb all of the fat). - small bowel bacterial overgrowth syndrome # Microscopy In the simplest form of the fecal fat test, a random fecal specimen is submitted to the hospital laboratory and examined under a microscope after staining with a Sudan III or Sudan IV dye ("Sudan staining"). Visible amounts of fat indicate some degree of fat malabsorption.. # Quantitative fecal fat test Quantitative fecal fat tests measure and report an amount of fat. This usually done over a period of three days, the patient collecting all of their feces into a container. The container is thoroughly mixed to homogenize the feces, this can be done with a paint mixer. A small sample from the feces is collected. The fat content is extracted with solvents and measured by saponification (turning the fat into soap). Normally up to 7 grams of fat can be malabsorbed in people consuming 100 grams of fat per day. In patients with diarrhea, up to 12 grams of fat may be malabsorbed since the presence of diarrhea interferes with fat absorption, even when the diarrhea is not due to fat malabsorption.	Fecal fat # Overview In medicine, a fecal fat test is a diagnostic test for fat malabsorption conditions (also referred to as steatorrhea). # Background In the small intestine, dietary fat (primarily triglycerides) is digested by enzymes such as pancreatic lipase into smaller molecules which can be absorbed through the wall of the small intestine and enter the circulation for metabolism and storage. As fat is a valuable nutrient, human feces normally contain very little undigested fat. However, a number of diseases of the pancreas and gastrointestinal tract are characterized by fat malabsorption. Examples of such diseases are: - disorders of exocrine pancreatic function, such as chronic pancreatitis, cystic fibrosis and Shwachman-Diamond syndrome (these are characterized by deficiency of pancreatic digestive enzymes) - celiac disease (in which the fat malabsorption in severe cases due to inflammatory damage to the integrity of the intestinal lining) - short bowel syndrome (in which much of the small intestine has had to be surgically removed and the remaining portion cannot completely absorb all of the fat). - small bowel bacterial overgrowth syndrome # Microscopy In the simplest form of the fecal fat test, a random fecal specimen is submitted to the hospital laboratory and examined under a microscope after staining with a Sudan III or Sudan IV dye ("Sudan staining"). Visible amounts of fat indicate some degree of fat malabsorption.. # Quantitative fecal fat test Quantitative fecal fat tests measure and report an amount of fat. This usually done over a period of three days, the patient collecting all of their feces into a container. The container is thoroughly mixed to homogenize the feces, this can be done with a paint mixer. A small sample from the feces is collected. The fat content is extracted with solvents and measured by saponification (turning the fat into soap). Normally up to 7 grams of fat can be malabsorbed in people consuming 100 grams of fat per day. In patients with diarrhea, up to 12 grams of fat may be malabsorbed since the presence of diarrhea interferes with fat absorption, even when the diarrhea is not due to fat malabsorption. Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Fecal_fat
5b6d808400a60335eea7af28679b178212f3b5e6	wikidoc	Hot flash	Hot flash # Overview Hot flashes (referred to in the United Kingdom as hot flushes or, at night, night sweats) is a symptom of the changing hormone levels that are considered to be characteristic of menopause. # Description Hot flashes are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from two to thirty minutes for each occurrence. The event may be repeated a few times each week or constantly throughout the day, with the frequency reducing over time. Excessive flushing can lead to rosacea. Some women undergoing menopause never have hot flashes. Others have mild or infrequent flashes. The worst sufferers experience dozens of hot flashes each day. Severe hot flashes can make it difficult to get a full night's sleep, which in turn can affect mood, concentration, and cause other physical problems. When hot flashes occur at night, they are called "night sweats." As estrogen is typically lowest at night, a woman might get night sweats without having any hot flashes during the daytime. # In younger women Younger women who are menstruating or expecting to menstruate soon (the premenstrual period typically lasts one week) may encounter hot and/or cold flashes. These episodes do not usually last long, with feelings of cold and heat alternating over the course of as short as a minute. Hot and cold flashes for younger women tend to occur only during times of menstruation or premenstruation (when estrogen is typically lowest). If they occur at other times in a young woman's menstrual cycle, then it might be a symptom of a problem with her pituitary gland; seeing a doctor is highly recommended. In younger women who are surgically menopausal, hot flashes are generally more intense than in older women, and they may last until natural age at menopause. # 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 ## Causes by Organ System ## Causes in Alphabetical Order Order\|here]] # Treatment Hormone replacement therapy (HRT) may relieve many of the symptoms of menopause. However, HRT increases the risk of breast cancer, stroke, and dementia and has other potentially serious short-term and long-term risks. The U.S. FDA and women's health advocates recommend that women who experience troublesome hot flashes try alternatives to hormonal therapies as the first line of treatment. If a woman chooses hormones, they suggest she take the lowest dose that alleviates her symptoms for as short a time as possible. In addition to traditional hormone replacement therapies, there are other strategies and natural supplements available to try. Such natural supplements include Yam (vegetable), black cohosh, and evening primrose. These natural supplements are used in natural creams and lotions. ## Dietary and behavior strategies - Dietary changes may relieve hot flashes. This includes avoiding caffeine, hot drinks, chocolate, spicy or hot foods and alcohol. - Wearing clothes in layers – both during the day and at night - allows a woman to shed clothing quickly when a hot flash occurs. - Two studies have found that slow, deep breathing reduced the frequency of hot flashes. In one study, this paced respiration decreased hot flashes by 39 percent and in the other by 44 percent. By comparison, this same research study found that progressive muscle relaxation was not effective in relieving hot flashes. # Other There are many other ailments than can cause hot flashes. For example, men who are castrated typically get hot flashes. de:Hitzewallung nl:Opvlieger	Hot flash Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hot flashes (referred to in the United Kingdom as hot flushes or, at night, night sweats) is a symptom of the changing hormone levels that are considered to be characteristic of menopause. # Description Hot flashes are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from two to thirty minutes for each occurrence. The event may be repeated a few times each week or constantly throughout the day, with the frequency reducing over time. Excessive flushing can lead to rosacea. Some women undergoing menopause never have hot flashes. Others have mild or infrequent flashes. The worst sufferers experience dozens of hot flashes each day. Severe hot flashes can make it difficult to get a full night's sleep, which in turn can affect mood, concentration, and cause other physical problems. When hot flashes occur at night, they are called "night sweats." As estrogen is typically lowest at night, a woman might get night sweats without having any hot flashes during the daytime. # In younger women Younger women who are menstruating or expecting to menstruate soon (the premenstrual period typically lasts one week) may encounter hot and/or cold flashes. These episodes do not usually last long, with feelings of cold and heat alternating over the course of as short as a minute. Hot and cold flashes for younger women tend to occur only during times of menstruation or premenstruation (when estrogen is typically lowest). If they occur at other times in a young woman's menstrual cycle, then it might be a symptom of a problem with her pituitary gland; seeing a doctor is highly recommended. In younger women who are surgically menopausal, hot flashes are generally more intense than in older women, and they may last until natural age at menopause. # 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 ## Causes by Organ System ## Causes in Alphabetical Order Order\|here]] # Treatment Hormone replacement therapy (HRT) may relieve many of the symptoms of menopause. However, HRT increases the risk of breast cancer, stroke, and dementia and has other potentially serious short-term and long-term risks[2]. The U.S. FDA and women's health advocates recommend that women who experience troublesome hot flashes try alternatives to hormonal therapies as the first line of treatment. If a woman chooses hormones, they suggest she take the lowest dose that alleviates her symptoms for as short a time as possible. In addition to traditional hormone replacement therapies, there are other strategies and natural supplements available to try. Such natural supplements include Yam (vegetable), black cohosh, and evening primrose. These natural supplements are used in natural creams and lotions. ## Dietary and behavior strategies - Dietary changes may relieve hot flashes. This includes avoiding caffeine, hot drinks, chocolate, spicy or hot foods and alcohol. - Wearing clothes in layers – both during the day and at night - allows a woman to shed clothing quickly when a hot flash occurs. - Two studies have found that slow, deep breathing reduced the frequency of hot flashes. In one study, this paced respiration decreased hot flashes by 39 percent and in the other by 44 percent. By comparison, this same research study found that progressive muscle relaxation was not effective in relieving hot flashes. # Other There are many other ailments than can cause hot flashes. For example, men who are castrated typically get hot flashes. de:Hitzewallung nl:Opvlieger Template:WikiDoc Sources Template:WH	https://www.wikidoc.org/index.php/Feeling_of_warmth
3f5de26258d0e97de3db65b3c6af4739b551b4e1	wikidoc	Felbamate	Felbamate # 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 Felbamate is a antiepileptic that is FDA approved for the treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anorexia, vomiting, insomnia, nausea, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Felbatol® is not indicated as a first line antiepileptic treatment. Felbatol® is recommended for use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. - If these criteria are met and the patient has been fully advised of the risk, and has provided written acknowledgement, Felbatol® can be considered for either monotherapy or adjunctive therapy in the treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children. ### Dosage - Felbatol® (felbamate) has been studied as monotherapy and adjunctive therapy in adults and as adjunctive therapy in children with seizures associated with Lennox-Gastaut syndrome. As Felbatol® is added to or substituted for existing AEDs, it is strongly recommended to reduce the dosage of those AEDs in the range of 20-33% to minimize side effects. - Dosage Adjustment in the Renally Impaired: Felbamate should be used with caution in patients with renal dysfunction. In the renally impaired, starting and maintenance doses should be reduced by one-half. Adjunctive therapy with medications which affect felbamate plasma concentrations, especially AEDs, may warrant further reductions in felbamate daily doses in patients with renal dysfunction. - The majority of patients received 3600 mg/day in clinical trials evaluating its use as both monotherapy and adjunctive therapy. - Monotherapy: (Initial therapy) Felbatol® (felbamate) has not been systematically evaluated as initial monotherapy. Initiate Felbatol® at 1200 mg/day in divided doses three or four times daily. The prescriber is advised to titrate previously untreated patients under close clinical supervision, increasing the dosage in 600-mg increments every 2 weeks to 2400 mg/day based on clinical response and thereafter to 3600 mg/day if clinically indicated. - Conversion to Monotherapy: Initiate Felbatol® at 1200 mg/day in divided doses three or four times daily. Reduce the dosage of concomitant AEDs by one-third at initiation of Felbatol® therapy. At week 2, increase the Felbatol® dosage to 2400 mg/day while reducing the dosage of other AEDs up to an additional one-third of their original dosage. At week 3, increase the Felbatol® dosage up to 3600 mg/day and continue to reduce the dosage of other AEDs as clinically indicated. - Adjunctive Therapy: Felbatol® should be added at 1200 mg/day in divided doses three or four times daily while reducing present AEDs by 20% in order to control plasma concentrations of concurrent phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase the dosage of Felbatol® by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is decreased. - While the above Felbatol® conversion guidelines may result in a Felbatol® 3600 mg/day dose within 3 weeks, in some patients titration to a 3600 mg/day Felbatol® dose has been achieved in as little as 3 days with appropriate adjustment of other AEDs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Felbamate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Felbamate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Adjunctive Therapy: Felbatol® should be added at 15 mg/kg/day in divided doses three or four times daily while reducing present AEDs by 20% in order to control plasma levels of concurrent phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase the dosage of Felbatol® by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is decreased. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Felbamate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Felbamate in pediatric patients. # Contraindications - Felbatol® is contraindicated in patients with known hypersensitivity to Felbatol®, its ingredients, or known sensitivity to other carbamates. It should not be used in patients with a history of any blood dyscrasia or hepatic dysfunction. # Warnings - See BOXED WARNING regarding aplastic anemia and hepatic failure. - Antiepileptic drugs should not be suddenly discontinued because of the possibility of increasing seizure frequency. - Antiepileptic drugs (AEDs) including Felbatol ®, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. - Table 1 shows absolute and relative risk by indication for all evaluated AEDs. - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. - Anyone considering prescribing Felbatol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Precautions - Dosage Adjustment in the Renally Impaired: A study in otherwise healthy individuals with renal dysfunction indicated that prolonged half-life and reduced clearance of felbamate are associated with diminishing renal function. Felbamate should be used with caution in patients with renal dysfunction - Laboratory Tests: Full hematologic evaluations should be performed before Felbatol® therapy, frequently during therapy, and for a significant period of time after discontinuation of Felbatol® therapy. While it might appear prudent to perform frequent CBCs in patients continuing on Felbatol®, there is no evidence that such monitoring will allow early detection of marrow suppression before aplastic anemia occurs. Complete pretreatment blood counts, including platelets and reticulocytes should be obtained as a baseline. If any hematologic abnormalities are detected during the course of treatment, immediate consultation with a hematologist is advised. Felbatol® should be discontinued if any evidence of bone marrow depression occurs. - See BOX WARNINGS for recommended monitoring of serum transaminases. If significant, confirmed liver abnormalities are detected during the course of Felbatol® treatment, Felbatol® should be discontinued immediately with continued liver function monitoring until values return to normal. - Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled that AEDs, including Felbatol®, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. - Pregnancy: Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 # Adverse Reactions ## Clinical Trials Experience - To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . - The most common adverse reactions seen in association with Felbatol® (felbamate) in adults during monotherapy are anorexia, vomiting, insomnia, nausea, and headache. The most common adverse reactions seen in association with Felbatol® in adults during adjunctive therapy are anorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache. - The most common adverse reactions seen in association with Felbatol® in children during adjunctive therapy are anorexia, vomiting, insomnia, headache, and somnolence. - The dropout rate because of adverse experiences or intercurrent illnesses among adult felbamate patients was 12 percent (120/977). The dropout rate because of adverse experiences or intercurrent illnesses among pediatric felbamate patients was six percent (22/357). In adults, the body systems associated with causing these withdrawals in order of frequency were: digestive (4.3%), psychological (2.2%), whole body (1.7%), neurological (1.5%), and dermatological (1.5%). In children, the body systems associated with causing these withdrawals in order of frequency were: digestive (1.7%), neurological (1.4%), dermatological (1.4%), psychological (1.1%), and whole body (1.0%). In adults, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency were: anorexia (1.6%), nausea (1.4%), rash (1.2%), and weight decrease (1.1%). In children, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency was rash (1.1%). - The prescriber should be aware that the figures cited in the following table cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different investigators, treatments, and uses including the use of Felbatol® (felbamate) as adjunctive therapy where the incidence of adverse events may be higher due to drug interactions. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. - The table that follows enumerates adverse events that occurred at an incidence of 2% or more among 58 adult patients who received Felbatol® monotherapy at dosages of 3600 mg/day in double-blind controlled trials. Table 3 presents reported adverse events that were classified using standard WHO-based dictionary terminology. - Table 4 enumerates adverse events that occurred at an incidence of 2% or more among 114 adult patients who received Felbatol® adjunctive therapy in add-on controlled trials at dosages up to 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology. - Many adverse experiences that occurred during adjunctive therapy may be a result of drug interactions. Adverse experiences during adjunctive therapy typically resolved with conversion to monotherapy, or with adjustment of the dosage of other antiepileptic drugs. Table 5 enumerates adverse events that occurred more than once among 31 pediatric patients who received Felbatol® up to 45 mg/kg/day or a maximum of 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology. - In the paragraphs that follow, the adverse clinical events, other than those in the preceding tables, that occurred in a total of 977 adults and 357 children exposed to Felbatol® (felbamate) and that are reasonably associated with its use are presented. They are listed in order of decreasing frequency. Because the reports cite events observed in open-label and uncontrolled studies, the role of Felbatol® in their causation cannot be reliably determined. - Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100-1/1000 patients; and rare events are those occurring in fewer than 1/1000 patients. - Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=1334) exposed to Felbatol®. - Frequent: Weight gain, asthenia, malaise, influenza-like symptoms; Rare: anaphylactoid reaction, substernal chest pain . - Frequent: Palpitation, tachycardia; Rare: supraventricular tachycardia. - Frequent: Agitation, psychological disturbance, aggressive reaction: Infrequent: hallucination, euphoria, suicide attempt, migraine. - Frequent: SGOT increased; Infrequent: esophagitis, appetite increased; Rare: GGT elevated. - Infrequent: Lymphadenopathy, leukopenia, leukocytosis, thrombocytopenia, granulocytopenia; Rare: antinuclear factor test positive, qualitative platelet disorder, agranulocytosis. - Infrequent: Hypokalemia, hyponatremia, LDH increased, alkaline phosphatase increased, hypophosphatemia; Rare: creatinine phosphokinase increased. - Infrequent: Dystonia. - Frequent: Pruritus; Infrequent: urticaria, bullous eruption; Rare: buccal mucous membrane swelling, Stevens-Johnson Syndrome. - Rare: Photosensitivity allergic reaction. ## Postmarketing Experience - Voluntary reports of adverse events in patients taking Felbatol® (usually in conjunction with other drugs) have been received since market introduction and may have no causal relationship with the drug(s). These include the following by body system: - neoplasm, sepsis, L.E. syndrome, SIDS, sudden death, edema, hypothermia, rigors, hyperpyrexia. - atrial fibrillation, atrial arrhythmia, cardiac arrest, torsade de pointes, cardiac failure, hypotension, hypertension, flushing, thrombophlebitis, ischemic necrosis, gangrene, peripheral ischemia, bradycardia, Henoch-Schönlein purpura (vasculitis). - delusion, paralysis, mononeuritis, cerebrovascular disorder, cerebral edema, coma, manic reaction, encephalopathy, paranoid reaction, nystagmus, choreoathetosis, extrapyramidal disorder, confusion, psychosis, status epilepticus, dyskinesia, dysarthria, respiratory depression, apathy, impaired concentration . - abnormal body odor, sweating, lichen planus, livedo reticularis, alopecia, toxic epidermal necrolysis. - hepatitis, hepatic failure, G.I. hemorrhage, hyperammonemia, pancreatitis, hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding, acquired megacolon, ileus, intestinal obstruction, enteritis, ulcerative stomatitis, glossitis, dysphagia, jaundice, gastric ulcer, gastric dilatation, gastroesophageal reflux. - fetal death, microcephaly, genital malformation, anencephaly, encephalocele. - increased and decreased prothrombin time, anemia, hypochromic anemia, aplastic anemia, pancytopenia, hemolytic uremic syndrome, increased mean corpuscular volume (mcv) with and without anemia, coagulation disorder, embolism-limb, disseminated intravascular coagulation, eosinophilia, hemolytic anemia, leukemia, including myelogenous leukemia, and lymphoma, including T-cell and B-cell lymphoproliferative disorders. - hypernatremia, hypoglycemia, SIADH, hypomagnesemia, dehydration, hyperglycemia, hypocalcemia. - arthralgia, muscle weakness, involuntary muscle contraction, rhabdomyolysis. - dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis, pleural effusion, respiratory insufficiency, pulmonary hemorrhage, asthma. - hemianopsia, decreased hearing, conjunctivitis. - menstrual disorder, acute renal failure, hepatorenal syndrome, hematuria, urinary retention, nephrosis, vaginal hemorrhage, abnormal renal function, dysuria, placental disorder. # Drug Interactions - The drug interaction data described in this section were obtained from controlled clinical trials and studies involving otherwise healthy adults with epilepsy. - Use in Conjunction with Other Antiepileptic Drugs: - The addition of Felbatol® to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs. The net effect of these interactions is summarized in Table 2: - Felbatol® causes an increase in steady-state phenytoin plasma concentrations. In 10 otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (Cmin) phenytoin plasma concentration was 17±5 micrograms/mL. The steady-state Cmin increased to 21±5 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 1800 mg/day in six of these subjects increased the steady-state phenytoin Cmin to 25±7 micrograms/mL. In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600 mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects. - In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of Felbatol® therapy resulted in phenytoin levels comparable to those prior to Felbatol® administration. - Felbatol® causes a decrease in the steady-state carbamazepine plasma concentrations and an increase in the steady-state carbamazepine epoxide plasma concentration. In nine otherwise healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (Cmin) carbamazepine concentration was 8±2 micrograms/mL. The carbamazepine steady-state Cmin decreased 31% to 5±1 micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered. Carbamazepine epoxide steady-state Cmin concentrations increased 57% from 1.0±0.3 to 1.6±0.4 micrograms/mL with the addition of felbamate. - In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen. - Felbatol® causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (Cmin) valproate plasma concentration was 63±16 micrograms/mL. The steady-state Cmin increased to 78±14 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state valproate Cmin to 96±25 micrograms/mL. Corresponding values for free valproate Cmin concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day Felbatol®, respectively. The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and 11.5%, with coadministration of 0, 1200, and 2400 mg/day of Felbatol®, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses of Felbatol®. - Coadministration of felbamate with phenobarbital causes an increase in phenobarbital plasma concentrations. In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state trough (Cmin) phenobarbital concentration was 14.2 micrograms/mL. The steady-state Cmin concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for one week. - Phenytoin causes an approximate doubling of the clearance of Felbatol® (felbamate) at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as monotherapy. - Carbamazepine causes an approximate 50% increase in the clearance of Felbatol® at steady-state and, therefore, the addition of carbamazepine results in an approximate 40% decrease in the steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as monotherapy. - Available data suggest that there is no significant effect of valproate on the clearance of Felbatol® at steady-state. Therefore, the addition of valproate is not expected to cause a clinically important effect on Felbatol® (felbamate) plasma concentrations. - It appears that phenobarbital may reduce plasma felbamate concentrations. Steady-state plasma felbamate concentrations were found to be 29% lower than the mean concentrations of a group of newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day. - The rate and extent of absorption of a 2400 mg dose of Felbatol® as monotherapy given as tablets was not affected when coadministered with antacids. - The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic parameters of Cmax, Cmin, AUC, Cl/kg or tmax at felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise healthy subjects with epilepsy. - A group of 24 nonsmoking, healthy white female volunteers established on an oral contraceptive regimen containing 30 µg ethinyl estradiol and 75 µg gestodene for at least 3 months received 2400 mg/day of felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles. Felbamate treatment resulted in a 42% decrease in the gestodene AUC 0-24, but no clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. No volunteer showed hormonal evidence of ovulation, but one volunteer reported intermenstrual bleeding during felbamate treatment. - There are no known interactions of Felbatol® with commonly used laboratory tests. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - The incidence of malformations was not increased compared to control in offspring of rats or rabbits given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human daily dose on a mg/kg basis, or 3 times (rat) and less than 2 times (rabbit) the human daily dose on a mg/m 2 basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation. The cause for these deaths is not known. The no effect dose for rat pup mortality was 6.9 times the human dose on a mg/kg basis or 1.5 times the human dose on a mg/m 2 basis. - Placental transfer of felbamate occurs in rat pups. There are, however, no 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. - To provide information regarding the effects of in utero exposure to Felbatol®, physicians are advised to recommend that pregnant patients taking Felbatol enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Felbamate in women who are pregnant. ### Labor and Delivery - The effect of felbamate on labor and delivery in humans is unknown. ### Nursing Mothers - Felbamate has been detected in human milk. The effect on the nursing infant is unknown ### Pediatric Use - The safety and effectiveness of Felbatol® in children other than those with Lennox-Gastaut syndrome has not been established. ### Geriatic Use - No systematic studies in geriatric patients have been conducted. Clinical studies of Felbatol® did not include sufficient numbers of patients 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, dosage 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 Felbamate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Felbamate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Felbamate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Felbamate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Felbamate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Felbamate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - perform frequent CBCs in patients continuing on Felbatol® - MONITORING OF SERUM TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT BASELINE AND PERIODICALLY THEREAFTER. # IV Compatibility There is limited information regarding IV Compatibility of Felbamate in the drug label. # Overdosage - Four subjects inadvertently received Felbatol® (felbamate) as adjunctive therapy in dosages ranging from 5400 to 7200 mg/day for durations between 6 and 51 days. One subject who received 5400 mg/day as monotherapy for 1 week reported no adverse experiences. Another subject attempted suicide by ingesting 12,000 mg of Felbatol® in a 12-hour period. The only adverse experiences reported were mild gastric distress and a resting heart rate of 100 bpm. No serious adverse reactions have been reported. General supportive measures should be employed if overdosage occurs. It is not known if felbamate is dialyzable. ### DRUG ABUSE AND DEPENDENCE - Abuse: Abuse potential was not evaluated in human studies. - Dependence: Rats administered felbamate orally at doses 8.3 times the recommended human dose 6 days each week for 5 consecutive weeks demonstrated no signs of physical dependence as measured by weight loss following drug withdrawal on day 7 of each week. # Pharmacology ## Mechanism of Action - The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. Felbamate is effective in mice and rats in the maximal electroshock test, the subcutaneous pentylenetetrazol seizure test, and the subcutaneous picrotoxin seizure test. Felbamate also exhibits anticonvulsant activity against seizures induced by intracerebroventricular administration of glutamate in rats and N-methyl-D,L-aspartic acid in mice. Protection against maximal electroshock-induced seizures suggests that felbamate may reduce seizure spread, an effect possibly predictive of efficacy in generalized tonic-clonic or partial seizures. Protection against pentylenetetrazol-induced seizures suggests that felbamate may increase seizure threshold, an effect considered to be predictive of potential efficacy in absence seizures. - Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory amino acid agonists NMDA, kainate, or quisqualate in vitro. - The monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock-induced seizure test in mice. The monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6) activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. These metabolites did not contribute significantly to the anticonvulsant action of felbamate. ## Structure - Felbatol® (felbamate) is an antiepileptic available as 400 mg and 600 mg tablets and as a 600 mg/5 mL suspension for oral administration. Its chemical name is 2-phenyl-1,3-propanediol dicarbamate. - Felbamate is a white to off-white crystalline powder with a characteristic odor. It is very slightly soluble in water, slightly soluble in ethanol, sparingly soluble in methanol, and freely soluble in dimethyl sulfoxide. The molecular weight is 238.24; felbamate's molecular formula is C 11 H 14 N 2 O 4 ; its structural formula is: - The inactive ingredients for Felbatol® (felbamate) Tablets 400 mg and 600 mg are starch, microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C Yellow No. 6, D&C Yellow No. 10, and FD&C Red No. 40 (600 mg tablets only). The inactive ingredients for Felbatol® (felbamate) Oral Suspension 600 mg/5 mL are sorbitol, glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, simethicone, polysorbate 80, methylparaben, saccharin sodium, propylparaben, FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and purified water. ## Pharmacodynamics - 1. Cardiovascular: In adults, there is no effect of felbamate on blood pressure. Small but statistically significant mean increases in heart rate were seen during adjunctive therapy and monotherapy; however, these mean increases of up to 5 bpm were not clinically significant. In children, no clinically relevant changes in blood pressure or heart rate were seen during adjunctive therapy or monotherapy with felbamate. - 2. Other Physiologic Effects: The only other change in vital signs was a mean decrease of approximately 1 respiration per minute in respiratory rate during adjunctive therapy in children. In adults, statistically significant mean reductions in body weight were observed during felbamate monotherapy and adjunctive therapy. In children, there were mean decreases in body weight during adjunctive therapy and monotherapy; however, these mean changes were not statistically significant. These mean reductions in adults and children were approximately 5% of the mean weights at baseline. ## Pharmacokinetics - The numbers in the pharmacokinetic section are mean ± standard deviation. - Felbamate is well-absorbed after oral administration. Over 90% of the radioactivity after a dose of 1000 mg 14 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been measured. The tablet and suspension were each shown to be bioequivalent to the capsule used in clinical trials, and pharmacokinetic parameters of the tablet and suspension are similar. There was no effect of food on absorption of the tablet; the effect of food on absorption of the suspension has not been evaluated. - Following oral administration, felbamate is the predominant plasma species (about 90% of plasma radioactivity). About 40-50% of absorbed dose appears unchanged in urine, and an additional 40% is present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity. - Binding of felbamate to human plasma protein was independent of felbamate concentrations between 10 and 310 micrograms/mL. Binding ranged from 22% to 25%, mostly to albumin, and was dependent on the albumin concentration. - Felbamate is excreted with a terminal half-life of 20-23 hours, which is unaltered after multiple doses. Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3600 mg is 30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1200 mg dose. Felbamate Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100-800 mg single doses and 1200-3600 mg daily doses. Cmin (trough) blood levels are also dose proportional. Multiple daily doses of 1200, 2400, and 3600 mg gave Cmin values of 30±5, 55±8, and 83±21 micrograms/mL (N=10 patients). Linear and dose proportional pharmacokinetics were also observed at doses above 3600 mg/day up to the maximum dose studied of 6000 mg/day. Felbamate gave dose proportional steady-state peak plasma concentrations in children age 4-12 over a range of 15, 30, and 45 mg/kg/day with peak concentrations of 17, 32, and 49 micrograms/mL. - The effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but plasma concentrations in males (N=5) and females (N=4) given felbamate have been similar. The effects of felbamate kinetics on hepatic functional impairment have not been evaluated. - Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy individuals with renal impairment. There was a 40-50% reduction in total body clearance and 9-15 hours prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal function. Reduced felbamate clearance and a longer half-life were associated with diminishing renal function. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in mice and rats. Mice received felbamate as a feed admixture for 92 weeks at doses of 300, 600, and 1200 mg/kg and rats were also dosed by feed admixture for 104 weeks at doses of 30, 100, and 300 (males) or 10, 30, and 100 (females) mg/kg. The maximum doses in these studies produced steady-state plasma concentrations that were equal to or less than the steady-state plasma concentrations in epileptic patients receiving 3600 mg/day. There was a statistically significant increase in hepatic cell adenomas in high-dose male and female mice and in high-dose female rats. Hepatic hypertrophy was significantly increased in a dose-related manner in mice, primarily males, but also in females. Hepatic hypertrophy was not found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the finding of liver hypertrophy resulting from liver enzyme induction has not been examined. There was a statistically significant increase in benign interstitial cell tumors of the testes in high-dose male rats receiving felbamate. The relevance of these findings to humans is unknown. - As a result of the synthesis process, felbamate could contain small amounts of two known animal carcinogens, the genotoxic compound ethyl carbamate (urethane) and the nongenotoxic compound methyl carbamate. It is theoretically possible that a 50 kg patient receiving 3600 mg of felbamate could be exposed to up to 0.72 micrograms of urethane and 1800 micrograms of methyl carbamate. These daily doses are approximately 1/35,000 (urethane) and 1/5,500 (methyl carbamate) on a mg/kg basis, and 1/10,000 (urethane) and 1/1,600 (methyl carbamate) on a mg/m2 basis, of the dose levels shown to be carcinogenic in rodents. Any presence of these two compounds in felbamate used in the lifetime carcinogenicity studies was inadequate to cause tumors. - Microbial and mammalian cell assays revealed no evidence of mutagenesis in the Ames Salmonella /microsome plate test, CHO/HGPRT mammalian cell forward gene mutation assay, sister chromatid exchange assay in CHO cells, and bone marrow cytogenetics assay. - Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 13.9 times the human total daily dose of 3600 mg on a mg/kg basis, or up to 3 times the human total daily dose on a mg/m2 basis. # Clinical Studies - The results of controlled clinical trials established the efficacy of Felbatol® (felbamate) as monotherapy and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and in partial and generalized seizures associated with Lennox-Gastaut syndrome in children. - Felbatol® (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy trial. Both trials were conducted according to an identical study design. During a 56-day baseline period, all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure frequencies were 12.4 per 28 days in the Felbatol® group and 21.3 per 28 days in the low-dose valproate group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the Felbatol® group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with Felbatol® or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or (4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each treatment group who met escape criteria. - In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the Felbatol® group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the percentage of patients who met escape criteria was 14% (3/21) in the Felbatol® group and 90% (19/21) in the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape criteria was statistically significant (P<.001) in favor of Felbatol®. These two studies by design were intended to demonstrate the effectiveness of Felbatol® monotherapy. The studies were not designed or intended to demonstrate comparative efficacy of the two drugs. For example, valproate was not used at the maximally effective dose. - A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods. Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at therapeutic levels were administered Felbatol® (felbamate) as add-on therapy at a starting dosage of 1400 mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56 patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with Felbatol® had fewer seizures than patients treated with placebo for each treatment sequence. There was a 23% (P=.018) difference in percentage seizure frequency reduction in favor of Felbatol®. - Felbatol® 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization, seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or more than one generalized seizure per day, and a minimum average of one partial or generalized tonic-clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was time to fourth seizure after randomization to treatment with Felbatol® or placebo. Thirteen (46%) of 28 patients in the Felbatol® group versus 29 (88%) of 33 patients in the placebo group experienced a fourth seizure. The median times to fourth seizure were greater than 28 days in the Felbatol® group and 5 days in the placebo group. The difference between Felbatol® and placebo in time to fourth seizure was statistically significant (P=.002) in favor of Felbatol®. - In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, Felbatol® 45 mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the Felbatol® group and 716 per month in the placebo group. Statistically significant differences in the effect on seizure frequency favored Felbatol® over placebo for total seizures (26% reduction vs. 5% increase, P<.001), atonic seizures (44% reduction vs. 7% reduction, P=.002), and generalized tonic-clonic seizures (40% reduction vs. 12% increase, P=.017). Parent/guardian global evaluations based on impressions of quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control significantly (P<.001) favored Felbatol® over placebo. - When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122 males and 142 females. # How Supplied - Felbatol® (felbamate) Tablets, 400 mg, are yellow, scored, capsule-shaped tablets, debossed 0430 on one side and FELBATOL 400 on the other; available in bottles of 100 (NDC 0037-0430-01). Felbatol® (felbamate) Tablets, 600 mg, are peach-colored, scored, capsule-shaped tablets, debossed 0431 on one side and FELBATOL 600 on the other; available in bottles of 100 (NDC 0037-0431-01). Felbatol® (felbamate) Oral Suspension, 600 mg/5 mL, is peach-colored; available in 8 oz bottles (NDC 0037-0442-67) and 32 oz bottles (NDC 0037-0442-17). ## Storage Shake suspension well before using. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense in tight container. # Images ## Drug Images ## Package and Label Display Panel ### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 100-COUNT BOTTLE, 400 MG TABLET NDC 0037-0430-01 100 Tablets Felbatol® (felbamate) 400 mg Tablets Rx Only MEDA Pharmaceuticals® LB-024G5-09 Rev. 12/10 Usual Dosage: For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense the accompanying Medication Guide to each patient. Dispense in a tight container. MEDA Pharmaceuticals® Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120 ### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 100-COUNT BOTTLE, 600 MG TABLET NDC 0037-0431-01 100 Tablets Felbatol® (felbamate) 600 mg Tablets Rx Only MEDA Pharmaceuticals® LB-024H5-09 Rev. 12/10 Usual Dosage: For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense the accompanying Medication Guide to each patient. Dispense in a tight container. MEDA Pharmaceuticals® Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120 ### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 8 FL OZ (237 ML) BOTTLE, 600 MG SUSPENSION NDC 0037-0442-67 8 fl oz (237 mL) Felbatol® (felbamate) Oral Suspension Each 5 mL contains 600 mg felbamate Rx Only SHAKE WELL MEDA Pharmaceuticals® LB-024F5-10 Rev. 12/10 Usual Dosage: For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense the accompanying Medication Guide to each patient. Dispense in a tight container. MEDA Pharmaceuticals® Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120 ### Ingredients and Appearance # Patient Counseling Information - Patients should be informed that the use of Felbatol® is associated with aplastic anemia and hepatic failure, potentially fatal conditions acutely or over a long term. - The physician should obtain written acknowledgement prior to initiation of Felbatol® therapy (see PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM section). - Patients should be instructed to read the Medication Guide supplied as required by law when Felbatol® is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. - Aplastic anemia in the general population is relatively rare. The absolute risk for the individual patient is not known with any degree of reliability, but patients on Felbatol® may be at more than a 100 fold greater risk for developing the syndrome than the general population. - The long term outlook for patients with aplastic anemia is variable. Although many patients are apparently cured, others require repeated transfusions and other treatments for relapses, and some, although surviving for years, ultimately develop serious complications that sometimes prove fatal (e.g., leukemia). - At present there is no way to predict who is likely to get aplastic anemia, nor is there a documented effective means to monitor the patient so as to avoid and/or reduce the risk. Patients with a history of any blood dyscrasia should not receive Felbatol®. - Patients should be advised to be alert for signs of infection, bleeding, easy bruising, or signs of anemia (fatigue, weakness, lassitude, etc.) and should be advised to report to the physician immediately if any such signs or symptoms appear. - Hepatic failure in the general population is relatively rare. The absolute risk for an individual patient is not known with any degree of reliability but patients on Felbatol® are at a greater risk for developing hepatic failure than the general population. - At present, there is no way to predict who is likely to develop hepatic failure, however, patients with a history of hepatic dysfunction should not be started on Felbatol®. - Patients should be advised to follow their physician's directives for liver function testing both before starting Felbatol® (felbamate) and at frequent intervals while taking Felbatol®. - Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they should occur. ### MEDICATION GUIDE - Read this Medication Guide before you start taking FELBATOL and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. - Do not stop taking FELBATOL without first talking to your healthcare provider. - Stopping FELBATOL suddenly can cause serious problems. - FELBATOL can cause serious side effects, including: - 1. FELBATOL may cause serious blood problems that may be life-threatening. - Call your healthcare provider right away if you have any of the following symptoms: - Fever, sore throat or other infections that come and go or do not go away - Frequent infections or an infection that does not go away - Easy bruising - Red or purple spots on your body - Bleeding gums or nose bleeds - Severe fatigue or weakness - 2. Liver problems that may be life-threatening. Call your healthcare provider right away if you have any of these symptoms: - yellowing of your skin or the whites of your eyes (jaundice) - dark urine - nausea or vomiting - loss of appetite - pain on the right side of your stomach (abdomen) - 3. Like other antiepileptic drugs, FELBATOL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. - Call your healthcare provider right away if you have any of these symptoms, - especially if they are new, worse, or worry you: - thoughts about suicide or dying - attempts to commit suicide - new or worse depression - new or worse anxiety - feeling agitated or restless - panic attacks - trouble sleeping (insomnia) - new or worse irritability - acting aggressive, being angry, or violent - acting on dangerous impulses - an extreme increase in activity and talking (mania) - other unusual changes in behavior or mood - Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. - Keep all follow-up visits with your healthcare provider as scheduled. - Call your healthcare provider between visits as needed, especially if you are worried about symptoms. - Stopping FELBATOL suddenly can cause serious problems. You should talk to your health care provider before stopping. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures. - Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. - FELBATOL is a prescription medicine used when other treatments have failed in: - adults alone or with other medicines to treat: - partial seizures with and without generalization - children with other medicines to treat: - seizures associated with Lennox-Gastaut syndrome - Do not take FELBATOL if you: - are allergic to felbamate, carbamates or any of the ingredients in FELBATOL. See the end of this Medication Guide for a complete list of ingredients in FELBATOL. - have or have had blood problems - have or have had liver problems - Before you take FELBATOL, tell your healthcare provider if you: - have kidney problems - have or have had depression, mood problems, or suicidal thoughts or behavior - have any other medical conditions - are pregnant or plan to become pregnant. It is not known if FELBATOL can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking FELBATOL. You and your healthcare provider will decide if you should take FELBATOL while you are pregnant. - If you become pregnant while taking FELBATOL, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334. - are breastfeeding or plan to breastfeed. FELBATOL may pass into your breast milk. You and your healthcare provider should decide if you should take FELBATOL while you breastfeed. - Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. - Taking FELBATOL with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. - Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. - Take FELBATOL exactly as your healthcare provider tells you. Your healthcare provider will tell you how much FELBATOL to take and when to take it. - Your healthcare provider may change your dose of FELBATOL. Do not change your dose of FELBATOL without talking to your healthcare provider. - Because of the risk of serious blood and liver problems, your healthcare provider may do blood tests before you start and while you take FELBATOL. - If you take too much FELBATOL, call your healthcare provider or local Poison Control Center right away. - Do not stop FELBATOL without first talking to your healthcare provider. - FELBATOL can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking FELBATOL, until you talk with your doctor. Taking FELBATOL with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. What are the possible side effects of FELBATOL? - See “WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT FELBATOL?” - The most common side effects of FELBATOL include: - weight loss - vomiting - trouble sleeping - nausea - dizziness - sleepiness - headache - double-vision - changes in the way that food tastes - These are not all the possible side effects of FELBATOL. For more information, ask your healthcare provider or pharmacist. - Tell your healthcare provider if you have any side effect that bothers you or that does not go away. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Store FELBATOL at room temperature between 68°F to 77°F (20°C to 25°C). - Keep FELBATOL and all medicines out of the reach of children. - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FELBATOL for a condition for which it was not prescribed. Do not give FELBATOL to other people, even if they have the same symptoms that you have. It may harm them. - This Medication Guide summarizes the most important information about FELBATOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about FELBATOL that is written for health professionals. - Active Ingredient: felbamate - Tablet Inactive Ingredients: starch, microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C yellow No. 6, D&C Yellow No. 10, and FD&C Red No. 40 (600 mg tablets only). - Suspension Inactive Ingredients: sorbitol, glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, simethicone, polysorbate 80, methylparaben, saccharain sodium, propylparaben, FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and purified water. - For more information, go to www. FELBATOL.com or call 1-800-526-3840. - This Medication Guide has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol - Alcohol-Felbamate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FELBATOL® # Look-Alike Drug Names There is limited information regarding Felbamate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Felbamate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Felbamate is a antiepileptic that is FDA approved for the treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anorexia, vomiting, insomnia, nausea, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Felbatol® is not indicated as a first line antiepileptic treatment. Felbatol® is recommended for use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. - If these criteria are met and the patient has been fully advised of the risk, and has provided written acknowledgement, Felbatol® can be considered for either monotherapy or adjunctive therapy in the treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children. ### Dosage - Felbatol® (felbamate) has been studied as monotherapy and adjunctive therapy in adults and as adjunctive therapy in children with seizures associated with Lennox-Gastaut syndrome. As Felbatol® is added to or substituted for existing AEDs, it is strongly recommended to reduce the dosage of those AEDs in the range of 20-33% to minimize side effects. - Dosage Adjustment in the Renally Impaired: Felbamate should be used with caution in patients with renal dysfunction. In the renally impaired, starting and maintenance doses should be reduced by one-half. Adjunctive therapy with medications which affect felbamate plasma concentrations, especially AEDs, may warrant further reductions in felbamate daily doses in patients with renal dysfunction. - The majority of patients received 3600 mg/day in clinical trials evaluating its use as both monotherapy and adjunctive therapy. - Monotherapy: (Initial therapy) Felbatol® (felbamate) has not been systematically evaluated as initial monotherapy. Initiate Felbatol® at 1200 mg/day in divided doses three or four times daily. The prescriber is advised to titrate previously untreated patients under close clinical supervision, increasing the dosage in 600-mg increments every 2 weeks to 2400 mg/day based on clinical response and thereafter to 3600 mg/day if clinically indicated. - Conversion to Monotherapy: Initiate Felbatol® at 1200 mg/day in divided doses three or four times daily. Reduce the dosage of concomitant AEDs by one-third at initiation of Felbatol® therapy. At week 2, increase the Felbatol® dosage to 2400 mg/day while reducing the dosage of other AEDs up to an additional one-third of their original dosage. At week 3, increase the Felbatol® dosage up to 3600 mg/day and continue to reduce the dosage of other AEDs as clinically indicated. - Adjunctive Therapy: Felbatol® should be added at 1200 mg/day in divided doses three or four times daily while reducing present AEDs by 20% in order to control plasma concentrations of concurrent phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase the dosage of Felbatol® by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is decreased. - While the above Felbatol® conversion guidelines may result in a Felbatol® 3600 mg/day dose within 3 weeks, in some patients titration to a 3600 mg/day Felbatol® dose has been achieved in as little as 3 days with appropriate adjustment of other AEDs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Felbamate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Felbamate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Adjunctive Therapy: Felbatol® should be added at 15 mg/kg/day in divided doses three or four times daily while reducing present AEDs by 20% in order to control plasma levels of concurrent phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase the dosage of Felbatol® by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is decreased. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Felbamate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Felbamate in pediatric patients. # Contraindications - Felbatol® is contraindicated in patients with known hypersensitivity to Felbatol®, its ingredients, or known sensitivity to other carbamates. It should not be used in patients with a history of any blood dyscrasia or hepatic dysfunction. # Warnings - See BOXED WARNING regarding aplastic anemia and hepatic failure. - Antiepileptic drugs should not be suddenly discontinued because of the possibility of increasing seizure frequency. - Antiepileptic drugs (AEDs) including Felbatol ®, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. - Table 1 shows absolute and relative risk by indication for all evaluated AEDs. - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. - Anyone considering prescribing Felbatol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Precautions - Dosage Adjustment in the Renally Impaired: A study in otherwise healthy individuals with renal dysfunction indicated that prolonged half-life and reduced clearance of felbamate are associated with diminishing renal function. Felbamate should be used with caution in patients with renal dysfunction - Laboratory Tests: Full hematologic evaluations should be performed before Felbatol® therapy, frequently during therapy, and for a significant period of time after discontinuation of Felbatol® therapy. While it might appear prudent to perform frequent CBCs in patients continuing on Felbatol®, there is no evidence that such monitoring will allow early detection of marrow suppression before aplastic anemia occurs. Complete pretreatment blood counts, including platelets and reticulocytes should be obtained as a baseline. If any hematologic abnormalities are detected during the course of treatment, immediate consultation with a hematologist is advised. Felbatol® should be discontinued if any evidence of bone marrow depression occurs. - See BOX WARNINGS for recommended monitoring of serum transaminases. If significant, confirmed liver abnormalities are detected during the course of Felbatol® treatment, Felbatol® should be discontinued immediately with continued liver function monitoring until values return to normal. - Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled that AEDs, including Felbatol®, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. - Pregnancy: Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 # Adverse Reactions ## Clinical Trials Experience - To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . - The most common adverse reactions seen in association with Felbatol® (felbamate) in adults during monotherapy are anorexia, vomiting, insomnia, nausea, and headache. The most common adverse reactions seen in association with Felbatol® in adults during adjunctive therapy are anorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache. - The most common adverse reactions seen in association with Felbatol® in children during adjunctive therapy are anorexia, vomiting, insomnia, headache, and somnolence. - The dropout rate because of adverse experiences or intercurrent illnesses among adult felbamate patients was 12 percent (120/977). The dropout rate because of adverse experiences or intercurrent illnesses among pediatric felbamate patients was six percent (22/357). In adults, the body systems associated with causing these withdrawals in order of frequency were: digestive (4.3%), psychological (2.2%), whole body (1.7%), neurological (1.5%), and dermatological (1.5%). In children, the body systems associated with causing these withdrawals in order of frequency were: digestive (1.7%), neurological (1.4%), dermatological (1.4%), psychological (1.1%), and whole body (1.0%). In adults, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency were: anorexia (1.6%), nausea (1.4%), rash (1.2%), and weight decrease (1.1%). In children, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency was rash (1.1%). - The prescriber should be aware that the figures cited in the following table cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different investigators, treatments, and uses including the use of Felbatol® (felbamate) as adjunctive therapy where the incidence of adverse events may be higher due to drug interactions. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. - The table that follows enumerates adverse events that occurred at an incidence of 2% or more among 58 adult patients who received Felbatol® monotherapy at dosages of 3600 mg/day in double-blind controlled trials. Table 3 presents reported adverse events that were classified using standard WHO-based dictionary terminology. - Table 4 enumerates adverse events that occurred at an incidence of 2% or more among 114 adult patients who received Felbatol® adjunctive therapy in add-on controlled trials at dosages up to 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology. - Many adverse experiences that occurred during adjunctive therapy may be a result of drug interactions. Adverse experiences during adjunctive therapy typically resolved with conversion to monotherapy, or with adjustment of the dosage of other antiepileptic drugs. Table 5 enumerates adverse events that occurred more than once among 31 pediatric patients who received Felbatol® up to 45 mg/kg/day or a maximum of 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology. - In the paragraphs that follow, the adverse clinical events, other than those in the preceding tables, that occurred in a total of 977 adults and 357 children exposed to Felbatol® (felbamate) and that are reasonably associated with its use are presented. They are listed in order of decreasing frequency. Because the reports cite events observed in open-label and uncontrolled studies, the role of Felbatol® in their causation cannot be reliably determined. - Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100-1/1000 patients; and rare events are those occurring in fewer than 1/1000 patients. - Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=1334) exposed to Felbatol®. - Frequent: Weight gain, asthenia, malaise, influenza-like symptoms; Rare: anaphylactoid reaction, substernal chest pain . - Frequent: Palpitation, tachycardia; Rare: supraventricular tachycardia. - Frequent: Agitation, psychological disturbance, aggressive reaction: Infrequent: hallucination, euphoria, suicide attempt, migraine. - Frequent: SGOT increased; Infrequent: esophagitis, appetite increased; Rare: GGT elevated. - Infrequent: Lymphadenopathy, leukopenia, leukocytosis, thrombocytopenia, granulocytopenia; Rare: antinuclear factor test positive, qualitative platelet disorder, agranulocytosis. - Infrequent: Hypokalemia, hyponatremia, LDH increased, alkaline phosphatase increased, hypophosphatemia; Rare: creatinine phosphokinase increased. - Infrequent: Dystonia. - Frequent: Pruritus; Infrequent: urticaria, bullous eruption; Rare: buccal mucous membrane swelling, Stevens-Johnson Syndrome. - Rare: Photosensitivity allergic reaction. ## Postmarketing Experience - Voluntary reports of adverse events in patients taking Felbatol® (usually in conjunction with other drugs) have been received since market introduction and may have no causal relationship with the drug(s). These include the following by body system: - neoplasm, sepsis, L.E. syndrome, SIDS, sudden death, edema, hypothermia, rigors, hyperpyrexia. - atrial fibrillation, atrial arrhythmia, cardiac arrest, torsade de pointes, cardiac failure, hypotension, hypertension, flushing, thrombophlebitis, ischemic necrosis, gangrene, peripheral ischemia, bradycardia, Henoch-Schönlein purpura (vasculitis). - delusion, paralysis, mononeuritis, cerebrovascular disorder, cerebral edema, coma, manic reaction, encephalopathy, paranoid reaction, nystagmus, choreoathetosis, extrapyramidal disorder, confusion, psychosis, status epilepticus, dyskinesia, dysarthria, respiratory depression, apathy, impaired concentration . - abnormal body odor, sweating, lichen planus, livedo reticularis, alopecia, toxic epidermal necrolysis. - hepatitis, hepatic failure, G.I. hemorrhage, hyperammonemia, pancreatitis, hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding, acquired megacolon, ileus, intestinal obstruction, enteritis, ulcerative stomatitis, glossitis, dysphagia, jaundice, gastric ulcer, gastric dilatation, gastroesophageal reflux. - fetal death, microcephaly, genital malformation, anencephaly, encephalocele. - increased and decreased prothrombin time, anemia, hypochromic anemia, aplastic anemia, pancytopenia, hemolytic uremic syndrome, increased mean corpuscular volume (mcv) with and without anemia, coagulation disorder, embolism-limb, disseminated intravascular coagulation, eosinophilia, hemolytic anemia, leukemia, including myelogenous leukemia, and lymphoma, including T-cell and B-cell lymphoproliferative disorders. - hypernatremia, hypoglycemia, SIADH, hypomagnesemia, dehydration, hyperglycemia, hypocalcemia. - arthralgia, muscle weakness, involuntary muscle contraction, rhabdomyolysis. - dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis, pleural effusion, respiratory insufficiency, pulmonary hemorrhage, asthma. - hemianopsia, decreased hearing, conjunctivitis. - menstrual disorder, acute renal failure, hepatorenal syndrome, hematuria, urinary retention, nephrosis, vaginal hemorrhage, abnormal renal function, dysuria, placental disorder. # Drug Interactions - The drug interaction data described in this section were obtained from controlled clinical trials and studies involving otherwise healthy adults with epilepsy. - Use in Conjunction with Other Antiepileptic Drugs: - The addition of Felbatol® to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs. The net effect of these interactions is summarized in Table 2: - Felbatol® causes an increase in steady-state phenytoin plasma concentrations. In 10 otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (Cmin) phenytoin plasma concentration was 17±5 micrograms/mL. The steady-state Cmin increased to 21±5 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 1800 mg/day in six of these subjects increased the steady-state phenytoin Cmin to 25±7 micrograms/mL. In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600 mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects. - In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of Felbatol® therapy resulted in phenytoin levels comparable to those prior to Felbatol® administration. - Felbatol® causes a decrease in the steady-state carbamazepine plasma concentrations and an increase in the steady-state carbamazepine epoxide plasma concentration. In nine otherwise healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (Cmin) carbamazepine concentration was 8±2 micrograms/mL. The carbamazepine steady-state Cmin decreased 31% to 5±1 micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered. Carbamazepine epoxide steady-state Cmin concentrations increased 57% from 1.0±0.3 to 1.6±0.4 micrograms/mL with the addition of felbamate. - In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen. - Felbatol® causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (Cmin) valproate plasma concentration was 63±16 micrograms/mL. The steady-state Cmin increased to 78±14 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state valproate Cmin to 96±25 micrograms/mL. Corresponding values for free valproate Cmin concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day Felbatol®, respectively. The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and 11.5%, with coadministration of 0, 1200, and 2400 mg/day of Felbatol®, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses of Felbatol®. - Coadministration of felbamate with phenobarbital causes an increase in phenobarbital plasma concentrations. In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state trough (Cmin) phenobarbital concentration was 14.2 micrograms/mL. The steady-state Cmin concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for one week. - Phenytoin causes an approximate doubling of the clearance of Felbatol® (felbamate) at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as monotherapy. - Carbamazepine causes an approximate 50% increase in the clearance of Felbatol® at steady-state and, therefore, the addition of carbamazepine results in an approximate 40% decrease in the steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as monotherapy. - Available data suggest that there is no significant effect of valproate on the clearance of Felbatol® at steady-state. Therefore, the addition of valproate is not expected to cause a clinically important effect on Felbatol® (felbamate) plasma concentrations. - It appears that phenobarbital may reduce plasma felbamate concentrations. Steady-state plasma felbamate concentrations were found to be 29% lower than the mean concentrations of a group of newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day. - The rate and extent of absorption of a 2400 mg dose of Felbatol® as monotherapy given as tablets was not affected when coadministered with antacids. - The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic parameters of Cmax, Cmin, AUC, Cl/kg or tmax at felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise healthy subjects with epilepsy. - A group of 24 nonsmoking, healthy white female volunteers established on an oral contraceptive regimen containing 30 µg ethinyl estradiol and 75 µg gestodene for at least 3 months received 2400 mg/day of felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles. Felbamate treatment resulted in a 42% decrease in the gestodene AUC 0-24, but no clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. No volunteer showed hormonal evidence of ovulation, but one volunteer reported intermenstrual bleeding during felbamate treatment. - There are no known interactions of Felbatol® with commonly used laboratory tests. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - The incidence of malformations was not increased compared to control in offspring of rats or rabbits given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human daily dose on a mg/kg basis, or 3 times (rat) and less than 2 times (rabbit) the human daily dose on a mg/m 2 basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation. The cause for these deaths is not known. The no effect dose for rat pup mortality was 6.9 times the human dose on a mg/kg basis or 1.5 times the human dose on a mg/m 2 basis. - Placental transfer of felbamate occurs in rat pups. There are, however, no 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. - To provide information regarding the effects of in utero exposure to Felbatol®, physicians are advised to recommend that pregnant patients taking Felbatol enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Felbamate in women who are pregnant. ### Labor and Delivery - The effect of felbamate on labor and delivery in humans is unknown. ### Nursing Mothers - Felbamate has been detected in human milk. The effect on the nursing infant is unknown ### Pediatric Use - The safety and effectiveness of Felbatol® in children other than those with Lennox-Gastaut syndrome has not been established. ### Geriatic Use - No systematic studies in geriatric patients have been conducted. Clinical studies of Felbatol® did not include sufficient numbers of patients 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, dosage 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 Felbamate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Felbamate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Felbamate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Felbamate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Felbamate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Felbamate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - perform frequent CBCs in patients continuing on Felbatol® - MONITORING OF SERUM TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT BASELINE AND PERIODICALLY THEREAFTER. # IV Compatibility There is limited information regarding IV Compatibility of Felbamate in the drug label. # Overdosage - Four subjects inadvertently received Felbatol® (felbamate) as adjunctive therapy in dosages ranging from 5400 to 7200 mg/day for durations between 6 and 51 days. One subject who received 5400 mg/day as monotherapy for 1 week reported no adverse experiences. Another subject attempted suicide by ingesting 12,000 mg of Felbatol® in a 12-hour period. The only adverse experiences reported were mild gastric distress and a resting heart rate of 100 bpm. No serious adverse reactions have been reported. General supportive measures should be employed if overdosage occurs. It is not known if felbamate is dialyzable. ### DRUG ABUSE AND DEPENDENCE - Abuse: Abuse potential was not evaluated in human studies. - Dependence: Rats administered felbamate orally at doses 8.3 times the recommended human dose 6 days each week for 5 consecutive weeks demonstrated no signs of physical dependence as measured by weight loss following drug withdrawal on day 7 of each week. # Pharmacology ## Mechanism of Action - The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. Felbamate is effective in mice and rats in the maximal electroshock test, the subcutaneous pentylenetetrazol seizure test, and the subcutaneous picrotoxin seizure test. Felbamate also exhibits anticonvulsant activity against seizures induced by intracerebroventricular administration of glutamate in rats and N-methyl-D,L-aspartic acid in mice. Protection against maximal electroshock-induced seizures suggests that felbamate may reduce seizure spread, an effect possibly predictive of efficacy in generalized tonic-clonic or partial seizures. Protection against pentylenetetrazol-induced seizures suggests that felbamate may increase seizure threshold, an effect considered to be predictive of potential efficacy in absence seizures. - Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory amino acid agonists NMDA, kainate, or quisqualate in vitro. - The monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock-induced seizure test in mice. The monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6) activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. These metabolites did not contribute significantly to the anticonvulsant action of felbamate. ## Structure - Felbatol® (felbamate) is an antiepileptic available as 400 mg and 600 mg tablets and as a 600 mg/5 mL suspension for oral administration. Its chemical name is 2-phenyl-1,3-propanediol dicarbamate. - Felbamate is a white to off-white crystalline powder with a characteristic odor. It is very slightly soluble in water, slightly soluble in ethanol, sparingly soluble in methanol, and freely soluble in dimethyl sulfoxide. The molecular weight is 238.24; felbamate's molecular formula is C 11 H 14 N 2 O 4 ; its structural formula is: - The inactive ingredients for Felbatol® (felbamate) Tablets 400 mg and 600 mg are starch, microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C Yellow No. 6, D&C Yellow No. 10, and FD&C Red No. 40 (600 mg tablets only). The inactive ingredients for Felbatol® (felbamate) Oral Suspension 600 mg/5 mL are sorbitol, glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, simethicone, polysorbate 80, methylparaben, saccharin sodium, propylparaben, FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and purified water. ## Pharmacodynamics - 1. Cardiovascular: In adults, there is no effect of felbamate on blood pressure. Small but statistically significant mean increases in heart rate were seen during adjunctive therapy and monotherapy; however, these mean increases of up to 5 bpm were not clinically significant. In children, no clinically relevant changes in blood pressure or heart rate were seen during adjunctive therapy or monotherapy with felbamate. - 2. Other Physiologic Effects: The only other change in vital signs was a mean decrease of approximately 1 respiration per minute in respiratory rate during adjunctive therapy in children. In adults, statistically significant mean reductions in body weight were observed during felbamate monotherapy and adjunctive therapy. In children, there were mean decreases in body weight during adjunctive therapy and monotherapy; however, these mean changes were not statistically significant. These mean reductions in adults and children were approximately 5% of the mean weights at baseline. ## Pharmacokinetics - The numbers in the pharmacokinetic section are mean ± standard deviation. - Felbamate is well-absorbed after oral administration. Over 90% of the radioactivity after a dose of 1000 mg 14 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been measured. The tablet and suspension were each shown to be bioequivalent to the capsule used in clinical trials, and pharmacokinetic parameters of the tablet and suspension are similar. There was no effect of food on absorption of the tablet; the effect of food on absorption of the suspension has not been evaluated. - Following oral administration, felbamate is the predominant plasma species (about 90% of plasma radioactivity). About 40-50% of absorbed dose appears unchanged in urine, and an additional 40% is present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity. - Binding of felbamate to human plasma protein was independent of felbamate concentrations between 10 and 310 micrograms/mL. Binding ranged from 22% to 25%, mostly to albumin, and was dependent on the albumin concentration. - Felbamate is excreted with a terminal half-life of 20-23 hours, which is unaltered after multiple doses. Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3600 mg is 30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1200 mg dose. Felbamate Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100-800 mg single doses and 1200-3600 mg daily doses. Cmin (trough) blood levels are also dose proportional. Multiple daily doses of 1200, 2400, and 3600 mg gave Cmin values of 30±5, 55±8, and 83±21 micrograms/mL (N=10 patients). Linear and dose proportional pharmacokinetics were also observed at doses above 3600 mg/day up to the maximum dose studied of 6000 mg/day. Felbamate gave dose proportional steady-state peak plasma concentrations in children age 4-12 over a range of 15, 30, and 45 mg/kg/day with peak concentrations of 17, 32, and 49 micrograms/mL. - The effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but plasma concentrations in males (N=5) and females (N=4) given felbamate have been similar. The effects of felbamate kinetics on hepatic functional impairment have not been evaluated. - Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy individuals with renal impairment. There was a 40-50% reduction in total body clearance and 9-15 hours prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal function. Reduced felbamate clearance and a longer half-life were associated with diminishing renal function. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in mice and rats. Mice received felbamate as a feed admixture for 92 weeks at doses of 300, 600, and 1200 mg/kg and rats were also dosed by feed admixture for 104 weeks at doses of 30, 100, and 300 (males) or 10, 30, and 100 (females) mg/kg. The maximum doses in these studies produced steady-state plasma concentrations that were equal to or less than the steady-state plasma concentrations in epileptic patients receiving 3600 mg/day. There was a statistically significant increase in hepatic cell adenomas in high-dose male and female mice and in high-dose female rats. Hepatic hypertrophy was significantly increased in a dose-related manner in mice, primarily males, but also in females. Hepatic hypertrophy was not found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the finding of liver hypertrophy resulting from liver enzyme induction has not been examined. There was a statistically significant increase in benign interstitial cell tumors of the testes in high-dose male rats receiving felbamate. The relevance of these findings to humans is unknown. - As a result of the synthesis process, felbamate could contain small amounts of two known animal carcinogens, the genotoxic compound ethyl carbamate (urethane) and the nongenotoxic compound methyl carbamate. It is theoretically possible that a 50 kg patient receiving 3600 mg of felbamate could be exposed to up to 0.72 micrograms of urethane and 1800 micrograms of methyl carbamate. These daily doses are approximately 1/35,000 (urethane) and 1/5,500 (methyl carbamate) on a mg/kg basis, and 1/10,000 (urethane) and 1/1,600 (methyl carbamate) on a mg/m2 basis, of the dose levels shown to be carcinogenic in rodents. Any presence of these two compounds in felbamate used in the lifetime carcinogenicity studies was inadequate to cause tumors. - Microbial and mammalian cell assays revealed no evidence of mutagenesis in the Ames Salmonella /microsome plate test, CHO/HGPRT mammalian cell forward gene mutation assay, sister chromatid exchange assay in CHO cells, and bone marrow cytogenetics assay. - Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 13.9 times the human total daily dose of 3600 mg on a mg/kg basis, or up to 3 times the human total daily dose on a mg/m2 basis. # Clinical Studies - The results of controlled clinical trials established the efficacy of Felbatol® (felbamate) as monotherapy and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and in partial and generalized seizures associated with Lennox-Gastaut syndrome in children. - Felbatol® (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy trial. Both trials were conducted according to an identical study design. During a 56-day baseline period, all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure frequencies were 12.4 per 28 days in the Felbatol® group and 21.3 per 28 days in the low-dose valproate group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the Felbatol® group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with Felbatol® or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or (4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each treatment group who met escape criteria. - In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the Felbatol® group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the percentage of patients who met escape criteria was 14% (3/21) in the Felbatol® group and 90% (19/21) in the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape criteria was statistically significant (P<.001) in favor of Felbatol®. These two studies by design were intended to demonstrate the effectiveness of Felbatol® monotherapy. The studies were not designed or intended to demonstrate comparative efficacy of the two drugs. For example, valproate was not used at the maximally effective dose. - A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods. Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at therapeutic levels were administered Felbatol® (felbamate) as add-on therapy at a starting dosage of 1400 mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56 patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with Felbatol® had fewer seizures than patients treated with placebo for each treatment sequence. There was a 23% (P=.018) difference in percentage seizure frequency reduction in favor of Felbatol®. - Felbatol® 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization, seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or more than one generalized seizure per day, and a minimum average of one partial or generalized tonic-clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was time to fourth seizure after randomization to treatment with Felbatol® or placebo. Thirteen (46%) of 28 patients in the Felbatol® group versus 29 (88%) of 33 patients in the placebo group experienced a fourth seizure. The median times to fourth seizure were greater than 28 days in the Felbatol® group and 5 days in the placebo group. The difference between Felbatol® and placebo in time to fourth seizure was statistically significant (P=.002) in favor of Felbatol®. - In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, Felbatol® 45 mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the Felbatol® group and 716 per month in the placebo group. Statistically significant differences in the effect on seizure frequency favored Felbatol® over placebo for total seizures (26% reduction vs. 5% increase, P<.001), atonic seizures (44% reduction vs. 7% reduction, P=.002), and generalized tonic-clonic seizures (40% reduction vs. 12% increase, P=.017). Parent/guardian global evaluations based on impressions of quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control significantly (P<.001) favored Felbatol® over placebo. - When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122 males and 142 females. # How Supplied - Felbatol® (felbamate) Tablets, 400 mg, are yellow, scored, capsule-shaped tablets, debossed 0430 on one side and FELBATOL 400 on the other; available in bottles of 100 (NDC 0037-0430-01). Felbatol® (felbamate) Tablets, 600 mg, are peach-colored, scored, capsule-shaped tablets, debossed 0431 on one side and FELBATOL 600 on the other; available in bottles of 100 (NDC 0037-0431-01). Felbatol® (felbamate) Oral Suspension, 600 mg/5 mL, is peach-colored; available in 8 oz bottles (NDC 0037-0442-67) and 32 oz bottles (NDC 0037-0442-17). ## Storage Shake suspension well before using. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense in tight container. # Images ## Drug Images ## Package and Label Display Panel ### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 100-COUNT BOTTLE, 400 MG TABLET NDC 0037-0430-01 100 Tablets Felbatol® (felbamate) 400 mg Tablets Rx Only MEDA Pharmaceuticals® LB-024G5-09 Rev. 12/10 Usual Dosage: For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense the accompanying Medication Guide to each patient. Dispense in a tight container. MEDA Pharmaceuticals® Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120 ### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 100-COUNT BOTTLE, 600 MG TABLET NDC 0037-0431-01 100 Tablets Felbatol® (felbamate) 600 mg Tablets Rx Only MEDA Pharmaceuticals® LB-024H5-09 Rev. 12/10 Usual Dosage: For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense the accompanying Medication Guide to each patient. Dispense in a tight container. MEDA Pharmaceuticals® Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120 ### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 8 FL OZ (237 ML) BOTTLE, 600 MG SUSPENSION NDC 0037-0442-67 8 fl oz (237 mL) Felbatol® (felbamate) Oral Suspension Each 5 mL contains 600 mg felbamate Rx Only SHAKE WELL MEDA Pharmaceuticals® LB-024F5-10 Rev. 12/10 Usual Dosage: For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense the accompanying Medication Guide to each patient. Dispense in a tight container. MEDA Pharmaceuticals® Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120 ### Ingredients and Appearance # Patient Counseling Information - Patients should be informed that the use of Felbatol® is associated with aplastic anemia and hepatic failure, potentially fatal conditions acutely or over a long term. - The physician should obtain written acknowledgement prior to initiation of Felbatol® therapy (see PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM section). - Patients should be instructed to read the Medication Guide supplied as required by law when Felbatol® is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. - Aplastic anemia in the general population is relatively rare. The absolute risk for the individual patient is not known with any degree of reliability, but patients on Felbatol® may be at more than a 100 fold greater risk for developing the syndrome than the general population. - The long term outlook for patients with aplastic anemia is variable. Although many patients are apparently cured, others require repeated transfusions and other treatments for relapses, and some, although surviving for years, ultimately develop serious complications that sometimes prove fatal (e.g., leukemia). - At present there is no way to predict who is likely to get aplastic anemia, nor is there a documented effective means to monitor the patient so as to avoid and/or reduce the risk. Patients with a history of any blood dyscrasia should not receive Felbatol®. - Patients should be advised to be alert for signs of infection, bleeding, easy bruising, or signs of anemia (fatigue, weakness, lassitude, etc.) and should be advised to report to the physician immediately if any such signs or symptoms appear. - Hepatic failure in the general population is relatively rare. The absolute risk for an individual patient is not known with any degree of reliability but patients on Felbatol® are at a greater risk for developing hepatic failure than the general population. - At present, there is no way to predict who is likely to develop hepatic failure, however, patients with a history of hepatic dysfunction should not be started on Felbatol®. - Patients should be advised to follow their physician's directives for liver function testing both before starting Felbatol® (felbamate) and at frequent intervals while taking Felbatol®. - Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they should occur. ### MEDICATION GUIDE - Read this Medication Guide before you start taking FELBATOL and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. - Do not stop taking FELBATOL without first talking to your healthcare provider. - Stopping FELBATOL suddenly can cause serious problems. - FELBATOL can cause serious side effects, including: - 1. FELBATOL may cause serious blood problems that may be life-threatening. - Call your healthcare provider right away if you have any of the following symptoms: - Fever, sore throat or other infections that come and go or do not go away - Frequent infections or an infection that does not go away - Easy bruising - Red or purple spots on your body - Bleeding gums or nose bleeds - Severe fatigue or weakness - 2. Liver problems that may be life-threatening. Call your healthcare provider right away if you have any of these symptoms: - yellowing of your skin or the whites of your eyes (jaundice) - dark urine - nausea or vomiting - loss of appetite - pain on the right side of your stomach (abdomen) - 3. Like other antiepileptic drugs, FELBATOL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. - Call your healthcare provider right away if you have any of these symptoms, - especially if they are new, worse, or worry you: - thoughts about suicide or dying - attempts to commit suicide - new or worse depression - new or worse anxiety - feeling agitated or restless - panic attacks - trouble sleeping (insomnia) - new or worse irritability - acting aggressive, being angry, or violent - acting on dangerous impulses - an extreme increase in activity and talking (mania) - other unusual changes in behavior or mood - Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. - Keep all follow-up visits with your healthcare provider as scheduled. - Call your healthcare provider between visits as needed, especially if you are worried about symptoms. - Stopping FELBATOL suddenly can cause serious problems. You should talk to your health care provider before stopping. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures. - Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. - FELBATOL is a prescription medicine used when other treatments have failed in: - adults alone or with other medicines to treat: - partial seizures with and without generalization - children with other medicines to treat: - seizures associated with Lennox-Gastaut syndrome - Do not take FELBATOL if you: - are allergic to felbamate, carbamates or any of the ingredients in FELBATOL. See the end of this Medication Guide for a complete list of ingredients in FELBATOL. - have or have had blood problems - have or have had liver problems - Before you take FELBATOL, tell your healthcare provider if you: - have kidney problems - have or have had depression, mood problems, or suicidal thoughts or behavior - have any other medical conditions - are pregnant or plan to become pregnant. It is not known if FELBATOL can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking FELBATOL. You and your healthcare provider will decide if you should take FELBATOL while you are pregnant. - If you become pregnant while taking FELBATOL, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334. - are breastfeeding or plan to breastfeed. FELBATOL may pass into your breast milk. You and your healthcare provider should decide if you should take FELBATOL while you breastfeed. - Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. - Taking FELBATOL with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. - Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. - Take FELBATOL exactly as your healthcare provider tells you. Your healthcare provider will tell you how much FELBATOL to take and when to take it. - Your healthcare provider may change your dose of FELBATOL. Do not change your dose of FELBATOL without talking to your healthcare provider. - Because of the risk of serious blood and liver problems, your healthcare provider may do blood tests before you start and while you take FELBATOL. - If you take too much FELBATOL, call your healthcare provider or local Poison Control Center right away. - Do not stop FELBATOL without first talking to your healthcare provider. - FELBATOL can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking FELBATOL, until you talk with your doctor. Taking FELBATOL with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. What are the possible side effects of FELBATOL? - See “WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT FELBATOL?” - The most common side effects of FELBATOL include: - weight loss - vomiting - trouble sleeping - nausea - dizziness - sleepiness - headache - double-vision - changes in the way that food tastes - These are not all the possible side effects of FELBATOL. For more information, ask your healthcare provider or pharmacist. - Tell your healthcare provider if you have any side effect that bothers you or that does not go away. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Store FELBATOL at room temperature between 68°F to 77°F (20°C to 25°C). - Keep FELBATOL and all medicines out of the reach of children. - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FELBATOL for a condition for which it was not prescribed. Do not give FELBATOL to other people, even if they have the same symptoms that you have. It may harm them. - This Medication Guide summarizes the most important information about FELBATOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about FELBATOL that is written for health professionals. - Active Ingredient: felbamate - Tablet Inactive Ingredients: starch, microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C yellow No. 6, D&C Yellow No. 10, and FD&C Red No. 40 (600 mg tablets only). - Suspension Inactive Ingredients: sorbitol, glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, simethicone, polysorbate 80, methylparaben, saccharain sodium, propylparaben, FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and purified water. - For more information, go to www. FELBATOL.com or call 1-800-526-3840. - This Medication Guide has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol - Alcohol-Felbamate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FELBATOL®[1] # Look-Alike Drug Names There is limited information regarding Felbamate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Felbamate
182ce6d0d18f044f3fa888537ca9d60e98ceafdf	wikidoc	Piroxicam	Piroxicam # 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 Piroxicam is a analgesic, anti-inflammatory agent that is FDA approved for the treatment of osteoarthritis, rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, pruritus, rash, abdominal pain, constipation, diarrhea, flatulence, heartburn, indigestion, loss of appetite, nausea, vomiting, anemia, increased liver function test, dizziness, headache, tinnitus, abnormal renal function. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Carefully consider the potential benefits and risks of piroxicam capsules and other treatment options before deciding to use piroxicam capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Piroxicam capsules are indicated: - For relief of the signs and symptoms of osteoarthritis. - For relief of the signs and symptoms of rheumatoid arthritis. - Dosing Information - The manufacturer recommends a single daily dose of 20 milligrams for treating OSTEOARTHRITIS. The daily dose may be divided. - Doses of 10 to 40 milligrams orally daily have produced therapeutic results in the available clinical studies. Available data indicate that doses of 30 to 40 milligrams/day provide no additional benefit over 20 milligrams/day; doses higher than 20 milligrams are associated with a significant increase in the incidence of gastrointestinal (GI) toxicity and ulceration, especially in the elderly. - A long plasma half-life permits once daily dosing and plasma steady-state levels are reached within 7 to 12 days; thus therapeutic effects should not be assessed for 2 weeks - Dosing Information - The manufacturer recommends a single daily dose of 20 milligrams for treating RHEUMATOID ARTHRITIS. The daily dose may be divided. - Doses of 10 to 40 milligrams orally daily have produced therapeutic results in the available clinical studies. Available data indicate that doses of 30 to 40 milligrams/day provide no additional benefit over 20 milligrams/day; doses higher than 20 milligrams are associated with a significant increase in the incidence of gastrointestinal (GI) toxicity and ulceration, especially in the elderly. - A long plasma half-life permits once daily dosing and plasma steady-state levels are reached within 7 to 12 days; thus therapeutic effects should not be assessed for 2 weeks ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Piroxicam in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Piroxicam was effective for treating primary dysmenorrhea. Effective doses were 2 tablets (40 milligrams) with food in the AM for 2 days, followed by 20 milligrams daily until abatement of symptoms or subsidence of menstruation. - Dosing Information - To achieve a rapid onset of effect as required for the treatment of acute gout, therapy should be initiated with a loading dose of 40 milligrams daily for 5 to 7 days. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Piroxicam in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Piroxicam in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Piroxicam in pediatric patients. # Contraindications - Piroxicam capsules are contraindicated in patients with known hypersensitivity to piroxicam. - Piroxicam capsules should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. - Piroxicam capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. # Warnings Cardiovascular Effects Cardiovascular Thrombotic Events - Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. - There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation). - Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension - NSAIDs, including piroxicam capsules, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including piroxicam capsules, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema - Fluid retention and edema have been observed in some patients taking NSAIDs. Piroxicam capsules should be used with caution in patients with fluid retention or heart failure. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation - NSAIDs, including piroxicam capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. - NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and, therefore, special care should be taken in treating this population. - To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease - No information is available from controlled clinical studies regarding the use of piroxicam capsules in patients with advanced renal disease. Therefore, treatment with piroxicam capsules is not recommended in these patients with advanced renal disease. If piroxicam capsule therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions - As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to piroxicam capsules. Piroxicam capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions - NSAIDs, including piroxicam capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Other Hypersensitivity Reactions - A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness have occasionally occurred in conjunction with the use of piroxicam. These include arthralgias, pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis. Pregnancy - In late pregnancy, as with other NSAIDs, piroxicam capsules should be avoided because it may cause premature closure of the ductus arteriosus. ### Precautions General - Piroxicam capsules cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. - The pharmacological activity of piroxicam capsules in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects - Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including piroxicam capsules. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with piroxicam capsules. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), piroxicam capsules should be discontinued (see ADVERSE REACTIONS). Hematological Effects - Anemia is sometimes seen in patients receiving NSAIDs, including piroxicam capsules. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including piroxicam capsules, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. - NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving piroxicam capsules who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Ophthalmologic Effects - Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is recommended that patients who develop visual complaints during treatment with piroxicam capsules have ophthalmic evaluations. Preexisting Asthma - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, piroxicam capsules should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. - Piroxicam capsules, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). - Piroxicam capsules, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,Bleeding,andPerforation). - Piroxicam capsules, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. - Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. - Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). - In late pregnancy, as with other NSAIDs, piroxicam capsules should be avoided because they may cause premature closure of the ductus arteriosus. Laboratory Tests - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.), or if abnormal liver tests persist or worsen, piroxicam capsules should be discontinued. # Adverse Reactions ## Clinical Trials Experience - In patients taking piroxicam capsules or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are: - Cardiovascular System: Edema. - Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal), vomiting. - Hemic and Lymphatic System: Anemia, increased bleeding time. - Nervous System: Dizziness, headache. - Skin and Appendages: Pruritus, rash. - Special Senses: Tinnitus. - Urogenital System: Abnormal renal function. - Additional adverse experiences reported occasionally include: - Body As a Whole: Fever, infection, sepsis. - Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope. - Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice, melena, rectal bleeding, stomatitis. - Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial rash, thrombocytopenia. - Metabolic and Nutritional: Weight changes. - Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo. - Respiratory System: Asthma, dyspnea. - Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat. - Special Senses: Blurred vision. - Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, oliguria/polyuria, proteinuria, renal failure. - Other adverse reactions which occur rarely are: - Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic), serum sickness. - Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction, palpitations, vasculitis. - Digestive System: Eructation, liver failure, pancreatitis. - Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia. - Hypersensitivity: Positive ANA. - Metabolic and Nutritional: Hyperglycemia, hypoglycemia. - Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations. - Respiratory: Respiratory depression, pneumonia. - Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, onycholysis, Stevens-Johnson syndrome, urticaria, vesiculobullous reaction. - Special Senses: Conjunctivitis, hearing impairment, swollen eyes. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Piroxicam in the drug label. # Drug Interactions Highly Protein Bound Drugs - Piroxicam is highly protein bound and, therefore, might be expected to displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage requirements when administering piroxicam capsules to patients on other highly protein bound drugs. Aspirin - When piroxicam is administered with aspirin, its protein binding is reduced, although the clearance of free piroxicam is not altered. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when piroxicam is administered (20 mg/day) in conjunction with aspirin (3900 mg/day). The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Methotrexate - NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. ACE-Inhibitors - Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Diuretics - Clinical studies, as well as postmarketing observations, have shown that piroxicam capsules can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium - NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin - The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy category C - Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Piroxicam capsules are not recommended for use in pregnant women since safety has not been established in humans. Piroxicam capsules should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects - Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. In animal studies of piroxicam, gastrointestinal tract toxicity was increased in pregnant females in the last trimester of pregnancy compared to nonpregnant females or females in earlier trimesters of pregnancy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Piroxicam in women who are pregnant. ### Labor and Delivery - In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of piroxicam on labor and delivery in pregnant women are unknown. ### Nursing Mothers - Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Piroxicam capsules are not recommended for use in nursing mothers. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - As with any NSAID, caution should be exercised in treating the elderly (65 years and older). Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and, therefore, care should be taken in treating this population. In addition to a past history of ulcer disease, older age and poor general health status (among other factors) may increase the risk for GI bleeding. To minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,Bleeding, and Perforation). - As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of non-steroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS, Renal Effects). - In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant disease or other drug therapy. ### Gender - There is no FDA guidance on the use of Piroxicam with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Piroxicam with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Piroxicam in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Piroxicam in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Piroxicam in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Piroxicam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Carefully consider the potential benefits and risks of piroxicam capsules USP and other treatment options before deciding to use piroxicam capsules USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). - After observing the response to initial therapy with piroxicam capsules USP, the dose and frequency should be adjusted to suit an individual patient's needs. - For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally once per day. If desired, the daily dose may be divided. Because of the long half-life of piroxicam capsules USP, steady-state blood levels are not reached for 7 to 12 days. Therefore, although the therapeutic effects of piroxicam are evident early in treatment, there is a progressive increase in response over several weeks and the effect of therapy should not be assessed for two weeks. ### Monitoring - There is limited information regarding Monitoring of Piroxicam in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Piroxicam in the drug label. # Overdosage - Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. - Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be considered when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the use of multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by more than 50% and systemic bioavailability by as much as 37% when activated charcoal is given as late as 6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. # Pharmacology ## Mechanism of Action There is limited information regarding Piroxicam Mechanism of Action in the drug label. ## Structure - Piroxicam capsules USP contain piroxicam which is a member of the oxicam group of non-steroidal anti-inflammatory drugs (NSAIDs). Each dark green and olive capsule contains 10 mg piroxicam, each dark green capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is 4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide. Members of the oxicam family are not carboxylic acids, but they are acidic by virtue of the enolic 4-hydroxy substituent. Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous alkaline solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). It has the following structural formula: C15H13N3O4S M.W. 331.35 - Each capsule, for oral administration, contains 10 mg or 20 mg piroxicam. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, corn starch, D&C Yellow No. 10, FD&C Green No. 3, gelatin, lactose, magnesium stearate, povidone, shellac, sodium lauryl sulfate, and titanium dioxide. The imprinting ink may contain antifoam DC 1510, 2-ethoxyethanol, lecithin, poly(dimethylsiloxane), propylene glycol, silicon dioxide, and sodium hydroxide. - Piroxicam capsules USP, 10 mg also contain: black iron oxide, FD&C Blue No. 1, and yellow iron oxide. ## Pharmacodynamics - Piroxicam capsules are a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of piroxicam, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. ## Pharmacokinetics Absorption - Piroxicam is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single 20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily ingestion of piroxicam capsules, 20 mg, usually stabilize at 3 to 8 mcg/mL. Most patients approximate steady- state plasma levels within 7 to 12 days. Higher levels, which approximate steady-state at two to three weeks, have been observed in patients in whom longer plasma half-lives of piroxicam occurred. - With food there is a slight delay in the rate but not the extent of absorption following oral administration. The concomitant administration of antacids (aluminum hydroxide or aluminum hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of orally administered piroxicam. Distribution - The apparent volume of distribution of piroxicam is approximately 0.14 L/kg. Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Metabolism - Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the 5'-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics and Special Populations, Poor Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are reported to not have any anti-inflammatory activity. - Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms compared to normal metabolizer type subjects (see Pharmacogenetics and Special Populations, Poor Metabolizers of CYP2C9 Substrates). Excretion - Piroxicam and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as in the feces. Approximately 5% of a piroxicam dose is excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours. Pharmacogenetics - CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C92 and CYP2C93 polymorphisms. Limited data from one published report that included nine subjects each with heterozygous CYP2C91/2 and CYP2C91/3 genotypes and one subject with the homozygous CYP2C93/3 genotype showed piroxicam systemic levels that were 1.7, 1.7 and 5.3 fold, respectively, higher compared to the 17 subjects with CYP2C91/1 or normal metabolizer genotype. The pharmacokinetics of piroxicam have not been evaluated in subjects with other CYP2C9 polymorphisms, such as 5, 6, 9 and 11. It is estimated that the frequency of the homozygous 3/3 genotype is 0.3% to 1.0% in various ethnic groups. Special Populations Pediatric - Piroxicam capsules have not been investigated in pediatric patients. Race - Pharmacokinetic differences due to race have not been identified. Hepatic Insufficiency - The effects of hepatic disease on piroxicam pharmacokinetics have not been established. However, a substantial portion of piroxicam elimination occurs by hepatic metabolism. Consequently, patients with hepatic disease may require reduced doses of piroxicam as compared to patients with normal hepatic function. Poor Metabolizers of CYP2C9 Substrates - Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Renal Insufficiency - Piroxicam pharmacokinetics have been investigated in patients with renal insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing adjustments. However, the pharmacokinetic properties of piroxicam in patients with severe renal insufficiency or those receiving hemodialysis are not known. Other Information - In controlled clinical trials, the effectiveness of piroxicam has been established for both acute exacerbations and long-term management of rheumatoid arthritis and osteoarthritis. - The therapeutic effects of piroxicam are evident early in the treatment of both diseases with a progressive increase in response over several (8 to 12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation. - Doses of 20 mg/day piroxicam display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus. - Piroxicam has been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a “steroid-sparing” effect has not been adequately studied to date. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Subacute, acute, and chronic toxicity studies have been carried out in rats, mice, dogs, and monkeys. The pathology most often seen was that characteristically associated with the animal toxicology of anti-inflammatory agents: renal papillary necrosis (see PRECAUTIONS) and gastrointestinal lesions. - Reproductive studies revealed no impairment of fertility in animals. # Clinical Studies - There is limited information regarding Clinical Studies of Piroxicam in the drug label. # How Supplied - Piroxicam capsules USP, 10 mg are a #2 capsule with a dark green cap and an olive body imprinted "93" "756" on the cap and body. They are available in bottles of 100. - Piroxicam capsules USP, 20 mg are a #2 capsule with a dark green cap and a dark green body imprinted "93" "757" on the cap and body. They are available in bottles of 100 and 500. ## Storage - Store at 20° to 25°C (68° to 77°F) . - Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. - Piroxicam capsules, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). - Piroxicam capsules, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,Bleeding,andPerforation). - Piroxicam capsules, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. - Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. - Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). - In late pregnancy, as with other NSAIDs, piroxicam capsules should be avoided because they may cause premature closure of the ductus arteriosus. # Precautions with Alcohol - Alcohol-Piroxicam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Feldene # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Piroxicam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Piroxicam is a analgesic, anti-inflammatory agent that is FDA approved for the treatment of osteoarthritis, rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, pruritus, rash, abdominal pain, constipation, diarrhea, flatulence, heartburn, indigestion, loss of appetite, nausea, vomiting, anemia, increased liver function test, dizziness, headache, tinnitus, abnormal renal function. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Carefully consider the potential benefits and risks of piroxicam capsules and other treatment options before deciding to use piroxicam capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Piroxicam capsules are indicated: - For relief of the signs and symptoms of osteoarthritis. - For relief of the signs and symptoms of rheumatoid arthritis. - Dosing Information - The manufacturer recommends a single daily dose of 20 milligrams for treating OSTEOARTHRITIS. The daily dose may be divided. - Doses of 10 to 40 milligrams orally daily have produced therapeutic results in the available clinical studies. Available data indicate that doses of 30 to 40 milligrams/day provide no additional benefit over 20 milligrams/day; doses higher than 20 milligrams are associated with a significant increase in the incidence of gastrointestinal (GI) toxicity and ulceration, especially in the elderly. - A long plasma half-life permits once daily dosing and plasma steady-state levels are reached within 7 to 12 days; thus therapeutic effects should not be assessed for 2 weeks - Dosing Information - The manufacturer recommends a single daily dose of 20 milligrams for treating RHEUMATOID ARTHRITIS. The daily dose may be divided. - Doses of 10 to 40 milligrams orally daily have produced therapeutic results in the available clinical studies. Available data indicate that doses of 30 to 40 milligrams/day provide no additional benefit over 20 milligrams/day; doses higher than 20 milligrams are associated with a significant increase in the incidence of gastrointestinal (GI) toxicity and ulceration, especially in the elderly. - A long plasma half-life permits once daily dosing and plasma steady-state levels are reached within 7 to 12 days; thus therapeutic effects should not be assessed for 2 weeks ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Piroxicam in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Piroxicam was effective for treating primary dysmenorrhea. Effective doses were 2 tablets (40 milligrams) with food in the AM for 2 days, followed by 20 milligrams daily until abatement of symptoms or subsidence of menstruation. - Dosing Information - To achieve a rapid onset of effect as required for the treatment of acute gout, therapy should be initiated with a loading dose of 40 milligrams daily for 5 to 7 days. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Piroxicam in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Piroxicam in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Piroxicam in pediatric patients. # Contraindications - Piroxicam capsules are contraindicated in patients with known hypersensitivity to piroxicam. - Piroxicam capsules should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. - Piroxicam capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. # Warnings Cardiovascular Effects Cardiovascular Thrombotic Events - Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. - There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation). - Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension - NSAIDs, including piroxicam capsules, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including piroxicam capsules, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema - Fluid retention and edema have been observed in some patients taking NSAIDs. Piroxicam capsules should be used with caution in patients with fluid retention or heart failure. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation - NSAIDs, including piroxicam capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. - NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and, therefore, special care should be taken in treating this population. - To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease - No information is available from controlled clinical studies regarding the use of piroxicam capsules in patients with advanced renal disease. Therefore, treatment with piroxicam capsules is not recommended in these patients with advanced renal disease. If piroxicam capsule therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions - As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to piroxicam capsules. Piroxicam capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions - NSAIDs, including piroxicam capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Other Hypersensitivity Reactions - A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness have occasionally occurred in conjunction with the use of piroxicam. These include arthralgias, pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis. Pregnancy - In late pregnancy, as with other NSAIDs, piroxicam capsules should be avoided because it may cause premature closure of the ductus arteriosus. ### Precautions General - Piroxicam capsules cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. - The pharmacological activity of piroxicam capsules in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects - Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including piroxicam capsules. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with piroxicam capsules. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), piroxicam capsules should be discontinued (see ADVERSE REACTIONS). Hematological Effects - Anemia is sometimes seen in patients receiving NSAIDs, including piroxicam capsules. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including piroxicam capsules, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. - NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving piroxicam capsules who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Ophthalmologic Effects - Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is recommended that patients who develop visual complaints during treatment with piroxicam capsules have ophthalmic evaluations. Preexisting Asthma - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, piroxicam capsules should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. - Piroxicam capsules, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). - Piroxicam capsules, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,Bleeding,andPerforation). - Piroxicam capsules, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. - Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. - Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). - In late pregnancy, as with other NSAIDs, piroxicam capsules should be avoided because they may cause premature closure of the ductus arteriosus. Laboratory Tests - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.), or if abnormal liver tests persist or worsen, piroxicam capsules should be discontinued. # Adverse Reactions ## Clinical Trials Experience - In patients taking piroxicam capsules or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are: - Cardiovascular System: Edema. - Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal), vomiting. - Hemic and Lymphatic System: Anemia, increased bleeding time. - Nervous System: Dizziness, headache. - Skin and Appendages: Pruritus, rash. - Special Senses: Tinnitus. - Urogenital System: Abnormal renal function. - Additional adverse experiences reported occasionally include: - Body As a Whole: Fever, infection, sepsis. - Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope. - Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice, melena, rectal bleeding, stomatitis. - Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial rash, thrombocytopenia. - Metabolic and Nutritional: Weight changes. - Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo. - Respiratory System: Asthma, dyspnea. - Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat. - Special Senses: Blurred vision. - Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, oliguria/polyuria, proteinuria, renal failure. - Other adverse reactions which occur rarely are: - Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic), serum sickness. - Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction, palpitations, vasculitis. - Digestive System: Eructation, liver failure, pancreatitis. - Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia. - Hypersensitivity: Positive ANA. - Metabolic and Nutritional: Hyperglycemia, hypoglycemia. - Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations. - Respiratory: Respiratory depression, pneumonia. - Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, onycholysis, Stevens-Johnson syndrome, urticaria, vesiculobullous reaction. - Special Senses: Conjunctivitis, hearing impairment, swollen eyes. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Piroxicam in the drug label. # Drug Interactions Highly Protein Bound Drugs - Piroxicam is highly protein bound and, therefore, might be expected to displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage requirements when administering piroxicam capsules to patients on other highly protein bound drugs. Aspirin - When piroxicam is administered with aspirin, its protein binding is reduced, although the clearance of free piroxicam is not altered. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when piroxicam is administered (20 mg/day) in conjunction with aspirin (3900 mg/day). The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Methotrexate - NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. ACE-Inhibitors - Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Diuretics - Clinical studies, as well as postmarketing observations, have shown that piroxicam capsules can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium - NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin - The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy category C - Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Piroxicam capsules are not recommended for use in pregnant women since safety has not been established in humans. Piroxicam capsules should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects - Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. In animal studies of piroxicam, gastrointestinal tract toxicity was increased in pregnant females in the last trimester of pregnancy compared to nonpregnant females or females in earlier trimesters of pregnancy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Piroxicam in women who are pregnant. ### Labor and Delivery - In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of piroxicam on labor and delivery in pregnant women are unknown. ### Nursing Mothers - Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Piroxicam capsules are not recommended for use in nursing mothers. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - As with any NSAID, caution should be exercised in treating the elderly (65 years and older). Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and, therefore, care should be taken in treating this population. In addition to a past history of ulcer disease, older age and poor general health status (among other factors) may increase the risk for GI bleeding. To minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,Bleeding, and Perforation). - As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of non-steroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS, Renal Effects). - In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant disease or other drug therapy. ### Gender - There is no FDA guidance on the use of Piroxicam with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Piroxicam with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Piroxicam in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Piroxicam in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Piroxicam in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Piroxicam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Carefully consider the potential benefits and risks of piroxicam capsules USP and other treatment options before deciding to use piroxicam capsules USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). - After observing the response to initial therapy with piroxicam capsules USP, the dose and frequency should be adjusted to suit an individual patient's needs. - For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally once per day. If desired, the daily dose may be divided. Because of the long half-life of piroxicam capsules USP, steady-state blood levels are not reached for 7 to 12 days. Therefore, although the therapeutic effects of piroxicam are evident early in treatment, there is a progressive increase in response over several weeks and the effect of therapy should not be assessed for two weeks. ### Monitoring - There is limited information regarding Monitoring of Piroxicam in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Piroxicam in the drug label. # Overdosage - Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. - Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be considered when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the use of multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by more than 50% and systemic bioavailability by as much as 37% when activated charcoal is given as late as 6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. # Pharmacology ## Mechanism of Action There is limited information regarding Piroxicam Mechanism of Action in the drug label. ## Structure - Piroxicam capsules USP contain piroxicam which is a member of the oxicam group of non-steroidal anti-inflammatory drugs (NSAIDs). Each dark green and olive capsule contains 10 mg piroxicam, each dark green capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is 4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide. Members of the oxicam family are not carboxylic acids, but they are acidic by virtue of the enolic 4-hydroxy substituent. Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous alkaline solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). It has the following structural formula: C15H13N3O4S M.W. 331.35 - Each capsule, for oral administration, contains 10 mg or 20 mg piroxicam. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, corn starch, D&C Yellow No. 10, FD&C Green No. 3, gelatin, lactose, magnesium stearate, povidone, shellac, sodium lauryl sulfate, and titanium dioxide. The imprinting ink may contain antifoam DC 1510, 2-ethoxyethanol, lecithin, poly(dimethylsiloxane), propylene glycol, silicon dioxide, and sodium hydroxide. - Piroxicam capsules USP, 10 mg also contain: black iron oxide, FD&C Blue No. 1, and yellow iron oxide. ## Pharmacodynamics - Piroxicam capsules are a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of piroxicam, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. ## Pharmacokinetics Absorption - Piroxicam is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single 20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily ingestion of piroxicam capsules, 20 mg, usually stabilize at 3 to 8 mcg/mL. Most patients approximate steady- state plasma levels within 7 to 12 days. Higher levels, which approximate steady-state at two to three weeks, have been observed in patients in whom longer plasma half-lives of piroxicam occurred. - With food there is a slight delay in the rate but not the extent of absorption following oral administration. The concomitant administration of antacids (aluminum hydroxide or aluminum hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of orally administered piroxicam. Distribution - The apparent volume of distribution of piroxicam is approximately 0.14 L/kg. Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Metabolism - Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the 5'-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics and Special Populations, Poor Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are reported to not have any anti-inflammatory activity. - Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms compared to normal metabolizer type subjects (see Pharmacogenetics and Special Populations, Poor Metabolizers of CYP2C9 Substrates). Excretion - Piroxicam and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as in the feces. Approximately 5% of a piroxicam dose is excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours. Pharmacogenetics - CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C92 and CYP2C93 polymorphisms. Limited data from one published report that included nine subjects each with heterozygous CYP2C91/2 and CYP2C91/3 genotypes and one subject with the homozygous CYP2C93/3 genotype showed piroxicam systemic levels that were 1.7, 1.7 and 5.3 fold, respectively, higher compared to the 17 subjects with CYP2C91/1 or normal metabolizer genotype. The pharmacokinetics of piroxicam have not been evaluated in subjects with other CYP2C9 polymorphisms, such as 5, 6, 9 and 11. It is estimated that the frequency of the homozygous 3/3 genotype is 0.3% to 1.0% in various ethnic groups. Special Populations Pediatric - Piroxicam capsules have not been investigated in pediatric patients. Race - Pharmacokinetic differences due to race have not been identified. Hepatic Insufficiency - The effects of hepatic disease on piroxicam pharmacokinetics have not been established. However, a substantial portion of piroxicam elimination occurs by hepatic metabolism. Consequently, patients with hepatic disease may require reduced doses of piroxicam as compared to patients with normal hepatic function. Poor Metabolizers of CYP2C9 Substrates - Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Renal Insufficiency - Piroxicam pharmacokinetics have been investigated in patients with renal insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing adjustments. However, the pharmacokinetic properties of piroxicam in patients with severe renal insufficiency or those receiving hemodialysis are not known. Other Information - In controlled clinical trials, the effectiveness of piroxicam has been established for both acute exacerbations and long-term management of rheumatoid arthritis and osteoarthritis. - The therapeutic effects of piroxicam are evident early in the treatment of both diseases with a progressive increase in response over several (8 to 12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation. - Doses of 20 mg/day piroxicam display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus. - Piroxicam has been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a “steroid-sparing” effect has not been adequately studied to date. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Subacute, acute, and chronic toxicity studies have been carried out in rats, mice, dogs, and monkeys. The pathology most often seen was that characteristically associated with the animal toxicology of anti-inflammatory agents: renal papillary necrosis (see PRECAUTIONS) and gastrointestinal lesions. - Reproductive studies revealed no impairment of fertility in animals. # Clinical Studies - There is limited information regarding Clinical Studies of Piroxicam in the drug label. # How Supplied - Piroxicam capsules USP, 10 mg are a #2 capsule with a dark green cap and an olive body imprinted "93" "756" on the cap and body. They are available in bottles of 100. - Piroxicam capsules USP, 20 mg are a #2 capsule with a dark green cap and a dark green body imprinted "93" "757" on the cap and body. They are available in bottles of 100 and 500. ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. - Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. - Piroxicam capsules, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). - Piroxicam capsules, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,Bleeding,andPerforation). - Piroxicam capsules, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. - Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. - Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). - In late pregnancy, as with other NSAIDs, piroxicam capsules should be avoided because they may cause premature closure of the ductus arteriosus. # Precautions with Alcohol - Alcohol-Piroxicam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Feldene # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Feldene
3f6177ae555e8f19c1e7918604ecc5660e1cde1c	wikidoc	Letrozole	Letrozole # 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 Letrozole is an aromatase inhibitor that is FDA approved for the treatment of breast cancer. Common adverse reactions include hot flashes, arthralgia, flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, and bone pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Letrozole tablets, USP are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. - The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals. - Letrozole tablets, USP are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of letrozole in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months. - Letrozole tablets, USP are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Letrozole in adult patients. ### Non–Guideline-Supported Use - 4 months of letrozole 2.5 mg orally once daily. - Letrozole 2.5 mg orally daily. - Letrozole 5 mg orally once day. - Letrozole (2.5 or 5 mg daily for 5 days). # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Letrozole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Letrozole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Letrozole in pediatric patients. # Contraindications - Letrozole tablets may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole tablets are contraindicated in women who are or may become pregnant. If letrozole tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. # Warnings ### Precautions - Bone Effects - Use of letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001) . Updated results from the BMD sub-study in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different . - In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen. In the extended adjuvant trial the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. - Cholesterol - Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC grade 3 to 4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of ≥ 1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., < = 1.5 X ULN) in 151/1843 (8.2%) on letrozole vs. 57/1,840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen. - Hepatic Impairment - Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined. - Fatigue and Dizziness - Because fatigue, dizziness and somnolence have been reported with the use of letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use. - Laboratory Test Abnormalities - No dose related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent. # Adverse Reactions ## Clinical Trials Experience - The median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 73 months for patients receiving letrozole and tamoxifen. - Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs. - Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients reporting one or more AE) were Grade 1 or Grade 2 applying the Common Toxicity Criteria Version 2.0/ Common Terminology Criteria for Adverse Events, version 3.0. Table 1 describes adverse reactions (Grades 1 to 4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). - When considering all grades during study treatment, a higher incidence of events was seen for letrozole regarding fractures (10.1% vs. 7.1%), myocardial infarctions (1% vs. 0.5%), and arthralgia (25.2% vs. 20.4%) (letrozole vs. tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs. 3.6%), endometrial hyperplasia/cancer (0.3% vs. 2.9%), and endometrial proliferation disorders (0.3% vs. 1.8%) (letrozole vs. tamoxifen respectively). - At a median follow up of 73 months, a higher incidence of events was seen for letrozole (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole regarding thromboembolic events (4.5% vs. 2.9%), and endometrial hyperplasia or cancer (2.9% vs. 0.4%) (tamoxifen vs. letrozole, respectively). - Bone Study - Results of a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only one patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2-year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm. - Lipid Study - In a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen. - The median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for safety was 28 months for patients receiving letrozole and placebo. - Table 2 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the Common Toxicity Criteria Version 2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia. - Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received letrozole was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole and 18.7% of the patients who received placebo. - The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received letrozole 6.8% (175) and placebo 6.5% (167). - A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains. - Lipid Sub-Study - In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed. - The extended adjuvant treatment trial was unblinded early. At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months. - During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of fractures was observed for letrozole (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (letrozole 12.2% vs. placebo 6.4%). - Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. - During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) the incidence of cardiovascular events was 9.8% for letrozole and 7% for placebo. - Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo. - Lipid Sub-Study - In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed. - A total of 455 patients were treated for a median time of exposure of 11 months. The incidence of adverse reactions was similar for letrozole and tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on letrozole and in 15/455 (3%) of patients on tamoxifen. - Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with letrozole 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 3. - Other less frequent (≤ 2%) adverse reactions considered consequential for both treatment groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis and pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes and development of hemiparesis. - Study discontinuations in the megestrol acetate comparison study for adverse reactions other than progression of tumor were 5/188 (2.7%) on letrozole 0.5 mg, in 4/174 (2.3%) on letrozole 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole doses than on the megestrol acetate arm (0.6% vs. 4.7%). There was also less vaginal bleeding (0.3% vs. 3.2%) on letrozole than on megestrol acetate. In the aminoglutethimide comparison study, discontinuations for reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg letrozole, 7/185 (3.8%) on 2.5 mg letrozole, and 7/178 (3.9%) of patients on aminoglutethimide. - Comparisons of the incidence of adverse reactions revealed no significant differences between the high and low dose letrozole groups in either study. Most of the adverse reactions observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness. - Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with letrozole 0.5 mg, letrozole 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in Table 4. - Other less frequent (< 5%) adverse reactions considered consequential and reported in at least three patients treated with letrozole, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo. - In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis, cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst. ## Postmarketing Experience - Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis, erythema multiforme and hepatitis have been reported. Cases of carpal tunnel syndrome and trigger finger have been identified during post approval use of letrozole. # Drug Interactions - Tamoxifen - Coadministration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials indicates that the therapeutic effect of letrozole therapy is not impaired if letrozole is administered immediately after tamoxifen. - Cimetidine - A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrozole pharmacokinetics. - Warfarin - An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics. - Other Anticancer Agents - There is no clinical experience to date on the use of letrozole in combination with other anticancer agents. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. - Letrozole caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well. - Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m2 basis). Adverse effects included: intrauterine mortality; increased resorptions and postimplantation loss; decreased numbers of live fetuses; and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole doses 1/10 the daily MHRD (mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae and fore- and hind legs. - Physicians should discuss the need for adequate contraception with women who are recently menopausal. Contraception should be used until postmenopausal status is clinically well established. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Letrozole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Letrozole during labor and delivery. ### Nursing Mothers - It is not known if letrozole 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 letrozole, 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 in pediatric patients have not been established. ### Geriatic Use - The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. About 1/3 of the patients were ≥ 70 years old. In the first-line study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients < 70. - For the extended adjuvant setting, more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - In the adjuvant setting, more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36 % of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients. ### Gender There is no FDA guidance on the use of Letrozole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Letrozole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Letrozole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Letrozole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Letrozole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Letrozole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Letrozole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Letrozole in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias. ### Management - Isolated cases of letrozole overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated. ## Chronic Overdose There is limited information regarding Chronic Overdose of Letrozole in the drug label. # Pharmacology ## Mechanism of Action - The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. - In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. - Letrozole is a non-steroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. - Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones. ## Structure - Letrozole tablets, USP for oral administration contains 2.5 mg of letrozole, a non-steroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile, and its structural formula is: - Letrozole, USP is a white to off-white powder, freely soluble in dichloromethane, slightly soluble in ethanol and practically insoluble in water. It has a molecular weight of 285.31, molecular formula C17H11N5, and a melting range of 184°C to 185°C. - Letrozole tablets, USP are available as 2.5 mg tablets for oral administration. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, D&C Red No. 27 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and triacetin. - USP Dissolution Test Pending. ## Pharmacodynamics - In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within 2 to 3 days. Suppression is dose related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher. - Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary. - No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1 mg, 0.5 mg and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels. ## Pharmacokinetics - Absorption and Distribution - Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole’s terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2 to 6 weeks. Plasma concentrations at steady-state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg). - Metabolism and Excretion - Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole. - In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19. - Pediatric, Geriatric and Race - In the study populations (adults ranging in age from 35 to > 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied. - Renal Impairment - In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg letrozole and half 0.5 mg letrozole, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations. - Hepatic Impairment - In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. - In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2 to 11 times ULN with minimal to severe ascites) had 2-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. ## Nonclinical Toxicology - A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen. - Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats). - Studies to investigate the effect of letrozole on fertility have not been conducted; however, repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m2 basis, respectively). Oral administration of letrozole to female rats starting 2 weeks before mating until pregnancy day 6 resulted in decreases in the incidence of successful mating and pregnancy at equal to or greater than 0.03 mg/kg/day (approximately 0.1 times the recommended human dose on a mg/m2 basis). An increase in pre-implantation loss was observed at doses equal to or greater than 0.003 mg/kg/day (approximately 0.01 times the recommended human dose on a mg/m2 basis). - Letrozole administered to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage, resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis at exposures less than exposure anticipated at the clinical dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures. - Reproductive Toxicology - Reproduction studies in rats at letrozole doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. - Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. # Clinical Studies There is limited information regarding Letrozole Clinical Studies in the drug label. # How Supplied There is limited information regarding Letrozole How Supplied in the drug label. ## Storage There is limited information regarding Letrozole Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Letrozole Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Letrozole 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 Letrozole Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Letrozole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Letrozole 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 Letrozole is an aromatase inhibitor that is FDA approved for the treatment of breast cancer. Common adverse reactions include hot flashes, arthralgia, flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, and bone pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Letrozole tablets, USP are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. - The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals. - Letrozole tablets, USP are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of letrozole in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months. - Letrozole tablets, USP are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Letrozole in adult patients. ### Non–Guideline-Supported Use - 4 months of letrozole 2.5 mg orally once daily.[1] - Letrozole 2.5 mg orally daily.[2] - Letrozole 5 mg orally once day.[3] - Letrozole (2.5 or 5 mg daily for 5 days).[4] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Letrozole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Letrozole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Letrozole in pediatric patients. # Contraindications - Letrozole tablets may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole tablets are contraindicated in women who are or may become pregnant. If letrozole tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. # Warnings ### Precautions - Bone Effects - Use of letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001) [see Adverse reactions (6.1)]. Updated results from the BMD sub-study in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6.2)]. - In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen. In the extended adjuvant trial the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. - Cholesterol - Consideration should be given to monitoring serum cholesterol. In the adjuvant trial hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. CTC grade 3 to 4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of ≥ 1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., < = 1.5 X ULN) in 151/1843 (8.2%) on letrozole vs. 57/1,840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen. - Hepatic Impairment - Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined. - Fatigue and Dizziness - Because fatigue, dizziness and somnolence have been reported with the use of letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use. - Laboratory Test Abnormalities - No dose related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent. # Adverse Reactions ## Clinical Trials Experience - The median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 73 months for patients receiving letrozole and tamoxifen. - Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs. - Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients reporting one or more AE) were Grade 1 or Grade 2 applying the Common Toxicity Criteria Version 2.0/ Common Terminology Criteria for Adverse Events, version 3.0. Table 1 describes adverse reactions (Grades 1 to 4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). - When considering all grades during study treatment, a higher incidence of events was seen for letrozole regarding fractures (10.1% vs. 7.1%), myocardial infarctions (1% vs. 0.5%), and arthralgia (25.2% vs. 20.4%) (letrozole vs. tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs. 3.6%), endometrial hyperplasia/cancer (0.3% vs. 2.9%), and endometrial proliferation disorders (0.3% vs. 1.8%) (letrozole vs. tamoxifen respectively). - At a median follow up of 73 months, a higher incidence of events was seen for letrozole (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole regarding thromboembolic events (4.5% vs. 2.9%), and endometrial hyperplasia or cancer (2.9% vs. 0.4%) (tamoxifen vs. letrozole, respectively). - Bone Study - Results of a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only one patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2-year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm. - Lipid Study - In a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen. - The median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for safety was 28 months for patients receiving letrozole and placebo. - Table 2 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the Common Toxicity Criteria Version 2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia. - Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received letrozole was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole and 18.7% of the patients who received placebo. - The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received letrozole 6.8% (175) and placebo 6.5% (167). - A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains. - Lipid Sub-Study - In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed. - The extended adjuvant treatment trial was unblinded early. At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months. - During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of fractures was observed for letrozole (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (letrozole 12.2% vs. placebo 6.4%). - Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. - During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) the incidence of cardiovascular events was 9.8% for letrozole and 7% for placebo. - Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo. - Lipid Sub-Study - In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed. - A total of 455 patients were treated for a median time of exposure of 11 months. The incidence of adverse reactions was similar for letrozole and tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on letrozole and in 15/455 (3%) of patients on tamoxifen. - Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with letrozole 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 3. - Other less frequent (≤ 2%) adverse reactions considered consequential for both treatment groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis and pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes and development of hemiparesis. - Study discontinuations in the megestrol acetate comparison study for adverse reactions other than progression of tumor were 5/188 (2.7%) on letrozole 0.5 mg, in 4/174 (2.3%) on letrozole 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole doses than on the megestrol acetate arm (0.6% vs. 4.7%). There was also less vaginal bleeding (0.3% vs. 3.2%) on letrozole than on megestrol acetate. In the aminoglutethimide comparison study, discontinuations for reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg letrozole, 7/185 (3.8%) on 2.5 mg letrozole, and 7/178 (3.9%) of patients on aminoglutethimide. - Comparisons of the incidence of adverse reactions revealed no significant differences between the high and low dose letrozole groups in either study. Most of the adverse reactions observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness. - Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with letrozole 0.5 mg, letrozole 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in Table 4. - Other less frequent (< 5%) adverse reactions considered consequential and reported in at least three patients treated with letrozole, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo. - In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis, cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst. ## Postmarketing Experience - Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis, erythema multiforme and hepatitis have been reported. Cases of carpal tunnel syndrome and trigger finger have been identified during post approval use of letrozole. # Drug Interactions - Tamoxifen - Coadministration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials indicates that the therapeutic effect of letrozole therapy is not impaired if letrozole is administered immediately after tamoxifen. - Cimetidine - A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrozole pharmacokinetics. - Warfarin - An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics. - Other Anticancer Agents - There is no clinical experience to date on the use of letrozole in combination with other anticancer agents. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. - Letrozole caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well. - Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m2 basis). Adverse effects included: intrauterine mortality; increased resorptions and postimplantation loss; decreased numbers of live fetuses; and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole doses 1/10 the daily MHRD (mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae and fore- and hind legs. - Physicians should discuss the need for adequate contraception with women who are recently menopausal. Contraception should be used until postmenopausal status is clinically well established. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Letrozole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Letrozole during labor and delivery. ### Nursing Mothers - It is not known if letrozole 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 letrozole, 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 in pediatric patients have not been established. ### Geriatic Use - The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. About 1/3 of the patients were ≥ 70 years old. In the first-line study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients < 70. - For the extended adjuvant setting, more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - In the adjuvant setting, more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36 % of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients. ### Gender There is no FDA guidance on the use of Letrozole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Letrozole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Letrozole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Letrozole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Letrozole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Letrozole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Letrozole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Letrozole in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias. ### Management - Isolated cases of letrozole overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated. ## Chronic Overdose There is limited information regarding Chronic Overdose of Letrozole in the drug label. # Pharmacology ## Mechanism of Action - The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. - In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. - Letrozole is a non-steroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. - Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones. ## Structure - Letrozole tablets, USP for oral administration contains 2.5 mg of letrozole, a non-steroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile, and its structural formula is: - Letrozole, USP is a white to off-white powder, freely soluble in dichloromethane, slightly soluble in ethanol and practically insoluble in water. It has a molecular weight of 285.31, molecular formula C17H11N5, and a melting range of 184°C to 185°C. - Letrozole tablets, USP are available as 2.5 mg tablets for oral administration. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, D&C Red No. 27 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and triacetin. - USP Dissolution Test Pending. ## Pharmacodynamics - In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within 2 to 3 days. Suppression is dose related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher. - Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary. - No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1 mg, 0.5 mg and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels. ## Pharmacokinetics - Absorption and Distribution - Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole’s terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2 to 6 weeks. Plasma concentrations at steady-state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg). - Metabolism and Excretion - Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole. - In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19. - Pediatric, Geriatric and Race - In the study populations (adults ranging in age from 35 to > 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied. - Renal Impairment - In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg letrozole and half 0.5 mg letrozole, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations. - Hepatic Impairment - In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. - In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2 to 11 times ULN with minimal to severe ascites) had 2-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. ## Nonclinical Toxicology - A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen. - Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats). - Studies to investigate the effect of letrozole on fertility have not been conducted; however, repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m2 basis, respectively). Oral administration of letrozole to female rats starting 2 weeks before mating until pregnancy day 6 resulted in decreases in the incidence of successful mating and pregnancy at equal to or greater than 0.03 mg/kg/day (approximately 0.1 times the recommended human dose on a mg/m2 basis). An increase in pre-implantation loss was observed at doses equal to or greater than 0.003 mg/kg/day (approximately 0.01 times the recommended human dose on a mg/m2 basis). - Letrozole administered to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage, resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis at exposures less than exposure anticipated at the clinical dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures. - Reproductive Toxicology - Reproduction studies in rats at letrozole doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. - Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. # Clinical Studies There is limited information regarding Letrozole Clinical Studies in the drug label. # How Supplied There is limited information regarding Letrozole How Supplied in the drug label. ## Storage There is limited information regarding Letrozole Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Letrozole Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Letrozole 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 Letrozole Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Letrozole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Femara
fc9f7d39a9fd4516067cb5e9163c99134fa037f4	wikidoc	Fenugreek	Fenugreek Fenugreek (Trigonella foenum-graecum) belongs to the family Fabaceae. Fenugreek is used both as a herb (the leaves) and as a spice (the seed). It is cultivated worldwide as a semi-arid crop. The name fenugreek or foenum-graecum is from Latin for "Greek hay". Zohary and Hopf note that it is not yet certain which wild strain of the genus Trigonella gave rise to the domesticated fenugreek but believe it was brought into cultivation in the Near East. Charred fenugreek seeds have been recovered from Tell Halal, Iraq, (radiocarbon dating to 4000 BC) and Bronze Age levels of Lachish, as well as desiccated seeds from the tomb of Tutankhamen. Cato the Elder lists fenugreek with clover and vetch as crops grown to feed cattle (De Agri Cultura, 27). The rhombic yellow to amber colored fenugreek seed, commonly called Methi, is frequently used in the preparation of pickles, curry powders and pastes, and is often encountered in the cuisine of the Indian subcontinent. The young leaves and sprouts of fenugreek are eaten as greens, and the fresh or dried leaves are used to flavor other dishes. The dried leaves (called kasuri methi) have a bitter taste and a strong characteristic smell. In India, fenugreek seeds are mixed with yogurt and used as a conditioner for hair. It is also one of the ingredients in the making of khakhra, a type of bread. It is used in injera/taita, a type of bread unique to Ethiopian and Eritrean cuisine. The word for fenugreek in Amharic is abesh, and the seed is reportedly also often used in Ethiopia as a natural herbal medicine in the treatment of diabetes. It is also sometimes used as an ingredient in the production of clarified butter (Amharic: qibé, Ethiopian and Eritrean Tigrinya: tesme), which is similar to Indian ghee. In Turkey, fenugreek gives its name, çemen, to a hot paste used in pastirma. In Yemen it is the main condiment and an ingredient added to the national dish called saltah. The Arabic word hulba for the seed resembles its Mandarin Chinese counterpart hu lu ba. Fenugreek, or Şambélilé in Persian, is also one of four herbs used for the Iranian recipe Ghormeh Sabzi. In Egypt, fenugreek seeds are prepared as tea. Fenugreek seeds are a rich source of the polysaccharide galactomannan. They are also a source of saponins such as diosgenin, yamogenin, gitogenin, tigogenin, and neotigogens. Other bioactive constituents of fenugreek include mucilage, volatile oils, and alkaloids such as choline and trigonelline. A side effect of consuming even small amounts of fenugreek (even as just an infusion in water) is a maple syrup or curry smell in the eater's sweat and urine, which is caused by the potent aroma compound sotolone. Fenugreek is frequently used in the production of flavoring for artificial syrups. The taste of toasted fenugreek is additionally based on substituted pyrazines, as is cumin. By itself, it has a somewhat bitter taste. Fenugreek is mainly used as digestive aid. Fenugreek seed is widely used as a galactagogue (milk producing agent) by nursing mothers to increase inadequate breast milk supply. It can be found in capsule form in many health food stores. Supplements of fenugreek seeds were shown to lower serum cholesterol, triglyceride, and low-density lipoprotein in human patients and experimental models of hypercholesterolemia and hypertriglyceridemia (Basch et al., 2003). Several human intervention trials demonstrated that the antidiabetic effects of fenugreek seeds ameliorate most metabolic symptoms associated with type-1 and type-2 diabetes in both humans and relevant animal models (Basch et al., 2003; Srinivas, 2005). Fenugreek is currently available commercially in encapsulated forms and is being prescribed as dietary supplements for the control of hypercholesterolemia and diabetes by practitioners of complementary and alternative medicine. In recent research, fenugreek seeds were shown to protect against experimental cancers of the breast (Amin et al., 2005) and colon (Raju et al., 2006). The hepatoprotective properties of fenugreek seeds have also been reported in experimental models (Raju and Bird, 2006; Kaviarasan et al., 2006; Thirunavukarrasu et al., 2003).	Fenugreek Fenugreek (Trigonella foenum-graecum) belongs to the family Fabaceae. Fenugreek is used both as a herb (the leaves) and as a spice (the seed). It is cultivated worldwide as a semi-arid crop. The name fenugreek or foenum-graecum is from Latin for "Greek hay". Zohary and Hopf note that it is not yet certain which wild strain of the genus Trigonella gave rise to the domesticated fenugreek but believe it was brought into cultivation in the Near East. Charred fenugreek seeds have been recovered from Tell Halal, Iraq, (radiocarbon dating to 4000 BC) and Bronze Age levels of Lachish, as well as desiccated seeds from the tomb of Tutankhamen.[1] Cato the Elder lists fenugreek with clover and vetch as crops grown to feed cattle (De Agri Cultura, 27). The rhombic yellow to amber colored fenugreek seed, commonly called Methi, is frequently used in the preparation of pickles, curry powders and pastes, and is often encountered in the cuisine of the Indian subcontinent. The young leaves and sprouts of fenugreek are eaten as greens, and the fresh or dried leaves are used to flavor other dishes. The dried leaves (called kasuri methi) have a bitter taste and a strong characteristic smell. In India, fenugreek seeds are mixed with yogurt and used as a conditioner for hair. It is also one of the ingredients in the making of khakhra, a type of bread. It is used in injera/taita, a type of bread unique to Ethiopian and Eritrean cuisine. The word for fenugreek in Amharic is abesh, and the seed is reportedly also often used in Ethiopia as a natural herbal medicine in the treatment of diabetes. It is also sometimes used as an ingredient in the production of clarified butter (Amharic: qibé, Ethiopian and Eritrean Tigrinya: tesme), which is similar to Indian ghee. In Turkey, fenugreek gives its name, çemen, to a hot paste used in pastirma. In Yemen it is the main condiment and an ingredient added to the national dish called saltah. The Arabic word hulba for the seed resembles its Mandarin Chinese counterpart hu lu ba. Fenugreek, or Şambélilé in Persian, is also one of four herbs used for the Iranian recipe Ghormeh Sabzi. In Egypt, fenugreek seeds are prepared as tea. Fenugreek seeds are a rich source of the polysaccharide galactomannan. They are also a source of saponins such as diosgenin, yamogenin, gitogenin, tigogenin, and neotigogens. Other bioactive constituents of fenugreek include mucilage, volatile oils, and alkaloids such as choline and trigonelline. A side effect of consuming even small amounts of fenugreek (even as just an infusion in water) is a maple syrup or curry smell in the eater's sweat and urine, which is caused by the potent aroma compound sotolone. Fenugreek is frequently used in the production of flavoring for artificial syrups. The taste of toasted fenugreek is additionally based on substituted pyrazines, as is cumin. By itself, it has a somewhat bitter taste. Fenugreek is mainly used as digestive aid. Fenugreek seed is widely used as a galactagogue (milk producing agent) by nursing mothers to increase inadequate breast milk supply. It can be found in capsule form in many health food stores.[2] Supplements of fenugreek seeds were shown to lower serum cholesterol, triglyceride, and low-density lipoprotein in human patients and experimental models of hypercholesterolemia and hypertriglyceridemia (Basch et al., 2003). Several human intervention trials demonstrated that the antidiabetic effects of fenugreek seeds ameliorate most metabolic symptoms associated with type-1 and type-2 diabetes in both humans and relevant animal models (Basch et al., 2003; Srinivas, 2005). Fenugreek is currently available commercially in encapsulated forms and is being prescribed as dietary supplements for the control of hypercholesterolemia and diabetes by practitioners of complementary and alternative medicine. In recent research, fenugreek seeds were shown to protect against experimental cancers of the breast (Amin et al., 2005) and colon (Raju et al., 2006). The hepatoprotective properties of fenugreek seeds have also been reported in experimental models (Raju and Bird, 2006; Kaviarasan et al., 2006; Thirunavukarrasu et al., 2003). Template:Herbs & spices # External links - Gernot Katzer's spice dictionary - Fenugreek - Ghormeh Sabzi, an Iranian recipe using fenugreek leaves - Memorial Sloan-Kettering Cancer Center - About Herbs, Botanicals & Other Products - Encyclopedia of Spices	https://www.wikidoc.org/index.php/Fenugreek
5aea3a4780771b53b7bd4b96d0c3d47a9c2d27e5	wikidoc	Ferrocene	Ferrocene Ferrocene is the chemical compound with the formula Fe(C5H5)2. Ferrocene is the prototypical metallocene, a type of organometallic chemical compound consisting of two cyclopentadienyl rings bound on opposite sides of a central metal atom. Such organometallic compounds are also known as sandwich compounds. # History Ferrocene, like many chemical compounds, was first prepared unintentionally. In 1951, Pauson and Kealy at Duquesne University reported the reaction of cyclopentadienyl magnesium bromide and ferric chloride with the goal of oxidatively coupling the diene. Instead, they obtained a light orange powder of "remarkable stability." This stability was accounted to the aromatic character of the negative charged cyclopentadienyls, but the sandwich structure of the η5 (pentahapto) compound was not recognized by them. Robert Burns Woodward and Geoffrey Wilkinson deduced the structure based on its reactivity. Independently Ernst Otto Fischer also came to the conclusion of the sandwich structure and started to synthesize other metallocenes such as nickelocene and cobtaltocene. Ferrocene's structure was confirmed by NMR spectroscopy and X-ray crystallography. Its distinctive "sandwich" structure led to an explosion of interest in compounds of d-block metals with hydrocarbons, and initiated the development of the now flourishing study of organometallic chemistry. Ernst Otto Fischer of the Ludwig-Maximilians-Universität München and Sir Geoffrey Wilkinson of Imperial College London shared a Nobel Prize with for their work on organometalic chemistry. Ferrocene is more efficiently prepared by the reaction of sodium cyclopentadienyl with anhydrous ferrous chloride in ethereal solvents. # Electronic structure The central iron atom in ferrocene is normally considered to be in the +2 oxidation state (this can be shown using Mossbauer spectroscopy). Each cyclopentadienyl ring is then allocated a single negative charge - this extra electron occupies a π orbital, bringing the number of π-electrons on each ring to six, and thus making them aromatic. These twelve electrons (six from each ring) are then shared with the metal via covalent bonding, which, when combined with the six d-electrons on Fe2+, results in the complex having an 18-electron, inert gas electron configuration. This configuration makes ferrocene particularly stable. # Physical properties Ferrocene is an air stable orange solid that readily sublimes in vacuum, especially upon heating. As expected for a symmetric and uncharged species, ferrocene is soluble in normal organic solvents, such as benzene but is insoluble in water. Ferrocene sublimates notably around 100 Celsius degree. The following table gives some typical value of vapor pressure of ferrocene at different temperatures: # Chemical properties ## Reaction with electrophiles Ferrocene undergoes many reactions characteristic of aromatic compounds, enabling the preparation of derivatives (substituted ferrocenes). The most common substitution patterns are 1-substituted (one substituent on one ring), 1,1'-disubstituted (one substituent on each ring), and 1,2-disubstituted (two substituents next to each other on the same ring). For example the reaction of ferrocene, aluminium chloride and Me2NPCl2 in hot heptane forms dichloroferrocenyl phosphine, while treatment with phenyldichlorophosphine under similar conditions forms P,P-diferrocenyl-P-phenyl phosphine. In common with anisole the reaction of ferrocene with P4S10 forms a dithiadiphosphetane disulfide. A common undergraduate experiment is the Friedel-Crafts reaction of ferrocene with acetic anhydride (or acetyl chloride) in the presence of phosphoric acid as a catalyst. ## Lithiation Ferrocene is readily deprotonated (e.g. by butyl lithium) to give 1,1'-dilithioferrocene, which in turn is a versatile nucleophile. It has been reported that the reaction of 1,1'-dilithioferrocene with selenium diethyldithiocarbamate forms a strained ferrocenophane where the two cyclopentadienyl ligands are lined by the selenium atom. This ferrocenophane can be converted to a polymer by a thermal ring-opening polymerization (ROP) to form poly(ferrocenyl selenide). Likewise by the reaction of silicon and phosphorus linked ferrocenophanes the poly(ferrocenylsilane)s and poly(ferrocenylphosphines)s can be obtained. ## Redox chemistry Unlike the majority of aromatic hydrocarbons, ferrocene undergoes a one-electron oxidation at a low potential, around 0.5 V vs. a saturated calomel electrode (SCE) (N.B. electron rich aromatic amines such as aniline, the heterocycles pyrrole and thiophene can be oxidized with ease by electrochemical means). The oxidation of ferrocene is a reaction which forms a stable cation which is not prone to decomposition while the oxidation products of amines (such as aniline) and thiophenes tend to form polymers such as polyaniline and polythiophene. By adding groups to the cyclopentadienyl ligands the redox potential of the resulting ferrocene can be altered; by the addition of an electron withdrawing group such as a carboxylic acid the potential can be shifted in the anodic direction (i.e. made more positive), while the addition of electron releasing groups such as methyl groups will shift the potential in the cathodic direction (more negative). Thus, decamethylferrocene is much more easy to oxidise than ferrocene itself. Ferrocene is often used as an internal standard for calibrating redox potentials in non-aqeous electrochemistry. Ferrocene can be oxidized using FeCl3 to give the blue-colored ferrocenium ion, +, which is often isolated as its − salt. Ferrocenium salts are sometimes used as oxidizing agents, in part because the redox product ferrocene is so inert and readily separated from the products. # Applications of ferrocene and its derivatives Ferrocene itself has few applications. However, known synthetic methods allow the preparation of countless derivatives (above), thus extending the range of applications. ## Fuel additives Ferrocene and its derivatives are antiknock agents used in the fuel for petrol engines; they are considered to be safer than tetraethyl lead, previously used. It is possible to buy at Halfords in the UK, a petrol additive solution which contains ferrocene which can be added to unleaded petrol to enable it to be used in vintage cars which were designed to run on leaded petrol. Unfortunately, the iron containing deposits formed from ferrocene can form a conductive coating on the spark plug surfaces leading to spark plug failure. In diesel-fuelled engines, ferrocene reduces the production of soot. ## Medical Some ferrocenium salts exhibit anticancer activity, and an experimental drug has been reported which is a ferrocenyl version of tamoxifen. The idea is that the tamoxifen will bind to the estrogen binding sites, resulting in a cytotoxicity effect. ## Materials chemistry Ferrocene, being readily sublimed, can be used to deposit certain kinds of fullerenes, especially carbon nanotubes. Due to the fact that many organic reactions can be used to modify ferrocenes, it is the case that vinyl ferrocene can be made. The vinyl ferrocene can be made by a Wittig reaction of the aldehyde, a phosphonium salt and sodium hydroxide. The vinyl ferrocene can be converted into a polymer which can be thought of as a ferrocenyl version of polystyrene (the phenyl groups are replaced with ferrocenyl groups). ## As a ligand scaffold Chiral ferrocenyl phosphines are employed as ligands for transition-metal catalyzed reactions. Some of them have found industrial applications in the synthesis of pharmaceuticals and agrochemicals. 1,1'-Bis(diphenylphosphino)ferrocene (dppf) is a diphosphine containing a ferrocene moiety; it is a valuable ligand for palladium coupling reactions. # Derivatives and variations Many other metals can be used in place of iron and many other hydrocarbons can be used instead of cyclopentadiene to form altered Cp ligands which are then attached to iron. For instance indene can be used in place of the cyclopentadiene to form bisbenzoferrocene.. In addition it is possible by heating ] in cyclohexane to form the pyridine version (azaferrocene) of ferrocene ].. This compound on boiling under reflux in benzene is converted to ferrocene. Because of the ease of substitution, many structurally unusual ferrocene derivatives have been prepared. For example, the penta(ferrocenyl)cyclopentadienyl ligand , features a cyclopentadiene derivatised with five ferrocene substituents. In hexaferrocenylbenzene, all six positions on a benzene molecule have ferrocenyl substituents (R) . X-ray diffraction analysis of this compound confirms that the cyclopentadienyl ligands are not co-planar with the benzene core but have alternating dihedral angles of +30° and −80°. Due to steric crowding the ferrocenyls are slightly bent with angles of 177° and have elongated C-Fe bonds. The quaternary cyclopentadienyl carbon atoms are also pyramidalized.	Ferrocene Template:Chembox new Ferrocene is the chemical compound with the formula Fe(C5H5)2. Ferrocene is the prototypical metallocene, a type of organometallic chemical compound consisting of two cyclopentadienyl rings bound on opposite sides of a central metal atom. Such organometallic compounds are also known as sandwich compounds.[1] # History Ferrocene, like many chemical compounds, was first prepared unintentionally. In 1951, Pauson and Kealy at Duquesne University reported the reaction of cyclopentadienyl magnesium bromide and ferric chloride with the goal of oxidatively coupling the diene. Instead, they obtained a light orange powder of "remarkable stability."[2] This stability was accounted to the aromatic character of the negative charged cyclopentadienyls, but the sandwich structure of the η5 (pentahapto) compound was not recognized by them. Robert Burns Woodward and Geoffrey Wilkinson deduced the structure based on its reactivity.[3] Independently Ernst Otto Fischer also came to the conclusion of the sandwich structure and started to synthesize other metallocenes such as nickelocene and cobtaltocene.[4] Ferrocene's structure was confirmed by NMR spectroscopy and X-ray crystallography.[5][6] Its distinctive "sandwich" structure led to an explosion of interest in compounds of d-block metals with hydrocarbons, and initiated the development of the now flourishing study of organometallic chemistry. Ernst Otto Fischer of the Ludwig-Maximilians-Universität München and Sir Geoffrey Wilkinson of Imperial College London shared a Nobel Prize with for their work on organometalic chemistry. Ferrocene is more efficiently prepared by the reaction of sodium cyclopentadienyl with anhydrous ferrous chloride in ethereal solvents. # Electronic structure The central iron atom in ferrocene is normally considered to be in the +2 oxidation state (this can be shown using Mossbauer spectroscopy). Each cyclopentadienyl ring is then allocated a single negative charge - this extra electron occupies a π orbital, bringing the number of π-electrons on each ring to six, and thus making them aromatic. These twelve electrons (six from each ring) are then shared with the metal via covalent bonding, which, when combined with the six d-electrons on Fe2+, results in the complex having an 18-electron, inert gas electron configuration. This configuration makes ferrocene particularly stable. # Physical properties Ferrocene is an air stable orange solid that readily sublimes in vacuum, especially upon heating. As expected for a symmetric and uncharged species, ferrocene is soluble in normal organic solvents, such as benzene but is insoluble in water. Ferrocene sublimates notably around 100 Celsius degree. The following table gives some typical value of vapor pressure of ferrocene at different temperatures[7]: # Chemical properties ## Reaction with electrophiles Ferrocene undergoes many reactions characteristic of aromatic compounds, enabling the preparation of derivatives (substituted ferrocenes). The most common substitution patterns are 1-substituted (one substituent on one ring), 1,1'-disubstituted (one substituent on each ring), and 1,2-disubstituted (two substituents next to each other on the same ring). For example the reaction of ferrocene, aluminium chloride and Me2NPCl2 in hot heptane forms dichloroferrocenyl phosphine,[8] while treatment with phenyldichlorophosphine under similar conditions forms P,P-diferrocenyl-P-phenyl phosphine.[9] In common with anisole the reaction of ferrocene with P4S10 forms a dithiadiphosphetane disulfide.[10] A common undergraduate experiment is the Friedel-Crafts reaction of ferrocene with acetic anhydride (or acetyl chloride) in the presence of phosphoric acid as a catalyst. ## Lithiation Ferrocene is readily deprotonated (e.g. by butyl lithium) to give 1,1'-dilithioferrocene, which in turn is a versatile nucleophile. It has been reported that the reaction of 1,1'-dilithioferrocene with selenium diethyldithiocarbamate forms a strained ferrocenophane where the two cyclopentadienyl ligands are lined by the selenium atom.[11] This ferrocenophane can be converted to a polymer by a thermal ring-opening polymerization (ROP) to form poly(ferrocenyl selenide). Likewise by the reaction of silicon and phosphorus linked ferrocenophanes the poly(ferrocenylsilane)s and poly(ferrocenylphosphines)s can be obtained.[12][13] ## Redox chemistry Unlike the majority of aromatic hydrocarbons, ferrocene undergoes a one-electron oxidation at a low potential, around 0.5 V vs. a saturated calomel electrode (SCE) (N.B. electron rich aromatic amines such as aniline, the heterocycles pyrrole and thiophene can be oxidized with ease by electrochemical means). The oxidation of ferrocene is a reaction which forms a stable cation which is not prone to decomposition while the oxidation products of amines (such as aniline) and thiophenes tend to form polymers such as polyaniline and polythiophene. By adding groups to the cyclopentadienyl ligands the redox potential of the resulting ferrocene can be altered; by the addition of an electron withdrawing group such as a carboxylic acid the potential can be shifted in the anodic direction (i.e. made more positive), while the addition of electron releasing groups such as methyl groups will shift the potential in the cathodic direction (more negative). Thus, decamethylferrocene is much more easy to oxidise than ferrocene itself. Ferrocene is often used as an internal standard for calibrating redox potentials in non-aqeous electrochemistry. Ferrocene can be oxidized using FeCl3 to give the blue-colored ferrocenium ion, [Fe(C5H5)2]+, which is often isolated as its [PF6]− salt. Ferrocenium salts are sometimes used as oxidizing agents, in part because the redox product ferrocene is so inert and readily separated from the products.[14] # Applications of ferrocene and its derivatives Ferrocene itself has few applications. However, known synthetic methods allow the preparation of countless derivatives (above), thus extending the range of applications. ## Fuel additives Ferrocene and its derivatives are antiknock agents used in the fuel for petrol engines; they are considered to be safer than tetraethyl lead, previously used.[15] It is possible to buy at Halfords in the UK, a petrol additive solution which contains ferrocene which can be added to unleaded petrol to enable it to be used in vintage cars which were designed to run on leaded petrol.[16] Unfortunately, the iron containing deposits formed from ferrocene can form a conductive coating on the spark plug surfaces leading to spark plug failure. In diesel-fuelled engines, ferrocene reduces the production of soot. ## Medical Some ferrocenium salts exhibit anticancer activity, and an experimental drug has been reported which is a ferrocenyl version of tamoxifen.[17] The idea is that the tamoxifen will bind to the estrogen binding sites, resulting in a cytotoxicity effect.[18][19][20] ## Materials chemistry Ferrocene, being readily sublimed, can be used to deposit certain kinds of fullerenes, especially carbon nanotubes. Due to the fact that many organic reactions can be used to modify ferrocenes, it is the case that vinyl ferrocene can be made. The vinyl ferrocene can be made by a Wittig reaction of the aldehyde, a phosphonium salt and sodium hydroxide.[21] The vinyl ferrocene can be converted into a polymer which can be thought of as a ferrocenyl version of polystyrene (the phenyl groups are replaced with ferrocenyl groups). ## As a ligand scaffold Chiral ferrocenyl phosphines are employed as ligands for transition-metal catalyzed reactions. Some of them have found industrial applications in the synthesis of pharmaceuticals and agrochemicals. 1,1'-Bis(diphenylphosphino)ferrocene (dppf) is a diphosphine containing a ferrocene moiety; it is a valuable ligand for palladium coupling reactions. # Derivatives and variations Many other metals can be used in place of iron and many other hydrocarbons can be used instead of cyclopentadiene to form altered Cp ligands which are then attached to iron. For instance indene can be used in place of the cyclopentadiene to form bisbenzoferrocene.[22]. In addition it is possible by heating [[Fe(η5-C5H5)(CO)2(η1-pyrrole)]] in cyclohexane to form the pyridine version (azaferrocene) of ferrocene [[Fe(η5-C5H5)(η5-C4H4N)]].[23]. This compound on boiling under reflux in benzene is converted to ferrocene.[24] Because of the ease of substitution, many structurally unusual ferrocene derivatives have been prepared. For example, the penta(ferrocenyl)cyclopentadienyl ligand [25], features a cyclopentadiene derivatised with five ferrocene substituents. In hexaferrocenylbenzene, all six positions on a benzene molecule have ferrocenyl substituents (R) [26]. X-ray diffraction analysis of this compound confirms that the cyclopentadienyl ligands are not co-planar with the benzene core but have alternating dihedral angles of +30° and −80°. Due to steric crowding the ferrocenyls are slightly bent with angles of 177° and have elongated C-Fe bonds. The quaternary cyclopentadienyl carbon atoms are also pyramidalized. [27]	https://www.wikidoc.org/index.php/Ferrocene
7df85f027cbfbdb97dd03ac882a423ccfe1067ea	wikidoc	Fertility	Fertility # Overview Fertility is the natural capability of giving life. As a measure, "Fertility Rate" is the number of children born per couple, person or population. This is different to fecundity, which is defined as the potential for reproduction (influenced by gamete production, fertilisation and carrying a pregnancy to term). In the English language, the term was originally applied only to females, but increasingly is applied to males as well, as common understanding of reproductive mechanisms increases and the importance of the male role is better known. Infertility is a deficient fertility. Human fertility depends on factors of nutrition, sexual behavior, culture, instinct, endocrinology, timing, economics, way of life, and emotions. Animal fertility is no less complex, and may display astounding mechanisms. # Demographics The fertility rate is a demographic measure of the number of children per woman. Although it has been until recently considered to be a fairly reliable indicator of population growth, it is no longer so in much of Asia. Due to selective abortion and other factors, the ratio of women relative to men in populations is declining. Therefore, the fertility rate as it has traditionally been defined is no longer an authoritative measure of population growth in China, India, and Myanmar. # Human fertility Both women and men have hormonal cycles which determine both when a woman can achieve pregnancy and when a man is most fertile. The female cycle is approximately twenty-eight days long, but the male cycle is variable. Men can ejaculate and produce sperm at any time of the month, but their sperm quality dips occasionally, which scientists guess is in relation to their internal cycle. Furthermore, age also plays a role, especially for women. ## Menstrual cycle Women are fertile only about seven days in each menstrual cycle. Ovulation occurs at about the fourteenth day of their menstrual cycle, this obviously being the most fertile time for females. The exact point of ovulation depends, however. If the egg is not fertilized by the male’s sperm, the egg will break down within 1–2 days into its components (mostly protein) and be reabsorbed by the body. However, sperm can survive inside the uterus for five days. Thus, a successful conception can result during seven days of the female cycle; five days before and two days after ovulation. ## Female fertility after 30 Women's fertility peaks in their early teens, and often deteriorates after 30. Of women trying to get pregnant, without using fertility drugs or in vitro fertilization: - At age 30, 75% will get pregnant within one year, and 91% within four years. - At age 35, 66% will get pregnant within one year, and 84% within four years. - At age 40, 44% will get pregnant within one year, and 64% within four years. The above figures are for pregnancies ending in a live birth and take into account the increasing rates of miscarriage in the ageing population. According to the March of Dimes, "about 9 percent of recognised pregnancies for women aged 20 to 24 ended in miscarriage. The risk rose to about 20 percent at age 35 to 39, and more than 50 percent by age 42". Birth defects, especially those involving chromosome number and arrangement, also increase with the age of the mother. According to the March of Dimes, "At age 25, a woman has about a 1-in-1,250 chance of having a baby with Down syndrome; at age 30, a 1-in-1,000 chance; at age 35, a 1-in-400 chance; at age 40, a 1-in-100 chance; and at 45, a 1-in-30 chance." The use of fertility drugs and/or in vitro fertilization can increase the chances of becoming pregnant at a later age. Successful pregnancies facilitated by fertility treatment have been documented in women as old as 67. Doctors recommend that women over 30 who have been unsuccessful in trying to conceive for more than 6 months undergo some kind of fertility testing .	Fertility Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753 # Overview Fertility is the natural capability of giving life. As a measure, "Fertility Rate" is the number of children born per couple, person or population. This is different to fecundity, which is defined as the potential for reproduction (influenced by gamete production, fertilisation and carrying a pregnancy to term). In the English language, the term was originally applied only to females, but increasingly is applied to males as well, as common understanding of reproductive mechanisms increases and the importance of the male role is better known. Infertility is a deficient fertility. Human fertility depends on factors of nutrition, sexual behavior, culture, instinct, endocrinology, timing, economics, way of life, and emotions. Animal fertility is no less complex, and may display astounding mechanisms. # Demographics The fertility rate is a demographic measure of the number of children per woman. Although it has been until recently considered to be a fairly reliable indicator of population growth, it is no longer so in much of Asia. Due to selective abortion and other factors, the ratio of women relative to men in populations is declining. Therefore, the fertility rate as it has traditionally been defined is no longer an authoritative measure of population growth in China, India, and Myanmar. # Human fertility Both women and men have hormonal cycles which determine both when a woman can achieve pregnancy and when a man is most fertile. The female cycle is approximately twenty-eight days long, but the male cycle is variable. Men can ejaculate and produce sperm at any time of the month, but their sperm quality dips occasionally, which scientists guess is in relation to their internal cycle. Furthermore, age also plays a role, especially for women. ## Menstrual cycle Women are fertile only about seven days in each menstrual cycle. Ovulation occurs at about the fourteenth day of their menstrual cycle, this obviously being the most fertile time for females. The exact point of ovulation depends, however[1]. If the egg is not fertilized by the male’s sperm, the egg will break down within 1–2 days into its components (mostly protein) and be reabsorbed by the body. However, sperm can survive inside the uterus for five days. Thus, a successful conception can result during seven days of the female cycle; five days before and two days after ovulation. ## Female fertility after 30 Women's fertility peaks in their early teens, and often deteriorates after 30. Of women trying to get pregnant, without using fertility drugs or in vitro fertilization: - At age 30, 75% will get pregnant within one year, and 91% within four years. - At age 35, 66% will get pregnant within one year, and 84% within four years. - At age 40, 44% will get pregnant within one year, and 64% within four years.[2] The above figures are for pregnancies ending in a live birth and take into account the increasing rates of miscarriage in the ageing population. According to the March of Dimes, "about 9 percent of recognised pregnancies for women aged 20 to 24 ended in miscarriage. The risk rose to about 20 percent at age 35 to 39, and more than 50 percent by age 42".[3] Birth defects, especially those involving chromosome number and arrangement, also increase with the age of the mother. According to the March of Dimes, "At age 25, a woman has about a 1-in-1,250 chance of having a baby with Down syndrome; at age 30, a 1-in-1,000 chance; at age 35, a 1-in-400 chance; at age 40, a 1-in-100 chance; and at 45, a 1-in-30 chance."[4] The use of fertility drugs and/or in vitro fertilization can increase the chances of becoming pregnant at a later age. Successful pregnancies facilitated by fertility treatment have been documented in women as old as 67.[5] Doctors recommend that women over 30 who have been unsuccessful in trying to conceive for more than 6 months undergo some kind of fertility testing [6].	https://www.wikidoc.org/index.php/Fertility
438844b7b41ad709d754c1ee91763ce5068f2d63	wikidoc	Fetishism	Fetishism # Overview A fetish (from French fétiche; from Portuguese feitiço; from Latin facticius, "artificial" and facere, "to make") is an object believed to have supernatural powers, or in particular a man-made object that has power over others. Essentially, fetishism is the attribution of inherent value or powers to an object. # History The concept was coined by Charles de Brosses in 1757, while comparing West African religion to the magical aspects of Ancient Egyptian religion. Later, Auguste Comte used the concept to apply an evolution theory to religion. In Compte's theory of the evolution of religion, he proposed that fetishism is the earliest (most primitive) stage, followed by the stages of polytheism and monotheism. In the end, some artifacts certain monotheist religions (Holy Cross, Consecrated Hosts, etc.) use for their rites are other incarnation of fetishism. However, this vision is denied by monotheist practitioners. In the 19th century, Tylor and McLennan held that the concept of fetishism allowed historians of religion to shift attention from the relationship between people and God to the relationship between people and material objects. They also held that it established models of causal explanations of natural events which they considered false as a central problem in history and sociology. # Practice Theoretically, fetishism is present in all religions, but its use in the study of religion is derived from studies of traditional West African religious beliefs, as well as Voodoo, which is derived from those beliefs. Blood is often considered a particularly powerful fetish or ingredient in fetishes. In addition to blood, other objects and substances, such as bones, fur, claws, feathers, water from certain places, certain types of plants and wood are common fetishes in the traditions of cultures worldwide. # Other uses of the term "fetishism" - In the 19th century Karl Marx appropriated the term to describe commodity fetishism as an important component of capitalism. Nowadays, (commodity and capital) fetishism is a central concept of marxism - Later Sigmund Freud appropriated the concept to describe a form of paraphilia where the object of affection is an inanimate object or a specific part of a person; see sexual fetish.	Fetishism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Click here to read about fetishistic disorder. # Overview A fetish (from French fétiche; from Portuguese feitiço; from Latin facticius, "artificial" and facere, "to make") is an object believed to have supernatural powers, or in particular a man-made object that has power over others. Essentially, fetishism is the attribution of inherent value or powers to an object. # History The concept was coined by Charles de Brosses in 1757, while comparing West African religion to the magical aspects of Ancient Egyptian religion. Later, Auguste Comte used the concept to apply an evolution theory to religion. In Compte's theory of the evolution of religion, he proposed that fetishism is the earliest (most primitive) stage, followed by the stages of polytheism and monotheism. In the end, some artifacts certain monotheist religions (Holy Cross, Consecrated Hosts, etc.) use for their rites are other incarnation of fetishism. However, this vision is denied by monotheist practitioners. In the 19th century, Tylor and McLennan held that the concept of fetishism allowed historians of religion to shift attention from the relationship between people and God to the relationship between people and material objects. They also held that it established models of causal explanations of natural events which they considered false as a central problem in history and sociology. # Practice Theoretically, fetishism is present in all religions, but its use in the study of religion is derived from studies of traditional West African religious beliefs, as well as Voodoo, which is derived from those beliefs. Blood is often considered a particularly powerful fetish or ingredient in fetishes. In addition to blood, other objects and substances, such as bones, fur, claws, feathers, water from certain places, certain types of plants and wood are common fetishes in the traditions of cultures worldwide. # Other uses of the term "fetishism" - In the 19th century Karl Marx appropriated the term to describe commodity fetishism as an important component of capitalism. Nowadays, (commodity and capital) fetishism is a central concept of marxism - Later Sigmund Freud appropriated the concept to describe a form of paraphilia where the object of affection is an inanimate object or a specific part of a person; see sexual fetish.	https://www.wikidoc.org/index.php/Fetishism
7f9478c8573aae0fc885ab3e1743b14d94543a51	wikidoc	Fibrillin	Fibrillin Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue. Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffold for deposition of elastin. # Clinical aspect Mutations in FBN1 and FBN2 are associated with adolescent idiopathic scoliosis . # Types ## Fibrillin-1 Fibrillin-1 is a major component of the microfibrils that form a sheath surrounding the amorphous elastin. It is believed that the microfibrils are composed of end-to-end polymers of fibrillin. To date, 3 forms of fibrillin have been described. The fibrillin-1 protein was isolated by Engvall in 1986, and mutations in the FBN1 gene cause Marfan syndrome. This protein is found in humans, and its gene is found on chromosome 15. At present more than 1500 different mutations have been described. ### Structure There is no complete, high-resolution structure of fibrillin-1. Instead, short fragments have been produced recombinantly and their structures solved by X-ray crystallography or using NMR spectroscopy. A recent example is the structure of the fibrillin-1 hybrid2 domain, in context of its flanking calcium binding epidermal growth factor domains, which was determined using X-ray crystallography to a resolution of 1.8 Å. The microfibrils that are made up of fibrillin protein are responsible for different cell-matrix interactions in the human body. ## Fibrillin-2 Fibrillin-2 was isolated in 1994 by Zhang and is thought to play a role in early elastogenesis. Mutations in the fibrillin-2 gene have been linked to Beal's Syndrome. ## Fibrillin-3 More recently, fibrillin-3 was described and is believed to be located mainly in the brain. Along with the brain, fibrillin-3 has been localized in the gonads and ovaries of field mice. ## Fibrillin-4 Fibrillin-4 was first discovered in zebrafish, and has a sequence similar to fibrillin-2.	Fibrillin Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue.[2] Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffold for deposition of elastin.[3] # Clinical aspect Mutations in FBN1 and FBN2 are associated with adolescent idiopathic scoliosis .[4] # Types ## Fibrillin-1 Fibrillin-1 is a major component of the microfibrils that form a sheath surrounding the amorphous elastin. It is believed that the microfibrils are composed of end-to-end polymers of fibrillin. To date, 3 forms of fibrillin have been described. The fibrillin-1 protein was isolated by Engvall in 1986,[5] and mutations in the FBN1 gene cause Marfan syndrome.[6][7] This protein is found in humans, and its gene is found on chromosome 15. At present more than 1500 different mutations have been described.[1][7] ### Structure There is no complete, high-resolution structure of fibrillin-1. Instead, short fragments have been produced recombinantly and their structures solved by X-ray crystallography or using NMR spectroscopy. A recent example is the structure of the fibrillin-1 hybrid2 domain, in context of its flanking calcium binding epidermal growth factor domains, which was determined using X-ray crystallography to a resolution of 1.8 Å.[1] The microfibrils that are made up of fibrillin protein are responsible for different cell-matrix interactions in the human body. ## Fibrillin-2 Fibrillin-2 was isolated in 1994 by Zhang[8] and is thought to play a role in early elastogenesis. Mutations in the fibrillin-2 gene have been linked to Beal's Syndrome. ## Fibrillin-3 More recently, fibrillin-3 was described and is believed to be located mainly in the brain.[9] Along with the brain, fibrillin-3 has been localized in the gonads and ovaries of field mice. ## Fibrillin-4 Fibrillin-4 was first discovered in zebrafish, and has a sequence similar to fibrillin-2.[10]	https://www.wikidoc.org/index.php/Fibrillin
2dee317e2941a5b8bb151b2fdc0ae1c9af17ec06	wikidoc	FibroTest	FibroTest # Overview FibroTest, known as FibroSure in the US, is a patented biomarker test that uses the results of six blood serum tests to generate a score that is correlated with the degree of liver damage in people with a variety of liver diseases. FibroTest has the same prognostic value as a liver biopsy. FibroTest has been evaluated in relation to liver biopsy (the current reference standard in liver disease assessment) in a large number of patients with hepatitis C, hepatitis B, alcoholic liver disease, Non-alcoholic fatty liver disease and in the general population. By 2008 it had been used in over 350,000 patients. FibroTest has been validated for the initial diagnosis of fibrosis, but also for the monitoring of patients. In 2006, the French National Authority for Health recommended the use of FibroTest as a first-line assessment tool for fibrosis with untreated chronic hepatitis C. # Procedure The FibroTest score is calculated from the results of a six-parameter blood test, combining six serum markers with the age and gender of the patient: Alpha-2-macroglobulin, Haptoglobin, Apolipoprotein A1, Gamma-glutamyl transpeptidase (GGT), Total bilirubin, and Alanine transaminase (ALT). ALT is used in a second assessment called ActiTest that is part of FibroTest. The equation for calculating the FibroTest score regression coefficient (logistic regression) is: z=4.467\times \log_{10} -1.357\times\log_{10} + 1.017 \times \log_{10} + 0.0281 \times Due to variability of components assays and analyzers, FibroTest assays can only be performed in validated laboratories. FibroTest cannot be used without algorithms that detects false positives and false negatives; the equation alone is not a diagnosis tool. The laboratory or physician connects to the BioPredictive website for calculation of the test results and prints the results sheet, which is available immediately and is accompanied by an interpretation aid and precautions for use. # Applicability Over 95% of tests are interpretable and allow a diagnosis of fibrosis and liver activity. In less than 5% of cases, likely false positives or false negatives are highlighted. FibroTest has been validated for chronic hepatitis C, chronic hepatitis B, chronic hepatitis C or B with HIV co-infection, alcoholic liver diseases (steatosis and steatohepatitis), and non-alcoholic steatohepatitis (diabetes, overweight, hypertriglyceridemia, hypercholesterolemia, hypertension). FibroTest is independent of ethnic origin, sex, genotype, viral load, transaminases or the presence of comorbidities. The test has been validated in those over the age of 65 years, children, patients with renal insufficiency or renal transplanation, hemophiliacs, patients with chronic inflammatory disease, and the general population. The tests are not applicable in 1 to 5% of cases. These cases can be detected by laboratory safety algorithms and when detected they are indicated on the results sheet: - Acute hepatitides, e.g., acute viral hepatitis A, B, C, D, E; drug-induced hepatitis - Extrahepatic cholestasis, e.g., pancreatic cancer, gallstones - Severe hemolysis, e.g., some cardiac valves - Gilbert's syndrome with high unconjugated hyperbilirubinemia - Acute inflammatory syndrome (the blood test may be postponed) # Interpretation The conversion of FibroTest score into stages according to the three most used histological classifications (METAVIR, Knodell and Ishak) for liver biopsies is: # Comparison with liver biopsy Liver biopsy is an imperfect tool; due to sampling errors, biopsy size (5 to 30 mm) and intra- and interobservor variability, it is now agreed that biopsy is an "imperfect Gold Standard". Biopsy continues to present inconveniences: 30% of patients complain of pain, up to 3% have been noted to have complications severe enough to require hospitalization and a 0.01-0.3% rate of deaths has been reported. There is a mean discordance of 25% between FibroTest and biopsy. Half of these discordances are attributable to an error of the biopsy, often too small, and the other half to FibroTest. The inventors report that FibroTest has comparable diagnostic and prognostic value as a 25 mm biopsy, while being noninvasive and easily repeatable. # FibroTest derivatives Four other tests derive from FibroTest, and are part of the FibroMax package of tests: - ActiTest: diagnostic of necrotico-inflammatory for hepatitis; - SteaoTest: diagnostic for liver steatosis; - NashTest: diagnostic for NASH (Non-alcoholic fatty liver disease) inflammation; - AshTest: diagnostic for Alcoholic liver disease inflammation. # Patent, License FibroTest tests and derivatives are patented since 2001 by APHP (Assistance publique - Hôpitaux de Paris), the Parisian public hospital system. In the US, FibroTest is marketed as FibroSure (a LabCorp trademark). BioPredictive is the company licensed by APHP to promote and operate the tests.	FibroTest Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview FibroTest, known as FibroSure in the US, is a patented biomarker test that uses the results of six blood serum tests to generate a score that is correlated with the degree of liver damage in people with a variety of liver diseases. FibroTest has the same prognostic value as a liver biopsy. FibroTest has been evaluated in relation to liver biopsy (the current reference standard in liver disease assessment) in a large number of patients with hepatitis C,[1] hepatitis B,[2] alcoholic liver disease,[3] Non-alcoholic fatty liver disease[4] and in the general population. By 2008 it had been used in over 350,000 patients.[2] FibroTest has been validated for the initial diagnosis of fibrosis, but also for the monitoring of patients.[citation needed] In 2006, the French National Authority for Health recommended the use of FibroTest as a first-line assessment tool for fibrosis with untreated chronic hepatitis C.[5] # Procedure The FibroTest score is calculated from the results of a six-parameter blood test, combining six serum markers with the age and gender of the patient: Alpha-2-macroglobulin, Haptoglobin, Apolipoprotein A1, Gamma-glutamyl transpeptidase (GGT), Total bilirubin, and Alanine transaminase (ALT). ALT is used in a second assessment called ActiTest that is part of FibroTest. The equation for calculating the FibroTest score regression coefficient (logistic regression) is:[6] <math>z=4.467\times \log_{10} [\alpha2 macroglobulin (g/L)]-1.357\times\log_{10} [Haptoglobin (g/L)] + 1.017 \times \log_{10} [GGT (IU/L)] + 0.0281 \times [Age (years)]</math> Due to variability of components assays and analyzers, FibroTest assays can only be performed in validated laboratories.[7] FibroTest cannot be used without algorithms that detects false positives and false negatives; the equation alone is not a diagnosis tool. The laboratory or physician connects to the BioPredictive website[8] for calculation of the test results and prints the results sheet, which is available immediately and is accompanied by an interpretation aid and precautions for use. # Applicability Over 95% of tests are interpretable and allow a diagnosis of fibrosis and liver activity. In less than 5% of cases, likely false positives or false negatives are highlighted. FibroTest has been validated for chronic hepatitis C,[1] chronic hepatitis B,[2] chronic hepatitis C or B with HIV co-infection,[9] alcoholic liver diseases (steatosis and steatohepatitis),[3] and non-alcoholic steatohepatitis (diabetes, overweight, hypertriglyceridemia, hypercholesterolemia, hypertension).[4] FibroTest is independent of ethnic origin, sex, genotype, viral load, transaminases or the presence of comorbidities. The test has been validated in those over the age of 65 years,[10] children,[11] patients with renal insufficiency or renal transplanation, hemophiliacs, patients with chronic inflammatory disease, and the general population. The tests are not applicable in 1 to 5% of cases. These cases can be detected by laboratory safety algorithms and when detected they are indicated on the results sheet:[2] - Acute hepatitides, e.g., acute viral hepatitis A, B, C, D, E; drug-induced hepatitis - Extrahepatic cholestasis, e.g., pancreatic cancer, gallstones - Severe hemolysis, e.g., some cardiac valves - Gilbert's syndrome with high unconjugated hyperbilirubinemia - Acute inflammatory syndrome (the blood test may be postponed) # Interpretation The conversion of FibroTest score into stages according to the three most used histological classifications (METAVIR, Knodell and Ishak) for liver biopsies is: # Comparison with liver biopsy Liver biopsy is an imperfect tool; due to sampling errors, biopsy size (5 to 30 mm) and intra- and interobservor variability, it is now agreed that biopsy is an "imperfect Gold Standard". Biopsy continues to present inconveniences: 30% of patients complain of pain, up to 3% have been noted to have complications severe enough to require hospitalization[12][13] and a 0.01-0.3% rate of deaths has been reported.[14][15][16] There is a mean discordance of 25% between FibroTest and biopsy. Half of these discordances are attributable to an error of the biopsy, often too small, and the other half to FibroTest.[17] The inventors report that FibroTest has comparable diagnostic and prognostic value as a 25 mm biopsy, while being noninvasive and easily repeatable.[1][3][18] # FibroTest derivatives Four other tests derive from FibroTest, and are part of the FibroMax package of tests: - ActiTest: diagnostic of necrotico-inflammatory for hepatitis; - SteaoTest: diagnostic for liver steatosis; - NashTest: diagnostic for NASH (Non-alcoholic fatty liver disease) inflammation; - AshTest: diagnostic for Alcoholic liver disease inflammation. # Patent, License FibroTest tests and derivatives are patented since 2001 by APHP (Assistance publique - Hôpitaux de Paris), the Parisian public hospital system. In the US, FibroTest is marketed as FibroSure (a LabCorp trademark). BioPredictive is the company licensed by APHP to promote and operate the tests.	https://www.wikidoc.org/index.php/FibroTest
54b9afcf6ee42a82097533591fe75b3b81bb88d4	wikidoc	Fibrocyte	Fibrocyte Fibrocyte is a very old term used to identify inactive mesenchymal cells, that is cells showing minimal cytoplasm,limited amounts of rough endoplasmic reticulum and lack of biochemical evidence of synthesis of proteins. The term "fibrocyte" contrasts with the term "fibroblast." Fibroblasts are connective tissue cells characterized by synthesis of proteins of the fibrous matrix, particularly the collagens. When tissue is injured, the predominant mesenchymal cells, the fibroblast, have been believed to be derived from the fibrocyte or possibly from smooth muscle cells lining vessels and glands. Commonly, fibroblasts express smooth muscle actin, a form of actin first found in smooth muscle cells and not found in resting fibrocytes. Fibroblasts expressing this form of actin are usually called "myo-fibroblasts." Recently, the term "fibrocyte" has also been applied to a blood born cell able to leave the blood, enter tissue and become a fibroblast. As part of the more general topic of stem cell biology, a number of studies have suggested that the blood contains marrow derived cells that can differentiate into fibroblasts. These cells have been reported to express the hematopoietic cell surface markers CD34+, CD45+, as well as as collagen. These cell can migrate to wound sites, suggesting a role in wound healing. There are several studies suggesting that fibrocytes mediate wound healing and fibrotic tissue repair.	Fibrocyte Fibrocyte is a very old term used to identify inactive mesenchymal cells, that is cells showing minimal cytoplasm,limited amounts of rough endoplasmic reticulum and lack of biochemical evidence of synthesis of proteins. The term "fibrocyte" contrasts with the term "fibroblast." Fibroblasts are connective tissue cells characterized by synthesis of proteins of the fibrous matrix, particularly the collagens. When tissue is injured, the predominant mesenchymal cells, the fibroblast, have been believed to be derived from the fibrocyte or possibly from smooth muscle cells lining vessels and glands. Commonly, fibroblasts express smooth muscle actin, a form of actin first found in smooth muscle cells and not found in resting fibrocytes. Fibroblasts expressing this form of actin are usually called "myo-fibroblasts." Recently, the term "fibrocyte" has also been applied to a blood born cell able to leave the blood, enter tissue and become a fibroblast. As part of the more general topic of stem cell biology, a number of studies have suggested that the blood contains marrow derived cells that can differentiate into fibroblasts. These cells have been reported to express the hematopoietic cell surface markers CD34+, CD45+, as well as as collagen. [1] These cell can migrate to wound sites, suggesting a role in wound healing.[2] There are several studies suggesting that fibrocytes mediate wound healing and fibrotic tissue repair.[3][4][5]	https://www.wikidoc.org/index.php/Fibrocyte
bf09f24f4fc08bcc4be27784cf968c969be9b7a2	wikidoc	Leiomyoma	Leiomyoma Synonyms and keywords: Uterine myoma; Fibroid; Fibroids; Uterine; Fibroid Tumor; Fibroid Uterus; Uterine fibromyoma; Leiomyomata # Overview Uterine leiomyoma was first discovered by Hippocrates in 460-375 B.C and called it “uterine stone”. Uterine leiomyoma may be classified according to their location into 3 subtypes: submucosal, subserous, and intramural. The pathogenesis of leiomyoma is characterized by benign smooth muscle neoplasm. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus. Chromosome aberrations such as t(12; 14)(q14-q15;q23–24), del(7)(q22q32), rearrangements involving 6p21, 10q, trisomy 12, and deletions of 1p3q has been associated with the development of leiomyoma. Uterine leiomyoma must be differentiated from other diseases that cause uterine mass, such as: uterine adenomyoma, pregnancy, hematometra, uterine sarcoma, uterine carcinosarcoma, and metastasis. Leiomyoma is more commonly observed among patients aged 40 years and older. Common risk factors in the development of uterine leiomyoma include African-American race, early menarche, prenatal exposure to diethylstilbestrol, having one or more pregnancies extending beyond 20 weeks, obesity, significant consumption of beef and other red meats, hypertension, family history, and alcohol consumption. Physical examination may be remarkable for enlarged, mobile uterus with an irregular contour on bimanual pelvic examination. The mainstay of therapy for uterine leiomyoma is oral contraceptive pills, either combination pills or progestin-only, Gonadotropin-releasing hormone analogs. Surgery is also part of mainstay therapy for uterine leiomyoma. # Historical Perspective - Uterine leiomyoma was first discovered by Hippocrates, an ancient Greek physician, in 460-375 B.C and called it “uterine stone”. - In the second century AD, Galen described the lesion as "scleromas". - In 1860 and 1863, Rokitansky and Klob coined the term fibroid. - In 1854, Virchow, a German pathologist, demonstrated that those tumors originated from the uterine smooth muscle. - In 1809, the first laparotomy was conducted by Ephraim McDowell to treat leiomyoma in Danville, USA. # Classification - Uterine leiomyoma may be classified according to the International Federation of Gynecology and Obstetrics (FIGO) classification system, based on their location in the uterus, into 8 subtypes: Intramural myomas FIGO types 3, 4, and 5 Located within the uterine wall Submucosal myomas Derived from myometrial cells below the endometrium and may protrude into the uterine cavity May be subclassified according to this protrusion: Type 0: pedunculated intracavitary Type 1: < 50% intramural Type 2: ≥ 50% intramural Subserosal myomas FIGO types 6 and 7 Derived from myometrium at the at the serous surface of the uterus Cervical myomas FIGO type 8 Usually located in the cervix - Intramural myomas FIGO types 3, 4, and 5 Located within the uterine wall - FIGO types 3, 4, and 5 - Located within the uterine wall - Submucosal myomas Derived from myometrial cells below the endometrium and may protrude into the uterine cavity May be subclassified according to this protrusion: Type 0: pedunculated intracavitary Type 1: < 50% intramural Type 2: ≥ 50% intramural - Derived from myometrial cells below the endometrium and may protrude into the uterine cavity - May be subclassified according to this protrusion: Type 0: pedunculated intracavitary Type 1: < 50% intramural Type 2: ≥ 50% intramural - Type 0: pedunculated intracavitary - Type 1: < 50% intramural - Type 2: ≥ 50% intramural - Subserosal myomas FIGO types 6 and 7 Derived from myometrium at the at the serous surface of the uterus - FIGO types 6 and 7 - Derived from myometrium at the at the serous surface of the uterus - Cervical myomas FIGO type 8 Usually located in the cervix - FIGO type 8 - Usually located in the cervix - Leiomyoma may be classified according to histology features into two subtypes of bening and malignant: Bening Mitotically active leiomyomas Myxoid leiomyomas Epithelioid leiomyomas Dissecting leiomyomas Neoplasm with uncertain clinical behavior Smooth muscle tumors of uncertain malignant potential Leiomyoma with bizarre nuclei Cellular leiomyomas Neoplasm with extrauterine disease Leiomyomatosis peritonealis disseminata Intravenous leiomyomatosis Benign metastasizing leiomyomas Multiorgan or primary extrauterine neoplasms Hereditary leiomyomatosis and renal cell carcinoma syndrome Lymphangioleiomyomatosis Cowden syndrome Vulvar and esophageal leiomyomatosis - Bening Mitotically active leiomyomas Myxoid leiomyomas Epithelioid leiomyomas Dissecting leiomyomas - Mitotically active leiomyomas - Myxoid leiomyomas - Epithelioid leiomyomas - Dissecting leiomyomas - Neoplasm with uncertain clinical behavior Smooth muscle tumors of uncertain malignant potential Leiomyoma with bizarre nuclei Cellular leiomyomas - Smooth muscle tumors of uncertain malignant potential - Leiomyoma with bizarre nuclei - Cellular leiomyomas - Neoplasm with extrauterine disease Leiomyomatosis peritonealis disseminata Intravenous leiomyomatosis Benign metastasizing leiomyomas - Leiomyomatosis peritonealis disseminata - Intravenous leiomyomatosis - Benign metastasizing leiomyomas - Multiorgan or primary extrauterine neoplasms Hereditary leiomyomatosis and renal cell carcinoma syndrome Lymphangioleiomyomatosis Cowden syndrome Vulvar and esophageal leiomyomatosis - Hereditary leiomyomatosis and renal cell carcinoma syndrome - Lymphangioleiomyomatosis - Cowden syndrome - Vulvar and esophageal leiomyomatosis # Pathophysiology - The pathogenesis of leiomyoma is characterized by benign smooth muscle neoplasm. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus. - It is thought that leiomyoma is the result of either transformation of normal uterine muscle cells into abnormal cells through somatic mutations, or through the growth of abnormal uterine muscle cells into tumors. - Genetic mutations involved in the pathogenesis of leiomyoma include: t(12;14)(q14-q15;q23–24) del(7)(q22q32) Rearrangements involving 6p21, 10q, trisomy 12 Deletions of 1p3q - t(12;14)(q14-q15;q23–24) - del(7)(q22q32) - Rearrangements involving 6p21, 10q, trisomy 12 - Deletions of 1p3q - On gross pathology, round, well circumscribed, non-encapsulated, solid white or tan nodules, and whorled are characteristic findings of leiomyoma. - On microscopic histopathological analysis, elongated and spindle-shaped cells with a cigar-shaped nucleus are characteristic findings of leiomyoma. # Causes - Chromosome aberrations in uterine leiomyoma include: T(12;14)(q14-q15;q23–24) Deletion of (7)(q22q32) Rearrangements involving 6p21, 10q Trisomy 12 Deletion of 1p3q have been associated with the development of leiomyoma - T(12;14)(q14-q15;q23–24) - Deletion of (7)(q22q32) - Rearrangements involving 6p21, 10q - Trisomy 12 - Deletion of 1p3q have been associated with the development of leiomyoma # Differentiating Leiomyoma from other Diseases # Epidemiology and Demographics ## Age - Leiomyoma commonly affects individuals between menarche and menopause. - The incidence increases with age during reproductive years. ## Race - Leiomyoma usually affects African-American women. Incidence rates are approximately threefold greater in African-American women than in white women. - Incidence rates are approximately threefold greater in African-American women than in white women. # Risk Factors - Common risk factors in the development of uterine leiomyoma include: African-American race Early menarche Prenatal exposure to diethylstilbestrol Parity Having one or more pregnancies extending beyond 20 weeks Obesity Diet Significant consumption of beef and other reds meats Vitamin D deficiency Alcohol consumption Smoking Hormonal contraception - African-American race - Early menarche - Prenatal exposure to diethylstilbestrol - Parity Having one or more pregnancies extending beyond 20 weeks - Having one or more pregnancies extending beyond 20 weeks - Obesity - Diet Significant consumption of beef and other reds meats Vitamin D deficiency - Significant consumption of beef and other reds meats - Vitamin D deficiency - Alcohol consumption - Smoking - Hormonal contraception # Natural History, Complications and Prognosis - The majority of patients with uterine leiomyoma remain asymptomatic for a long time; they are usually found incidentally on imaging or examined after patients start having symptoms. - Studies have shown that 7 to 40% of premenopausal patients with leiomyoma may witness regression of fibroids over 6 months to 3 years. - At menopause most fibroids will start to shrink as menstrual cycles stop and hormone levels wane. - Common complications of uterine leiomyoma include: Dysmenorrhea Dyspareunia Leiomyoma degeneration or torsion Transcervical prolapse Miscarriage - Dysmenorrhea - Dyspareunia - Leiomyoma degeneration or torsion - Transcervical prolapse - Miscarriage - Less common complications of uterine leiomyoma include: Venous compression Polycythemia from autonomous production of erythropoietin Hypercalcemia from autonomous production of parathyroid hormone-related protein Hyperprolactinemia - Venous compression - Polycythemia from autonomous production of erythropoietin - Hypercalcemia from autonomous production of parathyroid hormone-related protein - Hyperprolactinemia # Diagnosis ## Diagnostic Study of Choice - The diagnosis of uterine leiomyoma is based on a clinical diagnosis, which includes a pelvic exam and pelvic ultrasound finding of leiomyomas. - A pelvic ultrasound is indicated when patients suffer from symptoms of leiomyoma. - A biopsy is usually not needed to make the diagnosis, but should be performed if clinician is suspicious that the mass is not a fibroid. ## Symptoms - The majority of patients with leiomyoma are usually asymptomatic. - Symptoms of uterine leiomyoma may include the following: - Abnormal uterine bleeding - Heavy or prolonged menstrual bleeding - Painful sexual intercourse - Abdominal discomfort or bloating - Back pain - Urinary frequency - Urinary retention - Constipation - Infertility ## Physical Examination - Common physical examination findings of uterine leiomyoma include enlarged, mobile uterus with an irregular contour on bimanual pelvic examination. ## Imaging Findings - Pelvic ultrasound is helpful in the diagnosis of uterine leiomyoma. - Findings on an ultrasound diagnostic of uterine leiomyoma include fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam. ## Other Diagnostic Studies - Uterine leiomyoma may also be diagnosed using diagnostic hysteroscopy, magnetic resonance imaging, and hysterosalpingography. # Treatment ## Medical Therapy - Uterine leiomyomas usually shrink and regress during menopause and the postpartum period. - Literature is lacking concerning the medical therapy for leiomyoma, and due to their self-limited nature, expectant management is considered in some cases. - Pharmacologic medical therapy in the form of oral contraceptives is recommended among premenopausal patients with mild symptoms and mildly enlarged uteri. - Pharmacologic medical therapies for leiomyoma include: Estrogen-progestin contraceptives Levonorgestrel-releasing intrauterine system Progestin implants, injections, and pills Progesterone receptor modulators Ulipristal acetate Mifepristone Gonadotropin-releasing hormone agonists Nonsteroidal anti-inflammatory drugs Danazol and gestrinone - Estrogen-progestin contraceptives - Levonorgestrel-releasing intrauterine system - Progestin implants, injections, and pills - Progesterone receptor modulators - Ulipristal acetate - Mifepristone - Gonadotropin-releasing hormone agonists - Nonsteroidal anti-inflammatory drugs - Danazol and gestrinone ## Surgery - Surgery is the mainstay of therapy for uterine leiomyoma. - Uterine artery embolization in conjunction with laparotomic myomectomy is the most common approach to the treatment of leiomyoma. - Hysteroscopic myomectomy can also be performed for patients with uterine leiomyoma. - Surgical indications of leiomyoma include followings: Abnormal uterine bleeding or bulk-related symptoms Infertility or recurrent pregnancy loss - Abnormal uterine bleeding or bulk-related symptoms - Infertility or recurrent pregnancy loss - There is different types of surgery for leiomyoma include followings: Hysterectomy Myomectomy Endometrial ablation Myolysis Uterine artery occlusion - Hysterectomy - Myomectomy - Endometrial ablation - Myolysis - Uterine artery occlusion	Leiomyoma For patient information, click here. Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]; Cafer Zorkun, M.D., Ph.D. [3]; Shanshan Cen, M.D. [4]; Ammu Susheela, M.D. [5] Synonyms and keywords: Uterine myoma; Fibroid; Fibroids; Uterine; Fibroid Tumor; Fibroid Uterus; Uterine fibromyoma; Leiomyomata # Overview Uterine leiomyoma was first discovered by Hippocrates in 460-375 B.C and called it “uterine stone”. Uterine leiomyoma may be classified according to their location into 3 subtypes: submucosal, subserous, and intramural. The pathogenesis of leiomyoma is characterized by benign smooth muscle neoplasm. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus. Chromosome aberrations such as t(12; 14)(q14-q15;q23–24), del(7)(q22q32), rearrangements involving 6p21, 10q, trisomy 12, and deletions of 1p3q has been associated with the development of leiomyoma. Uterine leiomyoma must be differentiated from other diseases that cause uterine mass, such as: uterine adenomyoma, pregnancy, hematometra, uterine sarcoma, uterine carcinosarcoma, and metastasis. Leiomyoma is more commonly observed among patients aged 40 years and older. Common risk factors in the development of uterine leiomyoma include African-American race, early menarche, prenatal exposure to diethylstilbestrol, having one or more pregnancies extending beyond 20 weeks, obesity, significant consumption of beef and other red meats, hypertension, family history, and alcohol consumption. Physical examination may be remarkable for enlarged, mobile uterus with an irregular contour on bimanual pelvic examination. The mainstay of therapy for uterine leiomyoma is oral contraceptive pills, either combination pills or progestin-only, Gonadotropin-releasing hormone analogs. Surgery is also part of mainstay therapy for uterine leiomyoma. # Historical Perspective - Uterine leiomyoma was first discovered by Hippocrates, an ancient Greek physician, in 460-375 B.C and called it “uterine stone”. - In the second century AD, Galen described the lesion as "scleromas". - In 1860 and 1863, Rokitansky and Klob coined the term fibroid. - In 1854, Virchow, a German pathologist, demonstrated that those tumors originated from the uterine smooth muscle. - In 1809, the first laparotomy was conducted by Ephraim McDowell to treat leiomyoma in Danville, USA.[1] # Classification - Uterine leiomyoma may be classified according to the International Federation of Gynecology and Obstetrics (FIGO) classification system, based on their location in the uterus, into 8 subtypes:[2] Intramural myomas FIGO types 3, 4, and 5 Located within the uterine wall Submucosal myomas Derived from myometrial cells below the endometrium and may protrude into the uterine cavity May be subclassified according to this protrusion: Type 0: pedunculated intracavitary Type 1: < 50% intramural Type 2: ≥ 50% intramural Subserosal myomas FIGO types 6 and 7 Derived from myometrium at the at the serous surface of the uterus Cervical myomas FIGO type 8 Usually located in the cervix - Intramural myomas FIGO types 3, 4, and 5 Located within the uterine wall - FIGO types 3, 4, and 5 - Located within the uterine wall - Submucosal myomas Derived from myometrial cells below the endometrium and may protrude into the uterine cavity May be subclassified according to this protrusion: Type 0: pedunculated intracavitary Type 1: < 50% intramural Type 2: ≥ 50% intramural - Derived from myometrial cells below the endometrium and may protrude into the uterine cavity - May be subclassified according to this protrusion: Type 0: pedunculated intracavitary Type 1: < 50% intramural Type 2: ≥ 50% intramural - Type 0: pedunculated intracavitary - Type 1: < 50% intramural - Type 2: ≥ 50% intramural - Subserosal myomas FIGO types 6 and 7 Derived from myometrium at the at the serous surface of the uterus - FIGO types 6 and 7 - Derived from myometrium at the at the serous surface of the uterus - Cervical myomas FIGO type 8 Usually located in the cervix - FIGO type 8 - Usually located in the cervix - Leiomyoma may be classified according to histology features into two subtypes of bening and malignant:[3][4][5][6][7][8][9] Bening Mitotically active leiomyomas Myxoid leiomyomas Epithelioid leiomyomas Dissecting leiomyomas Neoplasm with uncertain clinical behavior Smooth muscle tumors of uncertain malignant potential Leiomyoma with bizarre nuclei Cellular leiomyomas Neoplasm with extrauterine disease Leiomyomatosis peritonealis disseminata Intravenous leiomyomatosis Benign metastasizing leiomyomas Multiorgan or primary extrauterine neoplasms Hereditary leiomyomatosis and renal cell carcinoma syndrome Lymphangioleiomyomatosis Cowden syndrome Vulvar and esophageal leiomyomatosis - Bening Mitotically active leiomyomas Myxoid leiomyomas Epithelioid leiomyomas Dissecting leiomyomas - Mitotically active leiomyomas - Myxoid leiomyomas - Epithelioid leiomyomas - Dissecting leiomyomas - Neoplasm with uncertain clinical behavior Smooth muscle tumors of uncertain malignant potential Leiomyoma with bizarre nuclei Cellular leiomyomas - Smooth muscle tumors of uncertain malignant potential - Leiomyoma with bizarre nuclei - Cellular leiomyomas - Neoplasm with extrauterine disease Leiomyomatosis peritonealis disseminata Intravenous leiomyomatosis Benign metastasizing leiomyomas - Leiomyomatosis peritonealis disseminata - Intravenous leiomyomatosis - Benign metastasizing leiomyomas - Multiorgan or primary extrauterine neoplasms Hereditary leiomyomatosis and renal cell carcinoma syndrome Lymphangioleiomyomatosis Cowden syndrome Vulvar and esophageal leiomyomatosis - Hereditary leiomyomatosis and renal cell carcinoma syndrome - Lymphangioleiomyomatosis - Cowden syndrome - Vulvar and esophageal leiomyomatosis # Pathophysiology - The pathogenesis of leiomyoma is characterized by benign smooth muscle neoplasm. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus. - It is thought that leiomyoma is the result of either transformation of normal uterine muscle cells into abnormal cells through somatic mutations, or through the growth of abnormal uterine muscle cells into tumors.[10][11] - Genetic mutations involved in the pathogenesis of leiomyoma include: [12] t(12;14)(q14-q15;q23–24) del(7)(q22q32) Rearrangements involving 6p21, 10q, trisomy 12 Deletions of 1p3q - t(12;14)(q14-q15;q23–24) - del(7)(q22q32) - Rearrangements involving 6p21, 10q, trisomy 12 - Deletions of 1p3q - On gross pathology, round, well circumscribed, non-encapsulated, solid white or tan nodules, and whorled are characteristic findings of leiomyoma.[13] - On microscopic histopathological analysis, elongated and spindle-shaped cells with a cigar-shaped nucleus are characteristic findings of leiomyoma. # Causes - Chromosome aberrations in uterine leiomyoma include:[14] T(12;14)(q14-q15;q23–24) Deletion of (7)(q22q32) Rearrangements involving 6p21, 10q Trisomy 12 Deletion of 1p3q have been associated with the development of leiomyoma - T(12;14)(q14-q15;q23–24) - Deletion of (7)(q22q32) - Rearrangements involving 6p21, 10q - Trisomy 12 - Deletion of 1p3q have been associated with the development of leiomyoma # Differentiating Leiomyoma from other Diseases # Epidemiology and Demographics ## Age - Leiomyoma commonly affects individuals between menarche and menopause. - The incidence increases with age during reproductive years.[97] ## Race - Leiomyoma usually affects African-American women.[97] Incidence rates are approximately threefold greater in African-American women than in white women. - Incidence rates are approximately threefold greater in African-American women than in white women. # Risk Factors - Common risk factors in the development of uterine leiomyoma include:[97][98][99][100][101][102][103] African-American race Early menarche Prenatal exposure to diethylstilbestrol Parity Having one or more pregnancies extending beyond 20 weeks Obesity Diet Significant consumption of beef and other reds meats Vitamin D deficiency Alcohol consumption Smoking Hormonal contraception - African-American race - Early menarche - Prenatal exposure to diethylstilbestrol - Parity Having one or more pregnancies extending beyond 20 weeks - Having one or more pregnancies extending beyond 20 weeks - Obesity - Diet Significant consumption of beef and other reds meats Vitamin D deficiency - Significant consumption of beef and other reds meats - Vitamin D deficiency - Alcohol consumption - Smoking - Hormonal contraception # Natural History, Complications and Prognosis - The majority of patients with uterine leiomyoma remain asymptomatic for a long time; they are usually found incidentally on imaging or examined after patients start having symptoms. - Studies have shown that 7 to 40% of premenopausal patients with leiomyoma may witness regression of fibroids over 6 months to 3 years.[104] - At menopause most fibroids will start to shrink as menstrual cycles stop and hormone levels wane.[104] - Common complications of uterine leiomyoma include:[105][106][107] Dysmenorrhea Dyspareunia Leiomyoma degeneration or torsion Transcervical prolapse Miscarriage - Dysmenorrhea - Dyspareunia - Leiomyoma degeneration or torsion - Transcervical prolapse - Miscarriage - Less common complications of uterine leiomyoma include:[108][109][110] Venous compression Polycythemia from autonomous production of erythropoietin Hypercalcemia from autonomous production of parathyroid hormone-related protein Hyperprolactinemia - Venous compression - Polycythemia from autonomous production of erythropoietin - Hypercalcemia from autonomous production of parathyroid hormone-related protein - Hyperprolactinemia # Diagnosis ## Diagnostic Study of Choice - The diagnosis of uterine leiomyoma is based on a clinical diagnosis, which includes a pelvic exam and pelvic ultrasound finding of leiomyomas. - A pelvic ultrasound is indicated when patients suffer from symptoms of leiomyoma. - A biopsy is usually not needed to make the diagnosis, but should be performed if clinician is suspicious that the mass is not a fibroid.[111] ## Symptoms - The majority of patients with leiomyoma are usually asymptomatic. - Symptoms of uterine leiomyoma may include the following:[112] - Abnormal uterine bleeding - Heavy or prolonged menstrual bleeding - Painful sexual intercourse - Abdominal discomfort or bloating - Back pain - Urinary frequency - Urinary retention - Constipation - Infertility ## Physical Examination - Common physical examination findings of uterine leiomyoma include enlarged, mobile uterus with an irregular contour on bimanual pelvic examination.[112] ## Imaging Findings - Pelvic ultrasound is helpful in the diagnosis of uterine leiomyoma. - Findings on an ultrasound diagnostic of uterine leiomyoma include fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam.[113] ## Other Diagnostic Studies - Uterine leiomyoma may also be diagnosed using diagnostic hysteroscopy, magnetic resonance imaging, and hysterosalpingography. # Treatment ## Medical Therapy - Uterine leiomyomas usually shrink and regress during menopause and the postpartum period. - Literature is lacking concerning the medical therapy for leiomyoma, and due to their self-limited nature, expectant management is considered in some cases.[114][115] - Pharmacologic medical therapy in the form of oral contraceptives is recommended among premenopausal patients with mild symptoms and mildly enlarged uteri.[116] - Pharmacologic medical therapies for leiomyoma include:[117][118][119][120] Estrogen-progestin contraceptives Levonorgestrel-releasing intrauterine system Progestin implants, injections, and pills Progesterone receptor modulators Ulipristal acetate Mifepristone Gonadotropin-releasing hormone agonists Nonsteroidal anti-inflammatory drugs Danazol and gestrinone - Estrogen-progestin contraceptives - Levonorgestrel-releasing intrauterine system - Progestin implants, injections, and pills - Progesterone receptor modulators - Ulipristal acetate - Mifepristone - Gonadotropin-releasing hormone agonists - Nonsteroidal anti-inflammatory drugs - Danazol and gestrinone ## Surgery - Surgery is the mainstay of therapy for uterine leiomyoma. - Uterine artery embolization in conjunction with laparotomic myomectomy is the most common approach to the treatment of leiomyoma. - Hysteroscopic myomectomy can also be performed for patients with uterine leiomyoma.[121] - Surgical indications of leiomyoma include followings: Abnormal uterine bleeding or bulk-related symptoms Infertility or recurrent pregnancy loss - Abnormal uterine bleeding or bulk-related symptoms - Infertility or recurrent pregnancy loss - There is different types of surgery for leiomyoma include followings:[122][123][124][125] Hysterectomy Myomectomy Endometrial ablation Myolysis Uterine artery occlusion - Hysterectomy - Myomectomy - Endometrial ablation - Myolysis - Uterine artery occlusion	https://www.wikidoc.org/index.php/Fibroid_Uterus
3c334d8e35f631573f5ee1b15d6ed6a150125f35	wikidoc	Filaggrin	Filaggrin Filaggrin (filament aggregating protein) is a filament-associated protein that binds to keratin fibers in epithelial cells. Ten to twelve filaggrin units are post-translationally hydrolyzed from a large profilaggrin precursor protein during terminal differentiation of epidermal cells. In humans, profilaggrin is encoded by the FLG gene, which is part of the S100 fused-type protein (SFTP) family within the epidermal differentiation complex on chromosome 1q21. # Profilaggrin Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the epidermis, these structures are present in the keratohyalin granules in cells of the stratum granulosum. Profilaggrin undergoes proteolytic processing to yield individual filaggrin monomers at the transition between the stratum granulosum and the stratum corneum, which may be facilitated by calcium-dependent enzymes. # Structure Filaggrin is characterized by a particularly high isoelectric point, which is the result of the relatively high presence of histidine in its primary structure. It is also relatively low in the sulfur-containing amino acids methionine and cysteine. # Function Filaggrin is essential for the regulation of epidermal homeostasis. Within the stratum corneum, filaggrin monomers can become incorporated into the lipid envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin intermediate filaments. Filaggrin undergoes further processing in the upper stratum corneum to release free amino acids that assist in water retention. Some studies attribute Filaggrin an important role in keeping the physiological acidic pH of the skin, through a breaking down mechanism to form histidine and subsequently trans-urocanic acid, however others have shown that the filaggrin–histidine–urocanic acid cascade is not essential for skin acidification. # Clinical significance Individuals with truncation mutations in the gene coding for filaggrin are strongly predisposed to a severe form of dry skin, ichthyosis vulgaris, and/or eczema. It has been shown that almost 50% of all severe cases of eczema may have at least one mutated filaggrin gene. R501X and 2284del4 are not generally found in non-Caucasian individuals, though novel mutations (3321delA and S2554X) that yield similar effects have been found in Japanese populations. Truncation mutations R501X and 2284del4 are the most common mutations in the Caucasian population, with 7 to 10% of the Caucasian population carrying at least one copy of these mutations. Autoantibodies in rheumatoid arthritis recognizing an epitope of citrullinated peptides are cross-reactive with filaggrin. The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations. Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression. In early infancy, the penetrance of filaggrin mutations may be increased by household exposure to cats.	Filaggrin Filaggrin (filament aggregating protein) is a filament-associated protein that binds to keratin fibers in epithelial cells. Ten to twelve filaggrin units are post-translationally hydrolyzed from a large profilaggrin precursor protein during terminal differentiation of epidermal cells.[1] In humans, profilaggrin is encoded by the FLG gene, which is part of the S100 fused-type protein (SFTP) family within the epidermal differentiation complex on chromosome 1q21.[2] # Profilaggrin Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the epidermis, these structures are present in the keratohyalin granules in cells of the stratum granulosum. Profilaggrin undergoes proteolytic processing to yield individual filaggrin monomers at the transition between the stratum granulosum and the stratum corneum, which may be facilitated by calcium-dependent enzymes.[3] # Structure Filaggrin is characterized by a particularly high isoelectric point, which is the result of the relatively high presence of histidine in its primary structure.[4] It is also relatively low in the sulfur-containing amino acids methionine and cysteine. # Function Filaggrin is essential for the regulation of epidermal homeostasis. Within the stratum corneum, filaggrin monomers can become incorporated into the lipid envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin intermediate filaments. Filaggrin undergoes further processing in the upper stratum corneum to release free amino acids that assist in water retention.[3] Some studies attribute Filaggrin an important role in keeping the physiological acidic pH of the skin, through a breaking down mechanism to form histidine and subsequently trans-urocanic acid,[5] however others have shown that the filaggrin–histidine–urocanic acid cascade is not essential for skin acidification.[6] # Clinical significance Individuals with truncation mutations in the gene coding for filaggrin are strongly predisposed to a severe form of dry skin, ichthyosis vulgaris, and/or eczema.[7] It has been shown that almost 50% of all severe cases of eczema may have at least one mutated filaggrin gene. R501X and 2284del4 are not generally found in non-Caucasian individuals, though novel mutations (3321delA and S2554X) that yield similar effects have been found in Japanese populations.[8] Truncation mutations R501X and 2284del4 are the most common mutations in the Caucasian population, with 7 to 10% of the Caucasian population carrying at least one copy of these mutations.[9] Autoantibodies in rheumatoid arthritis recognizing an epitope of citrullinated peptides are cross-reactive with filaggrin.[10] The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations.[11][12][13] Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression.[14] In early infancy, the penetrance of filaggrin mutations may be increased by household exposure to cats.[15]	https://www.wikidoc.org/index.php/Filaggrin
a6215f809c7a579b189730d0aeef33b77b87e16a	wikidoc	Filopodia	Filopodia The filopodia are slender cytoplasmic projections, similar to lamellipodia, which extend from the leading edge of migrating cells. They contain actin filaments cross-linked into bundles by actin-binding proteins, e.g. fimbrin (Hanein et al, 1997). Filopodia form focal adhesions with the substratum, linking it to the cell surface (Lodish et al, 2004). A cell migrates along a surface by extending filopodia at the leading edge. The filopodia attach to the substratum further down the migratory pathway, then contraction of stress fibres retracts the rear of the cell to move the cell forwards. Activation of the Rho family of small Ras-related GTPases and their downstream intermediates results in the construction of actin fibers (Ohta et al, 1999). Growth factors bind to receptor tyrosine kinases resulting in the polymerization of actin filaments, which cross-linked, make up the supporting cytoskeletal elements of filopodia. Rho activity also results in the activation of the phosphorylation of the ezrin-moesin-radixin group promoting the binding of actin filaments to the filopodia membrane (Ohta et al, 1999). To close a wound in vertebrates, growth factors stimulate the formation of filopodia in fibroblasts to direct fibroblast division and close the wound (Bentley et al, 1986). In developing neurons, filopodia extend from the growth cone at the leading edge. In neurons deprived of filopodia by the removal of actin filaments, growth cone extension continues as normal but direction of growth is disrupted and highly irregular (Bentley et al, 1986).	Filopodia The filopodia are slender cytoplasmic projections, similar to lamellipodia, which extend from the leading edge of migrating cells. They contain actin filaments cross-linked into bundles by actin-binding proteins, e.g. fimbrin (Hanein et al, 1997). Filopodia form focal adhesions with the substratum, linking it to the cell surface (Lodish et al, 2004). A cell migrates along a surface by extending filopodia at the leading edge. The filopodia attach to the substratum further down the migratory pathway, then contraction of stress fibres retracts the rear of the cell to move the cell forwards. Activation of the Rho family of small Ras-related GTPases and their downstream intermediates results in the construction of actin fibers (Ohta et al, 1999). Growth factors bind to receptor tyrosine kinases resulting in the polymerization of actin filaments, which cross-linked, make up the supporting cytoskeletal elements of filopodia. Rho activity also results in the activation of the phosphorylation of the ezrin-moesin-radixin group promoting the binding of actin filaments to the filopodia membrane (Ohta et al, 1999). To close a wound in vertebrates, growth factors stimulate the formation of filopodia in fibroblasts to direct fibroblast division and close the wound (Bentley et al, 1986). In developing neurons, filopodia extend from the growth cone at the leading edge. In neurons deprived of filopodia by the removal of actin filaments, growth cone extension continues as normal but direction of growth is disrupted and highly irregular (Bentley et al, 1986).	https://www.wikidoc.org/index.php/Filopodia
64d078896b17a8dc0b0a4524833ce892fec711ce	wikidoc	First aid	First aid # Overview First aid is the provision of limited care for an illness or injury, which is provided, usually by a lay person, to a sick or injured patient until definitive medical treatment can be accessed, or until the illness or injury is dealt with (as not all illnesses or injuries will require a higher level of treatment). It generally consists of series of simple, sometimes life saving, medical techniques, that an individual, either with or without formal medical training, can be trained to perform with minimal equipment. First aid can also be performed on animals other than humans, although this article refers specifically to human first aid. # Historical Perspective The Knights Hospitaller were probably the first to specialize in battlefield care for the wounded. Similarly, knights founded the Order of St. John in the 11th century to train other knights specifically how to treat common battlefield injuries. St. John Ambulance was formed in 1877 to teach first aid (a term devised by the order) in large railway centres and mining districts. The order and its training began to spread throughout the British Empire and Europe. As well, in 1859 Henry Dunant helped organize villagers in Switzerland to help victims of the Battle of Solferino. Four years later, four nations met in Geneva and formed the organization which has grown into the Red Cross. Developments in first aid and many other medical techniques have been fueled in large by wars: the American Civil War prompted Clara Barton to organize the American Red Cross. Today, there are several groups that promote first aid, such as the military and the Scouting movement. New techniques and equipment have helped make today’s first aid simple and effective. # Aims The 3 main aims of first aid, commonly referred to as the “3 Ps” are: - Preserve life - Prevent further injury - Promote recovery - In addition, some trainers may also advocate a 4th ‘P’ - Protect yourself, although this is not technically an ‘aim’ of providing first aid, and some people would consider that it is adequately covered by ‘Prevent further injury’ as this is to the casualty, yourself or others. # Training Much of first aid is common sense, and people are almost certain to learn some elements as they go through their life (such as knowing to apply an adhesive bandage to a small cut on a finger). However, effective life-saving first aid requires hands-on training by experts, especially where it relates to potentially fatal illnesses and injuries, such as those that require Cardiopulmonary resuscitation (CPR), as the procedures may be invasive, and carry a risk of further injury to the patient - which the ‘3 aims’ of first aid above, clearly try to avoid. As with any training, it is more useful if it occurs before an actual emergency, although in many countries, emergency ambulance dispatchers will give basic first aid instructions over the phone while the ambulance is on its way. To be adequately trained, a person must attend a course (hopefully leading to a qualification recognised in their country), but then, due to regular changes in procedures and protocols, based on updated clinical knowledge, must attend regular refresher courses or re-certification in order to ensure they are doing the best for their patient (and in some countries, to minimise the chance of being held liable for further injury or deterioration). Training in first aid is often available through community organizations such as the Red Cross and St. John Ambulance, or through commercial providers, who will train people for a fee. This commercial training is most common for training of employees to perform first aid in their workplace. Many community organisations, such as the ones above, also provide a commercial service, which complements their community programmes. # Key First Aid Skills There are certain skills which can be regarded as core, regardless of where or how first aid is taught. First aiders are taught to focus on the "ABC"s of first aid before giving additional treatment: - Airway - Breathing - Circulation This means any first aider should first evaluate and attempt to treat problems with a casualty's airway. If the airway is open the first aider should then evaluate and attempt to treat problems with breathing followed by circulation (circulation of blood). Some instructors add a fourth step of "D" for Deadly Bleeds which is technically already included in the circulation check. Variations on techniques to evaluate and maintain the ABCs depend on the skill level of the first aider. Once the ABCs are secured first aiders can begin more advance treatment. Some countries teach the same order of priority using the "3 Bs": - Breathing - Bleeding - Bones This means that any first aider should first seek to treat any problems with Breathing, before attempting to deal with a bleed or broken bone (which is not to say that they should not be considered at the time - such as in the case of a spinal injury, where a variation on the technique can be used to open the airway). ## Preserving Life As the key skill to first aid is preserving life, the single most important training a first aider can receive is in the primary diagnosis and care of an unconscious or unresponsive patient. The most common mnemonic used to remember the procedure for this is ABC, which stands for Airway, Breathing and Circulation. In order to preserve life, all persons require to have an open airway - a clear passage where air can move in through the mouth or nose through the pharynx and down in to the lungs, without obstruction. Conscious people will maintain their own airway automatically, but those who are unconscious (with a GCS of less than 8) may be unable to maintain a patent airway, as the part of the brain which autonomously controls in normal situations may not be functioning. If an unconscious patient is lying on his or her back, the tongue may fall backward, obstructing the oropharynx (sometimes incorrectly called “swallowing” the tongue). This can be easily rectified by a first aider tipping the head backwards, which mechanically lifts the tongue clear. If the patient was breathing, a first aider would normally then place them in the recovery position, with the patient leant over on their side, which also has the effect of clearing the tongue from the pharynx. It also avoids a common cause of death in unconscious patients, which is choking on regurgitated stomach contents. The airway can also become blocked through a foreign object becoming lodged in the pharynx or larynx, commonly called choking. The first aider will be taught to deal with this through a combination of ‘back slaps’ and ‘abdominal thrusts’. Once the airway has been opened, the first aider would assess to see if the patient is breathing. If there is no breathing, or the patient is not breathing normally, such as agonal breathing, the first aider would undertake what is probably the most recognised first aid procedure - Cardiopulmonary resuscitation or CPR, which involves breathing for the patient, and manually massaging the heart to promote blood flow around the body. ## Promoting Recovery The first aider is also likely to be trained in dealing with injuries such as cuts, grazes or broken bones. They may be able to deal with the situation in its entirety (a small adhesive bandage on a paper cut), or may be required to maintain the condition of something like a broken bone, until the next stage of definitive care (usually an ambulance) arrives. # First Aid Symbols Although commonly associated with first aid, the symbol of a red cross is an official protective symbol of the Red Cross. According to the Geneva Conventions and other international law, the use of this and similar symbols is reserved for official agencies of the International Red Cross and Red Crescent, and as a protective emblem for medical personnel and facilities in combat situations. Use by any other person or organization is illegal, and may lead to prosecution. The internationally accepted symbol for first aid is the white cross on a green background shown at the start of the page. Some organizations may make use the Star of Life, although this is usually reserved for use by Ambulance services, or symbols such as the Maltese Cross such as the Order of Malta Ambulance Corps and St John Ambulance, or other symbols. - ISO First Aid Symbol - Symbol of the Red Cross - Maltese Cross - Star of life # First Aid Training Around the World ## Australia In Australia, Nationally recognised First Aid certificates may only be issued by registered training organizations who are accredited on the National Training Information System (NTIS). Most First Aid certificates are issued at one of 3 levels: - Level 1 (or “Basic First Aid”, or “Basic Life Support”): is a 1-day course covering primarily life-threatening emergencies: CPR, bleeding, chocking and other life-threatening medical emergencies. - Level 2 (“Senior First Aid”) is a 2 day course that covers all the aspects of training in Level 1, as well as specialised training for treatment of burns, bites, stings, electric shock and poisons. Level 2 reaccreditation is a 1 day course which must be taken every 3 years. - Level 3 (“Occupational First Aid”) is a 4-day course covering advanced first aid, use of oxygen and Automated external defibrillators and documentation. It is suitable for workplace First Aiders and those who manage First Aid facilities. Other courses outside these levels are commonly taught, including CPR-only courses, Advanced Resuscitation, Remote Area or Wilderness First Aid, Administering Medications (such as salbutamol or the Epi-Pen) and specialised courses for parents, school teachers, community first responders or hazardous workplace first aiders. ## Canada In Canada, first aid certificates are awarded by one of several organizations including the Red Cross, the Lifesaving Society of Canada, St. John Ambulance, the Heart and Stroke Foundation, and Ski Patrol. Workplace safety regulations vary depending on occupation. Many workplaces opt to have their employees trained in Standard First Aid (see below). - Emergency First Aid: is an 8-hour course covering primarily life-threatening emergencies: CPR, bleeding, choking and other life-threatening medical emergencies. - Standard First Aid: is a 16-hour course that covers the same material as Emergency First Aid and will include training for some, but not all, of the following: breaks; burns; poisons, bites and stings; eye injuries; head and neck injuries; chest injuries; wound care; emergency child birth; and multiple casualty management. - Medical First Responder (BTLS - known by different names among different Canadian organizations): is a 40 hour course. It requires Standard First Aid certification as a prerequisite. Candidates are trained in the use of oxygen, Automated external defibrillators, airway management, and the use of additional emergency equipment. CPR certification in Canada is broken into several levels. Depending on the level, the lay person will learn CPR and choking procedures for adults, children, and infants. CPR H.C.P. (Health Care Professional) also provides training on artificial respiration, the use of bag valve masks, and suction. This level of qualification is usually not offered to the general public. ## Ireland In Ireland, the workplace qualification is the Occupational First Aid Certificate. The Health and Safety Authority issue the standards for fisrt aid at work and hold a register of qualified instructors, examiners and organisations that can provide the course. The certificate is awarded after a three day course and is valid for three years from date of issue. Organisations offering the certificate include, Irelands largest first aid organisation, the Order of Malta Ambulance Corps, the St John Ambulance Brigade and the Irish Red Cross. ## United Kingdom In the United Kingdom, there are two main types of first aid courses offered. An “Emergency Aid for Appointed Persons” course typically lasts one day, and covers the basics, focusing on critical interventions for conditions such as cardiac arrest and severe bleeding, and is usually not formally assessed. A “First Aid at Work” course is usually a four-day course (two days for a re-qualification) that covers the full spectrum of first aid, and is formally assessed by recognised Health and Safety Executive assessors. Certificates for the “First Aid at Work” course are issued by the training organisation and are valid for a period of three years from the date the delegate passes the course. Other courses offered by training organisations such as St. John Ambulance, St. Andrew’s Ambulance Association or the British Red Cross include Baby & Child Courses, manual handling, people moving, and courses geared towards more advanced life support, such as defibrillation and administration of medical gases such as oxygen & entonox). # Specific First Aid Disciplines There are several types of first aid (and first aider) which require specific additional training. These are usually undertaken to fulfill the demands of the work or activity undertaken. - Aquatic/Marine first aid - Usually practised by professionals such as lifeguards or in diver rescue, and covers the specific problems which may be faced after water-based rescue. - Battlefield first aid - This takes in to account the specific needs of treating wounded combatants and non-combatants during armed conflict. - Hyperbaric first aid - Which may be practised by SCUBA diving professionals, who need to treat conditions such as the bends. - Oxygen first aid - Providing oxygen to casualties who suffer from conditions resulting in hypoxia. - Wilderness first aid is the provision of first aid under conditions where the arrival of emergency responders or the evacuation of an injured person may be delayed due to constraints of terrain, weather, and available persons or equipment. It may be necessary to care for an injured person for several hours or days. # Conditions That Often Require First Aid Also see medical emergency. - Altitude sickness, which can begin in susceptible people at altitudes as low as 5,000 feet, can cause potentially fatal swelling of the brain or lungs. - Anaphylaxis, a life-threatening condition in which the airway can become constricted and the patient may go into shock. The reaction can be caused by a systemic allergic reaction to allergens such as insect bites or peanuts. Anaphylaxis is initially treated with injection of epinephrine. - Battlefield First aid - This protocol refers to treating shrapnel, gunshot wounds, burns, bone fractures, etc. as seen either in the ‘traditional’ battlefield setting or in an area subject to damage by large scale weaponry, such as a bomb blast or other terrorist activity. - Bone fracture, a break in a bone initially treated by stabilizing the fracture with a splint. - Burns, which can result in damage to tissues and loss of body fluids through the burn site. - Choking, blockage of the airway which can quickly result in death due to lack of oxygen if the patient’s trachea is not cleared, for example by the Heimlich Maneuver. - Childbirth. - Cramps in muscles due to lactic acid build up caused either by inadequate oxygenation of muscle or lack of water or salt. - Joint dislocation. - Diving disorders resulting from too much pressure. - Near drowning or asphyxiation. - Gastrointestinal bleeding. - Gender-specific conditions, such as dysmenorrhea and testicular torsion. - Heart attack, or inadequate blood flow to the blood vessels supplying the heart muscle. - Heat stroke, also known as sunstroke or hyperthermia, which tends to occur during heavy exercise in high humidity, or with inadequate water, though it may occur spontaneously in some chronically ill persons. Sunstroke, especially when the victim has been unconscious, often causes major damage to body systems such as brain, kidney, liver, gastric tract. Unconsciousness for more than two hours usually leads to permanent disability. Emergency treatment involves rapid cooling of the patient. - Heat syncope, another stage in the same process as heat stroke, occurs under similar conditions as heat stroke and is not distinguished from the latter by some authorities. - Heavy bleeding, treated by applying pressure (manually and later with a pressure bandage) to the wound site and elevating the limb if possible. - Hyperglycemia, or diabetic coma. - Hypoglycemia, or insulin shock. - Hypothermia, or Exposure, occurs when a person’s core body temperature falls below 33.7°C (92.6°F). First aid for a mildly hypothermic patient includes rewarming, but rewarming a severely hypothermic person could result in a fatal arrhythmia, an irregular heart rhythm. - Insect and animal bites and stings. - Muscle strain. - Poisoning, which can occur by injection, inhalation, absorption, or ingestion. - Seizures, or a malfunction in the electrical activity in the brain. Three types of seizures include a grand mal (which usually features convulsions as well as temporary respiratory abnormalities, change in skin complexion, etc) and petit mal (which usually features twitching, rapid blinking, and/or fidgeting as well as altered consciousness and temporary respiratory abnormalities). - Sprain, a temporary dislocation of a joint that immediately reduces automatically but may result in ligament damage. - Stroke, a temporary loss of blood supply to the brain. - Sucking chest wound, a life threatening hole in the chest which can cause the chest cavity to fill with air and prevent the lung from filling, treated by covering with an occlusive dressing to let air out but not in. - Toothache, which can result in severe pain and loss of the tooth but is rarely life threatening. - Wounds and bleeding, including laceration, incision and abrasion, and avulsion. # Related Chapters - Abdominal thrusts - Ambulance - Artificial respiration - Cardiopulmonary resuscitation (CPR) - Occlusive dressing - Oxygen first aid - Triage - Tourniquet - Recovery position	First aid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview First aid is the provision of limited care for an illness or injury, which is provided, usually by a lay person, to a sick or injured patient until definitive medical treatment can be accessed, or until the illness or injury is dealt with (as not all illnesses or injuries will require a higher level of treatment). It generally consists of series of simple, sometimes life saving, medical techniques, that an individual, either with or without formal medical training, can be trained to perform with minimal equipment. First aid can also be performed on animals other than humans, although this article refers specifically to human first aid. # Historical Perspective The Knights Hospitaller were probably the first to specialize in battlefield care for the wounded. Similarly, knights founded the Order of St. John in the 11th century to train other knights specifically how to treat common battlefield injuries.[1] St. John Ambulance was formed in 1877 to teach first aid (a term devised by the order) in large railway centres and mining districts. The order and its training began to spread throughout the British Empire and Europe.[2] As well, in 1859 Henry Dunant helped organize villagers in Switzerland to help victims of the Battle of Solferino. Four years later, four nations met in Geneva and formed the organization which has grown into the Red Cross. Developments in first aid and many other medical techniques have been fueled in large by wars: the American Civil War prompted Clara Barton to organize the American Red Cross.[3] Today, there are several groups that promote first aid, such as the military and the Scouting movement. New techniques and equipment have helped make today’s first aid simple and effective. # Aims The 3 main aims of first aid, commonly referred to as the “3 Ps” are: - Preserve life - Prevent further injury - Promote recovery - In addition, some trainers may also advocate a 4th ‘P’ - Protect yourself, although this is not technically an ‘aim’ of providing first aid, and some people would consider that it is adequately covered by ‘Prevent further injury’ as this is to the casualty, yourself or others. # Training Much of first aid is common sense, and people are almost certain to learn some elements as they go through their life (such as knowing to apply an adhesive bandage to a small cut on a finger). However, effective life-saving first aid requires hands-on training by experts, especially where it relates to potentially fatal illnesses and injuries, such as those that require Cardiopulmonary resuscitation (CPR), as the procedures may be invasive, and carry a risk of further injury to the patient - which the ‘3 aims’ of first aid above, clearly try to avoid. As with any training, it is more useful if it occurs before an actual emergency, although in many countries, emergency ambulance dispatchers will give basic first aid instructions over the phone while the ambulance is on its way. To be adequately trained, a person must attend a course (hopefully leading to a qualification recognised in their country), but then, due to regular changes in procedures and protocols, based on updated clinical knowledge, must attend regular refresher courses or re-certification in order to ensure they are doing the best for their patient (and in some countries, to minimise the chance of being held liable for further injury or deterioration). Training in first aid is often available through community organizations such as the Red Cross and St. John Ambulance, or through commercial providers, who will train people for a fee. This commercial training is most common for training of employees to perform first aid in their workplace. Many community organisations, such as the ones above, also provide a commercial service, which complements their community programmes. # Key First Aid Skills There are certain skills which can be regarded as core, regardless of where or how first aid is taught. First aiders are taught to focus on the "ABC"s of first aid before giving additional treatment: - Airway - Breathing - Circulation This means any first aider should first evaluate and attempt to treat problems with a casualty's airway. If the airway is open the first aider should then evaluate and attempt to treat problems with breathing followed by circulation (circulation of blood). Some instructors add a fourth step of "D" for Deadly Bleeds which is technically already included in the circulation check. Variations on techniques to evaluate and maintain the ABCs depend on the skill level of the first aider. Once the ABCs are secured first aiders can begin more advance treatment. Some countries teach the same order of priority using the "3 Bs": - Breathing - Bleeding - Bones This means that any first aider should first seek to treat any problems with Breathing, before attempting to deal with a bleed or broken bone (which is not to say that they should not be considered at the time - such as in the case of a spinal injury, where a variation on the technique can be used to open the airway). ## Preserving Life As the key skill to first aid is preserving life, the single most important training a first aider can receive is in the primary diagnosis and care of an unconscious or unresponsive patient. The most common mnemonic used to remember the procedure for this is ABC, which stands for Airway, Breathing and Circulation. In order to preserve life, all persons require to have an open airway - a clear passage where air can move in through the mouth or nose through the pharynx and down in to the lungs, without obstruction. Conscious people will maintain their own airway automatically, but those who are unconscious (with a GCS of less than 8) may be unable to maintain a patent airway, as the part of the brain which autonomously controls in normal situations may not be functioning. If an unconscious patient is lying on his or her back, the tongue may fall backward, obstructing the oropharynx (sometimes incorrectly called “swallowing” the tongue). This can be easily rectified by a first aider tipping the head backwards, which mechanically lifts the tongue clear.[4] If the patient was breathing, a first aider would normally then place them in the recovery position, with the patient leant over on their side, which also has the effect of clearing the tongue from the pharynx. It also avoids a common cause of death in unconscious patients, which is choking on regurgitated stomach contents. The airway can also become blocked through a foreign object becoming lodged in the pharynx or larynx, commonly called choking. The first aider will be taught to deal with this through a combination of ‘back slaps’ and ‘abdominal thrusts’. Once the airway has been opened, the first aider would assess to see if the patient is breathing. If there is no breathing, or the patient is not breathing normally, such as agonal breathing, the first aider would undertake what is probably the most recognised first aid procedure - Cardiopulmonary resuscitation or CPR, which involves breathing for the patient, and manually massaging the heart to promote blood flow around the body. ## Promoting Recovery The first aider is also likely to be trained in dealing with injuries such as cuts, grazes or broken bones. They may be able to deal with the situation in its entirety (a small adhesive bandage on a paper cut), or may be required to maintain the condition of something like a broken bone, until the next stage of definitive care (usually an ambulance) arrives. # First Aid Symbols Although commonly associated with first aid, the symbol of a red cross is an official protective symbol of the Red Cross. According to the Geneva Conventions and other international law, the use of this and similar symbols is reserved for official agencies of the International Red Cross and Red Crescent, and as a protective emblem for medical personnel and facilities in combat situations. Use by any other person or organization is illegal, and may lead to prosecution. The internationally accepted symbol for first aid is the white cross on a green background shown at the start of the page. Some organizations may make use the Star of Life, although this is usually reserved for use by Ambulance services, or symbols such as the Maltese Cross such as the Order of Malta Ambulance Corps and St John Ambulance, or other symbols. - ISO First Aid Symbol - Symbol of the Red Cross - Maltese Cross - Star of life # First Aid Training Around the World ## Australia In Australia, Nationally recognised First Aid certificates may only be issued by registered training organizations who are accredited on the National Training Information System (NTIS). Most First Aid certificates are issued at one of 3 levels: - Level 1 (or “Basic First Aid”, or “Basic Life Support”): is a 1-day course covering primarily life-threatening emergencies: CPR, bleeding, chocking and other life-threatening medical emergencies. - Level 2 (“Senior First Aid”) is a 2 day course that covers all the aspects of training in Level 1, as well as specialised training for treatment of burns, bites, stings, electric shock and poisons. Level 2 reaccreditation is a 1 day course which must be taken every 3 years. - Level 3 (“Occupational First Aid”) is a 4-day course covering advanced first aid, use of oxygen and Automated external defibrillators and documentation. It is suitable for workplace First Aiders and those who manage First Aid facilities. Other courses outside these levels are commonly taught, including CPR-only courses, Advanced Resuscitation, Remote Area or Wilderness First Aid, Administering Medications (such as salbutamol or the Epi-Pen) and specialised courses for parents, school teachers, community first responders or hazardous workplace first aiders. ## Canada In Canada, first aid certificates are awarded by one of several organizations including the Red Cross, the Lifesaving Society of Canada, St. John Ambulance, the Heart and Stroke Foundation, and Ski Patrol. Workplace safety regulations vary depending on occupation. Many workplaces opt to have their employees trained in Standard First Aid (see below). - Emergency First Aid: is an 8-hour course covering primarily life-threatening emergencies: CPR, bleeding, choking and other life-threatening medical emergencies. - Standard First Aid: is a 16-hour course that covers the same material as Emergency First Aid and will include training for some, but not all, of the following: breaks; burns; poisons, bites and stings; eye injuries; head and neck injuries; chest injuries; wound care; emergency child birth; and multiple casualty management. - Medical First Responder (BTLS - known by different names among different Canadian organizations): is a 40 hour course. It requires Standard First Aid certification as a prerequisite. Candidates are trained in the use of oxygen, Automated external defibrillators, airway management, and the use of additional emergency equipment. CPR certification in Canada is broken into several levels. Depending on the level, the lay person will learn CPR and choking procedures for adults, children, and infants. CPR H.C.P. (Health Care Professional) also provides training on artificial respiration, the use of bag valve masks, and suction. This level of qualification is usually not offered to the general public. ## Ireland In Ireland, the workplace qualification is the Occupational First Aid Certificate. The Health and Safety Authority issue the standards for fisrt aid at work and hold a register of qualified instructors, examiners and organisations that can provide the course. The certificate is awarded after a three day course and is valid for three years from date of issue. Organisations offering the certificate include, Irelands largest first aid organisation, the Order of Malta Ambulance Corps, the St John Ambulance Brigade and the Irish Red Cross. ## United Kingdom In the United Kingdom, there are two main types of first aid courses offered. An “Emergency Aid for Appointed Persons” course typically lasts one day, and covers the basics, focusing on critical interventions for conditions such as cardiac arrest and severe bleeding, and is usually not formally assessed. A “First Aid at Work” course is usually a four-day course (two days for a re-qualification) that covers the full spectrum of first aid, and is formally assessed by recognised Health and Safety Executive assessors. Certificates for the “First Aid at Work” course are issued by the training organisation and are valid for a period of three years from the date the delegate passes the course. Other courses offered by training organisations such as St. John Ambulance, St. Andrew’s Ambulance Association or the British Red Cross include Baby & Child Courses, manual handling, people moving, and courses geared towards more advanced life support, such as defibrillation and administration of medical gases such as oxygen & entonox). # Specific First Aid Disciplines There are several types of first aid (and first aider) which require specific additional training. These are usually undertaken to fulfill the demands of the work or activity undertaken. - Aquatic/Marine first aid - Usually practised by professionals such as lifeguards or in diver rescue, and covers the specific problems which may be faced after water-based rescue. - Battlefield first aid - This takes in to account the specific needs of treating wounded combatants and non-combatants during armed conflict. - Hyperbaric first aid - Which may be practised by SCUBA diving professionals, who need to treat conditions such as the bends. - Oxygen first aid - Providing oxygen to casualties who suffer from conditions resulting in hypoxia. - Wilderness first aid is the provision of first aid under conditions where the arrival of emergency responders or the evacuation of an injured person may be delayed due to constraints of terrain, weather, and available persons or equipment. It may be necessary to care for an injured person for several hours or days. # Conditions That Often Require First Aid Also see medical emergency. - Altitude sickness, which can begin in susceptible people at altitudes as low as 5,000 feet, can cause potentially fatal swelling of the brain or lungs. - Anaphylaxis, a life-threatening condition in which the airway can become constricted and the patient may go into shock. The reaction can be caused by a systemic allergic reaction to allergens such as insect bites or peanuts. Anaphylaxis is initially treated with injection of epinephrine. - Battlefield First aid - This protocol refers to treating shrapnel, gunshot wounds, burns, bone fractures, etc. as seen either in the ‘traditional’ battlefield setting or in an area subject to damage by large scale weaponry, such as a bomb blast or other terrorist activity. - Bone fracture, a break in a bone initially treated by stabilizing the fracture with a splint. - Burns, which can result in damage to tissues and loss of body fluids through the burn site. - Choking, blockage of the airway which can quickly result in death due to lack of oxygen if the patient’s trachea is not cleared, for example by the Heimlich Maneuver. - Childbirth. - Cramps in muscles due to lactic acid build up caused either by inadequate oxygenation of muscle or lack of water or salt. - Joint dislocation. - Diving disorders resulting from too much pressure. - Near drowning or asphyxiation. - Gastrointestinal bleeding. - Gender-specific conditions, such as dysmenorrhea and testicular torsion. - Heart attack, or inadequate blood flow to the blood vessels supplying the heart muscle. - Heat stroke, also known as sunstroke or hyperthermia, which tends to occur during heavy exercise in high humidity, or with inadequate water, though it may occur spontaneously in some chronically ill persons. Sunstroke, especially when the victim has been unconscious, often causes major damage to body systems such as brain, kidney, liver, gastric tract. Unconsciousness for more than two hours usually leads to permanent disability. Emergency treatment involves rapid cooling of the patient. - Heat syncope, another stage in the same process as heat stroke, occurs under similar conditions as heat stroke and is not distinguished from the latter by some authorities. - Heavy bleeding, treated by applying pressure (manually and later with a pressure bandage) to the wound site and elevating the limb if possible. - Hyperglycemia, or diabetic coma. - Hypoglycemia, or insulin shock. - Hypothermia, or Exposure, occurs when a person’s core body temperature falls below 33.7°C (92.6°F). First aid for a mildly hypothermic patient includes rewarming, but rewarming a severely hypothermic person could result in a fatal arrhythmia, an irregular heart rhythm. - Insect and animal bites and stings. - Muscle strain. - Poisoning, which can occur by injection, inhalation, absorption, or ingestion. - Seizures, or a malfunction in the electrical activity in the brain. Three types of seizures include a grand mal (which usually features convulsions as well as temporary respiratory abnormalities, change in skin complexion, etc) and petit mal (which usually features twitching, rapid blinking, and/or fidgeting as well as altered consciousness and temporary respiratory abnormalities). - Sprain, a temporary dislocation of a joint that immediately reduces automatically but may result in ligament damage. - Stroke, a temporary loss of blood supply to the brain. - Sucking chest wound, a life threatening hole in the chest which can cause the chest cavity to fill with air and prevent the lung from filling, treated by covering with an occlusive dressing to let air out but not in. - Toothache, which can result in severe pain and loss of the tooth but is rarely life threatening. - Wounds and bleeding, including laceration, incision and abrasion, and avulsion. # Related Chapters - Abdominal thrusts - Ambulance - Artificial respiration - Cardiopulmonary resuscitation (CPR) - Occlusive dressing - Oxygen first aid - Triage - Tourniquet - Recovery position	https://www.wikidoc.org/index.php/First_aid
80b87b10ea1f4df7d7cb64b48ba77aeb9127acd5	wikidoc	Flagellum	Flagellum # Overview A flagellum (plural: flagella) is a long, slender projection from the cell body, composed of microtubules and surrounded by the plasma membrane. In small, single-cell organisms they may function to propel the cell by beating in a whip-like motion; in larger animals, they often serve to move fluids along mucous membranes such as the lining of the trachea. Eukaryotic flagella are quite different from the flagella of prokaryotes and bacteria. They have an internal structure comprised of nine microtubule doublets, forming a cylinder around a central pair of microtubules. The nine peripheral doublets are linked to each other by proteins such as dynein, a molecular motor which can cause flagella to bend. A eukaryotic cell usually has only one or two flagella. As in prokaryotes, the eukaryotic flagellum may be used in locomotion; one well known example of this is the sperm cell, in which the "tail" of the sperm (a flagellum) is used to propel the cell forward. However, all non-dividing eukaryotic cells contain a flagellum (or cilium), not only sperm cells. Stationary cells (such as kidney, intestine, and nerve cells) also contain flagella (cilia) which project from the cell body out into the extracellular environment. There, these flagella can serve in sensation or in the movement of extracellular fluid. The main differences among bacterial, archaeal, and eukaryotic flagella are summarized below: - Bacterial flagella are helical filaments that rotate like screws. - Archaeal flagella are superficially similar to bacterial flagella, but are different in many details and considered non-homologous. - Eukaryotic flagella - those of animal, plant, and protist cells - are complex cellular projections that lash back and forth. Sometimes eukaryotic flagella are called cilia or undulipodia to emphasize their distinctiveness. # Bacterial flagellum The bacterial flagellum is composed of the protein flagellin. Its shape is a 20 nanometer-thick hollow tube. It is helical and has a sharp bend just outside the outer membrane; this "hook" allows the helix to point directly away from the cell. A shaft runs between the hook and the basal body, passing through protein rings in the cell's membrane that act as bearings. Gram-positive organisms have 2 of these basal body rings, one in the peptidoglycan layer and one in the plasma membrane. Gram-negative organisms have 4 such rings: the L ring associates with the lipopolysaccharides, the P ring associates with peptidoglycan layer, the M ring is imbedded in the plasma membrane, and the S ring is directly attached to the plasma membrane. The filament ends with a capping protein. The bacterial flagellum is driven by a rotary engine composed of protein, located at the flagellum's anchor point on the inner cell membrane. The engine is powered by proton motive force, i.e., by the flow of protons (e.g., hydrogen ions) across the bacterial cell membrane due to a concentration gradient set up by the cell's metabolism (in Vibrio species the motor is a sodium ion pump rather than a proton pump). The rotor transports protons across the membrane, and is turned in the process. The rotor alone can operate at 6,000 to 17,000 rpm, but with the flagellar filament attached usually only reaches 200 to 1000 rpm. The components of the bacterial flagellum are capable of self-assembly without the aid of enzymes or other factors. Both the basal body and the filament have a hollow core, through which the component proteins of the flagellum are able to move into their respective positions. During assembly, protein components are added at the flagellar tip rather than at the base. The basal body has several traits in common with some types of secretory pores, such as the hollow rod-like "plug" in their centers extending out through the plasma membrane. Given the structural similarities, it was thought that bacterial flagella may have evolved from such pores; however, it is now known that these pores are derived from flagella. Different species of bacteria have different numbers and arrangements of flagella. Monotrichous bacteria have a single flagellum (e.g., Vibrio cholerae). Lophotrichous bacteria have multiple flagella located at the same spot on the bacteria's surfaces which act in concert to drive the bacteria in a single direction. Amphitrichous bacteria have a single flagellum on each of two opposite ends (only one flagellum operates at a time, allowing the bacteria to reverse course rapidly by switching which flagellum is active). Peritrichous bacteria have flagella projecting in all directions (e.g., Escherichia coli). Some species of bacteria (such as Spirochetes) have a specialized type of flagellum called an "axial filament" that is located in the periplasmic space, the rotation of which causes the entire bacterium to move forward in a corkscrew-like motion. Counterclockwise rotation of monotrichous polar flagella thrust the cell forward with the flagella trailing behind. Periodically, the direction of rotation is briefly reversed, causing what is known as a "tumble" in which the cell seems to thrash about in place. This results in the reorientation of the cell. When moving in a favorable direction, "tumbles" are unlikely; however, when the cell's direction of motion is unfavorable (e.g., away from a chemical attractant), a tumble may occur, with the chance that the cell will be thus reoriented in the correct direction. # Archaeal flagellum The archaeal flagellum is superficially similar to the bacterial (or eubacterial) flagellum; in the 1980s they were thought to be homologous on the basis of gross morphology and behavior (Cavalier-Smith, 1987). Both flagella consist of filaments extending outside of the cell, and rotate to propel the cell. However, discoveries in the 1990s have revealed numerous detailed differences between the archaeal and bacterial flagella; these include: - Bacterial flagella are powered by a flow of H+ ions (or occasionally Na+ ions); archaeal flagella are almost certainly powered by ATP. The torque-generating motor that powers rotation of the archaeal flagellum has not been identified. - While bacterial cells often have many flagellar filaments, each of which rotates independently, the archaeal flagellum is composed of a bundle of many filaments that rotate as a single assembly. - Bacterial flagella grow by the addition of flagellin subunits at the tip; archaeal flagella grow by the addition of subunits to the base. - Bacterial flagella are thicker than archaeal flagella, and the bacterial filament has a large enough hollow "tube" inside that the flagellin subunits can flow up the inside of the filament and get added at the tip; the archaeal flagellum is too thin to allow this. - Many components of bacterial flagella share sequence similarity to components of the type III secretion systems, but the components of bacterial and archaeal flagella share no sequence similarity. Instead, some components of archaeal flagella share sequence and morphological similarity with components of type IV pili, which are assembled through the action of type II secretion systems (the nomenclature of pili and protein secretion systems is not consistent). These differences mean that the bacterial and archaeal flagella are a classic case of biological analogy, or convergent evolution, rather than homology. However, in comparison to the decades of well-publicized study of bacterial flagella (e.g. by Berg), archaeal flagella have only recently begun to get serious scientific attention. Therefore, many assume erroneously that there is only one basic kind of prokaryotic flagellum, and that archaeal flagella are homologous to it. For example, Cavalier-Smith (2002) is aware of the differences between archaeal and bacterial flagellins, but retains the misconception that the basal bodies are homologous. # Eukaryotic flagellum The eukaryotic flagellum is completely different from the prokaryote flagellum in both structure and evolutionary origin. The only shared characteristics among bacterial, archaeal, and eukaryotic flagella are their superficial appearance; they are intracellular extensions used in creating movement. Along with cilia, they make up a group of organelles known as undulipodia. A eukaryotic flagellum is a bundle of nine fused pairs of microtubule doublets surrounding two central single microtubules. The so-called "9+2" structure is characteristic of the core of the eukaryotic flagellum called an axoneme. At the base of a eukaryotic flagellum is a basal body, "blepharoplast" or kinetosome, which is the microtubule organizing center for flagellar microtubules and is about 500 nanometers long. Basal bodies are structurally identical to centrioles. The flagellum is encased within the cell's plasma membrane, so that the interior of the flagellum is accessible to the cell's cytoplasm. Each of the outer 9 doublet microtubules extends a pair of dynein arms (an "inner" and an "outer" arm) to the adjacent microtubule; these dynein arms are responsible for flagellar beating, as the force produced by the arms causes the microtubule doublets to slide against each other and the flagellum as a whole to bend. These dynein arms produce force through ATP hydrolysis. The flagellar axoneme also contains radial spokes, polypeptide complexes extending from each of the outer 9 mictrotubule doublets towards the central pair, with the "head" of the spoke facing inwards. The radial spoke is thought to be involved in the regulation of flagellar motion, although its exact function and method of action are not yet understood. Motile flagella serve for the propulsion of single cells (e.g. swimming of protozoa and spermatozoa) and the transport of fluids (e.g. transport of mucus by stationary flagellated cells in the trachea). Additionally, immotile flagella are vital organelles in sensation and signal transduction across a wide variety of cell types (e.g. eye: rod photoreceptor cells, nose: olfactory receptor neurons, ear: kinocilium in cochlea). Intraflagellar transport (IFT), the process by which axonemal subunits, transmembrane receptors, and other proteins are moved up and down the length of the flagellum, is essential for proper functioning of the flagellum, in both motility and signal transduction. For information on biologists' ideas about how the various flagella may have evolved, see evolution of flagella.	Flagellum Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A flagellum (plural: flagella) is a long, slender projection from the cell body, composed of microtubules and surrounded by the plasma membrane. In small, single-cell organisms they may function to propel the cell by beating in a whip-like motion; in larger animals, they often serve to move fluids along mucous membranes such as the lining of the trachea. Eukaryotic flagella are quite different from the flagella of prokaryotes and bacteria. They have an internal structure comprised of nine microtubule doublets, forming a cylinder around a central pair of microtubules. The nine peripheral doublets are linked to each other by proteins such as dynein, a molecular motor which can cause flagella to bend. A eukaryotic cell usually has only one or two flagella. As in prokaryotes, the eukaryotic flagellum may be used in locomotion; one well known example of this is the sperm cell, in which the "tail" of the sperm (a flagellum) is used to propel the cell forward. However, all non-dividing eukaryotic cells contain a flagellum (or cilium), not only sperm cells. Stationary cells (such as kidney, intestine, and nerve cells) also contain flagella (cilia) which project from the cell body out into the extracellular environment. There, these flagella can serve in sensation or in the movement of extracellular fluid. The main differences among bacterial, archaeal, and eukaryotic flagella are summarized below: - Bacterial flagella are helical filaments that rotate like screws. - Archaeal flagella are superficially similar to bacterial flagella, but are different in many details and considered non-homologous. - Eukaryotic flagella - those of animal, plant, and protist cells - are complex cellular projections that lash back and forth. Sometimes eukaryotic flagella are called cilia or undulipodia to emphasize their distinctiveness. # Bacterial flagellum The bacterial flagellum is composed of the protein flagellin. Its shape is a 20 nanometer-thick hollow tube. It is helical and has a sharp bend just outside the outer membrane; this "hook" allows the helix to point directly away from the cell. A shaft runs between the hook and the basal body, passing through protein rings in the cell's membrane that act as bearings. Gram-positive organisms have 2 of these basal body rings, one in the peptidoglycan layer and one in the plasma membrane. Gram-negative organisms have 4 such rings: the L ring associates with the lipopolysaccharides, the P ring associates with peptidoglycan layer, the M ring is imbedded in the plasma membrane, and the S ring is directly attached to the plasma membrane. The filament ends with a capping protein. The bacterial flagellum is driven by a rotary engine composed of protein, located at the flagellum's anchor point on the inner cell membrane. The engine is powered by proton motive force, i.e., by the flow of protons (e.g., hydrogen ions) across the bacterial cell membrane due to a concentration gradient set up by the cell's metabolism (in Vibrio species the motor is a sodium ion pump rather than a proton pump). The rotor transports protons across the membrane, and is turned in the process. The rotor alone can operate at 6,000 to 17,000 rpm, but with the flagellar filament attached usually only reaches 200 to 1000 rpm. The components of the bacterial flagellum are capable of self-assembly without the aid of enzymes or other factors. Both the basal body and the filament have a hollow core, through which the component proteins of the flagellum are able to move into their respective positions. During assembly, protein components are added at the flagellar tip rather than at the base. The basal body has several traits in common with some types of secretory pores, such as the hollow rod-like "plug" in their centers extending out through the plasma membrane. Given the structural similarities, it was thought that bacterial flagella may have evolved from such pores; however, it is now known that these pores are derived from flagella. Different species of bacteria have different numbers and arrangements of flagella. Monotrichous bacteria have a single flagellum (e.g., Vibrio cholerae). Lophotrichous bacteria have multiple flagella located at the same spot on the bacteria's surfaces which act in concert to drive the bacteria in a single direction. Amphitrichous bacteria have a single flagellum on each of two opposite ends (only one flagellum operates at a time, allowing the bacteria to reverse course rapidly by switching which flagellum is active). Peritrichous bacteria have flagella projecting in all directions (e.g., Escherichia coli). Some species of bacteria (such as Spirochetes) have a specialized type of flagellum called an "axial filament" that is located in the periplasmic space, the rotation of which causes the entire bacterium to move forward in a corkscrew-like motion. Counterclockwise rotation of monotrichous polar flagella thrust the cell forward with the flagella trailing behind. Periodically, the direction of rotation is briefly reversed, causing what is known as a "tumble" in which the cell seems to thrash about in place. This results in the reorientation of the cell. When moving in a favorable direction, "tumbles" are unlikely; however, when the cell's direction of motion is unfavorable (e.g., away from a chemical attractant), a tumble may occur, with the chance that the cell will be thus reoriented in the correct direction. # Archaeal flagellum The archaeal flagellum is superficially similar to the bacterial (or eubacterial) flagellum; in the 1980s they were thought to be homologous on the basis of gross morphology and behavior (Cavalier-Smith, 1987). Both flagella consist of filaments extending outside of the cell, and rotate to propel the cell. However, discoveries in the 1990s have revealed numerous detailed differences between the archaeal and bacterial flagella; these include: - Bacterial flagella are powered by a flow of H+ ions (or occasionally Na+ ions); archaeal flagella are almost certainly powered by ATP. The torque-generating motor that powers rotation of the archaeal flagellum has not been identified. - While bacterial cells often have many flagellar filaments, each of which rotates independently, the archaeal flagellum is composed of a bundle of many filaments that rotate as a single assembly. - Bacterial flagella grow by the addition of flagellin subunits at the tip; archaeal flagella grow by the addition of subunits to the base. - Bacterial flagella are thicker than archaeal flagella, and the bacterial filament has a large enough hollow "tube" inside that the flagellin subunits can flow up the inside of the filament and get added at the tip; the archaeal flagellum is too thin to allow this. - Many components of bacterial flagella share sequence similarity to components of the type III secretion systems, but the components of bacterial and archaeal flagella share no sequence similarity. Instead, some components of archaeal flagella share sequence and morphological similarity with components of type IV pili, which are assembled through the action of type II secretion systems (the nomenclature of pili and protein secretion systems is not consistent). These differences mean that the bacterial and archaeal flagella are a classic case of biological analogy, or convergent evolution, rather than homology. However, in comparison to the decades of well-publicized study of bacterial flagella (e.g. by Berg), archaeal flagella have only recently begun to get serious scientific attention. Therefore, many assume erroneously that there is only one basic kind of prokaryotic flagellum, and that archaeal flagella are homologous to it. For example, Cavalier-Smith (2002) is aware of the differences between archaeal and bacterial flagellins, but retains the misconception that the basal bodies are homologous.[citation needed] # Eukaryotic flagellum The eukaryotic flagellum is completely different from the prokaryote flagellum in both structure and evolutionary origin. The only shared characteristics among bacterial, archaeal, and eukaryotic flagella are their superficial appearance; they are intracellular extensions used in creating movement. Along with cilia, they make up a group of organelles known as undulipodia. A eukaryotic flagellum is a bundle of nine fused pairs of microtubule doublets surrounding two central single microtubules. The so-called "9+2" structure is characteristic of the core of the eukaryotic flagellum called an axoneme. At the base of a eukaryotic flagellum is a basal body, "blepharoplast" or kinetosome, which is the microtubule organizing center for flagellar microtubules and is about 500 nanometers long. Basal bodies are structurally identical to centrioles. The flagellum is encased within the cell's plasma membrane, so that the interior of the flagellum is accessible to the cell's cytoplasm. Each of the outer 9 doublet microtubules extends a pair of dynein arms (an "inner" and an "outer" arm) to the adjacent microtubule; these dynein arms are responsible for flagellar beating, as the force produced by the arms causes the microtubule doublets to slide against each other and the flagellum as a whole to bend. These dynein arms produce force through ATP hydrolysis. The flagellar axoneme also contains radial spokes, polypeptide complexes extending from each of the outer 9 mictrotubule doublets towards the central pair, with the "head" of the spoke facing inwards. The radial spoke is thought to be involved in the regulation of flagellar motion, although its exact function and method of action are not yet understood. Motile flagella serve for the propulsion of single cells (e.g. swimming of protozoa and spermatozoa) and the transport of fluids (e.g. transport of mucus by stationary flagellated cells in the trachea). Additionally, immotile flagella are vital organelles in sensation and signal transduction across a wide variety of cell types (e.g. eye: rod photoreceptor cells, nose: olfactory receptor neurons, ear: kinocilium in cochlea). Intraflagellar transport (IFT), the process by which axonemal subunits, transmembrane receptors, and other proteins are moved up and down the length of the flagellum, is essential for proper functioning of the flagellum, in both motility and signal transduction. For information on biologists' ideas about how the various flagella may have evolved, see evolution of flagella.	https://www.wikidoc.org/index.php/Flagella
846ea643c57767a927217877ce57cb78ed5fda1e	wikidoc	Flagellin	Flagellin Flagellin is a protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons. Flagellin is the principal substituent of bacterial flagellum, and is present in large amounts on nearly all flagellated bacteria. # Structure The structure of flagellin is responsible for the helical shape of the flagellar filament, which is important for its proper function. The N- and C-termini of flagellin form the inner core of the flagellin protein, and is responsible for flagellin's ability to polymerize into a filament. The central portion of the protein makes up the outer surface of the flagellar filament. While the termini of the protein is quite similar between all bacterial flagellins, the central portion is wildly variable. # Immune response ## In mammals Mammals often have acquired immune responses (T-cell and antibody responses) to flagellated bacterium occurs frequently to flagellar antigens. Some bacteria are able to switch between multiple flagellin genes in order to evade this response. The propensity of the immune response to flagellin may be explained by two facts: - First, flagellin is an extremely abundant protein in flagellated bacteria. - Secondly, there exists a specific innate immune receptor that recognizes flagellin, Toll-like receptor 5 (TLR5). ## In plants In addition a 22 amino acid sequence (flg22) of the conserved N-terminal part of flagellin is known to activate plant defence mechanisms. Flagellin perception in Arabidopsis thaliana functions via the receptor-like-kinase, FLS2 (flagellin-sensitive-2)). Mitogen-activated-protein-kinases (MAPK) acts as signalling compounds and more than 900 genes are affected upon flg22 treatment. Pre-stimulation with a synthetic flg22-peptide led to enhanced resistance against bacterial invaders.	Flagellin Flagellin is a protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons. Flagellin is the principal substituent of bacterial flagellum, and is present in large amounts on nearly all flagellated bacteria. # Structure The structure of flagellin is responsible for the helical shape of the flagellar filament, which is important for its proper function. The N- and C-termini of flagellin form the inner core of the flagellin protein, and is responsible for flagellin's ability to polymerize into a filament. The central portion of the protein makes up the outer surface of the flagellar filament. While the termini of the protein is quite similar between all bacterial flagellins, the central portion is wildly variable. # Immune response ## In mammals Mammals often have acquired immune responses (T-cell and antibody responses) to flagellated bacterium occurs frequently to flagellar antigens. Some bacteria are able to switch between multiple flagellin genes in order to evade this response. The propensity of the immune response to flagellin may be explained by two facts: - First, flagellin is an extremely abundant protein in flagellated bacteria. - Secondly, there exists a specific innate immune receptor that recognizes flagellin, Toll-like receptor 5 (TLR5). ## In plants In addition a 22 amino acid sequence (flg22) of the conserved N-terminal part of flagellin is known to activate plant defence mechanisms. Flagellin perception in Arabidopsis thaliana functions via the receptor-like-kinase, FLS2 (flagellin-sensitive-2)). Mitogen-activated-protein-kinases (MAPK) acts as signalling compounds and more than 900 genes are affected upon flg22 treatment. Pre-stimulation with a synthetic flg22-peptide led to enhanced resistance against bacterial invaders. # External links - Flagellin at the US National Library of Medicine Medical Subject Headings (MeSH) More detailed information: Research article: bacterial flagellin and plant disease resistance, published by Zipfel. et al (2004) ) Abstract Article Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Flagellin
3edf4925849d7a66dd9cf7aeae9bf3e4dd584953	wikidoc	Flavoxate	Flavoxate # 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 Flavoxate is a anticholinergic agent that is FDA approved for the treatment of dysuria, urgency, nocturia, suprapubic pain, frequency and incontinence as may occur in cystitis, prostatitis, urethritis, urethrocystitis/urethrotrigonitis.. Common adverse reactions include Nausea, vomiting, headache, blurred vision, drowsiness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Flavoxate HCl tablets are indicated for symptomatic relief of dysuria, urgency, nocturia, suprapubic pain, frequency and incontinence as may occur in cystitis, prostatitis, urethritis, urethrocystitis/urethrotrigonitis. Flavoxate HCl tablets are not indicated for definitive treatment, but are compatible with drugs used for the treatment of urinary tract infections. ### Dosage - One or two 100 mg tablets 3 or 4 times a day. With improvement of symptoms, the dose may be reduced. This drug cannot be recommended for infants and children under 12 years of age because safety and efficacy have not been demonstrated in this age group. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flavoxate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flavoxate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - This drug cannot be recommended for infants and children under 12 years of age because safety and efficacy have not been demonstrated in this age group. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flavoxate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flavoxate in pediatric patients. # Contraindications - Flavoxate HCl tablets are contraindicated in patients who have any of the following obstructive conditions: pyloric or duodenal obstruction, obstructive intestinal lesions or ileus, achalasia, gastrointestinal hemorrhage and obstructive uropathies of the lower urinary tract. # Warnings - Flavoxate HCl should be given cautiously in patients with suspected glaucoma. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency. - Nausea, vomiting, dry mouth. - Vertigo, headache, mental confusion, especially in the elderly, drowsiness, nervousness. - Leukopenia (one case which was reversible upon discontinuation of the drug). - Tachycardia and palpitation. - Urticaria and other dermatoses, eosinophilia and hyperpyrexia. - Increased ocular tension, blurred vision, disturbance in eye accommodation. - Dysuria. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Flavoxate in the drug label. # Drug Interactions There is limited information regarding Flavoxate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats and rabbits at doses up to 34 times the human dose and revealed no evidence of impaired fertility or harm to the fetus due to flavoxate HCl. There are, however, no 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 Flavoxate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Flavoxate 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, caution should be exercised when flavoxate HCl is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in children below the age of 12 years have not been established. ### Geriatic Use There is no FDA guidance on the use of Flavoxate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Flavoxate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Flavoxate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Flavoxate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Flavoxate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Flavoxate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Flavoxate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Flavoxate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Flavoxate in the drug label. # Overdosage - The oral LD50 for flavoxate HCl in rats is 4273 mg/kg. The oral LD50 for flavoxate HCl in mice is 1837 mg/kg. - It is not known whether flavoxate HCl is dialyzable. # Pharmacology ## Mechanism of Action - Flavoxate hydrochloride counteracts smooth muscle spasm of the urinary tract and exerts its effect directly on the muscle. ## Structure - Flavoxate HCl tablets contain flavoxate hydrochloride, a synthetic urinary tract spasmolytic. - Chemically, flavoxate hydrochloride is 2-piperidinoethyl 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate hydrochloride. The empirical formula of flavoxate hydrochloride is C24H25NO4HCl. The molecular weight is 427.94. The structural formula appears below: - Flavoxate HCl is supplied in tablets for oral administration. Each round, white, film-coated Flavoxate HCl tablet is debossed "PAD" and "0115" on one side and plain on the other side and contains flavoxate hydrochloride, 100 mg. Inactive ingredients consist of colloidal silicon dioxide, ethyl acrylate, hypromellose, lactose monohydrate, magnesium stearate, methyl methacrylate, microcrystalline cellulose, nonoxynol 100 and sodium starch glycolate. Film coating is composed of hypromellose 2910 6cP and polyethylene glycol. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Flavoxate in the drug label. ## Pharmacokinetics - In a single study of 11 normal male subjects, the time to onset of action was 55 minutes. The peak effect was observed at 112 minutes. 57% of the flavoxate HCl was excreted in the urine within 24 hours. ## Nonclinical Toxicology - Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of flavoxate HCl have not been performed. # Clinical Studies There is limited information regarding Clinical Studies of Flavoxate in the drug label. # How Supplied - Flavoxate HCl Tablets, 100 mg, are supplied as round, white, film-coated tablets debossed "PAD" and "0115" on one side and plain on the other side, in bottles of 100. ## Storage - Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 100 MG TABLET BOTTLE Rx Only NDC 0574-0115-01 Flavoxate HCl Tablets 100 mg 100 Tablets ### Ingredients and Appearance # Patient Counseling Information - Patients should be informed that if drowsiness and blurred vision occur, they should not operate a motor vehicle or machinery or participate in activities where alertness is required. # Precautions with Alcohol - Alcohol-Flavoxate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Urispas® # Look-Alike Drug Names There is limited information regarding Flavoxate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Flavoxate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Flavoxate is a anticholinergic agent that is FDA approved for the treatment of dysuria, urgency, nocturia, suprapubic pain, frequency and incontinence as may occur in cystitis, prostatitis, urethritis, urethrocystitis/urethrotrigonitis.. Common adverse reactions include Nausea, vomiting, headache, blurred vision, drowsiness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Flavoxate HCl tablets are indicated for symptomatic relief of dysuria, urgency, nocturia, suprapubic pain, frequency and incontinence as may occur in cystitis, prostatitis, urethritis, urethrocystitis/urethrotrigonitis. Flavoxate HCl tablets are not indicated for definitive treatment, but are compatible with drugs used for the treatment of urinary tract infections. ### Dosage - One or two 100 mg tablets 3 or 4 times a day. With improvement of symptoms, the dose may be reduced. This drug cannot be recommended for infants and children under 12 years of age because safety and efficacy have not been demonstrated in this age group. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flavoxate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flavoxate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - This drug cannot be recommended for infants and children under 12 years of age because safety and efficacy have not been demonstrated in this age group. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flavoxate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flavoxate in pediatric patients. # Contraindications - Flavoxate HCl tablets are contraindicated in patients who have any of the following obstructive conditions: pyloric or duodenal obstruction, obstructive intestinal lesions or ileus, achalasia, gastrointestinal hemorrhage and obstructive uropathies of the lower urinary tract. # Warnings - Flavoxate HCl should be given cautiously in patients with suspected glaucoma. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency. - Nausea, vomiting, dry mouth. - Vertigo, headache, mental confusion, especially in the elderly, drowsiness, nervousness. - Leukopenia (one case which was reversible upon discontinuation of the drug). - Tachycardia and palpitation. - Urticaria and other dermatoses, eosinophilia and hyperpyrexia. - Increased ocular tension, blurred vision, disturbance in eye accommodation. - Dysuria. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Flavoxate in the drug label. # Drug Interactions There is limited information regarding Flavoxate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats and rabbits at doses up to 34 times the human dose and revealed no evidence of impaired fertility or harm to the fetus due to flavoxate HCl. There are, however, no 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 Flavoxate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Flavoxate 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, caution should be exercised when flavoxate HCl is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in children below the age of 12 years have not been established. ### Geriatic Use There is no FDA guidance on the use of Flavoxate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Flavoxate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Flavoxate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Flavoxate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Flavoxate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Flavoxate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Flavoxate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Flavoxate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Flavoxate in the drug label. # Overdosage - The oral LD50 for flavoxate HCl in rats is 4273 mg/kg. The oral LD50 for flavoxate HCl in mice is 1837 mg/kg. - It is not known whether flavoxate HCl is dialyzable. # Pharmacology ## Mechanism of Action - Flavoxate hydrochloride counteracts smooth muscle spasm of the urinary tract and exerts its effect directly on the muscle. ## Structure - Flavoxate HCl tablets contain flavoxate hydrochloride, a synthetic urinary tract spasmolytic. - Chemically, flavoxate hydrochloride is 2-piperidinoethyl 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate hydrochloride. The empirical formula of flavoxate hydrochloride is C24H25NO4•HCl. The molecular weight is 427.94. The structural formula appears below: - Flavoxate HCl is supplied in tablets for oral administration. Each round, white, film-coated Flavoxate HCl tablet is debossed "PAD" and "0115" on one side and plain on the other side and contains flavoxate hydrochloride, 100 mg. Inactive ingredients consist of colloidal silicon dioxide, ethyl acrylate, hypromellose, lactose monohydrate, magnesium stearate, methyl methacrylate, microcrystalline cellulose, nonoxynol 100 and sodium starch glycolate. Film coating is composed of hypromellose 2910 6cP and polyethylene glycol. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Flavoxate in the drug label. ## Pharmacokinetics - In a single study of 11 normal male subjects, the time to onset of action was 55 minutes. The peak effect was observed at 112 minutes. 57% of the flavoxate HCl was excreted in the urine within 24 hours. ## Nonclinical Toxicology - Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of flavoxate HCl have not been performed. # Clinical Studies There is limited information regarding Clinical Studies of Flavoxate in the drug label. # How Supplied - Flavoxate HCl Tablets, 100 mg, are supplied as round, white, film-coated tablets debossed "PAD" and "0115" on one side and plain on the other side, in bottles of 100. ## Storage - Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 100 MG TABLET BOTTLE Rx Only NDC 0574-0115-01 Flavoxate HCl Tablets 100 mg 100 Tablets ### Ingredients and Appearance # Patient Counseling Information - Patients should be informed that if drowsiness and blurred vision occur, they should not operate a motor vehicle or machinery or participate in activities where alertness is required. # Precautions with Alcohol - Alcohol-Flavoxate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Urispas®[1] # Look-Alike Drug Names There is limited information regarding Flavoxate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Flavoxate
2d61d8abcdc5cf23de464dcb53828aacfbb2e92f	wikidoc	Quinolone	Quinolone # Overview The quinolones are a family of broad-spectrum antibiotics. The parent of the group is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluoro group attached the central ring system, typically at the 6-position. # Mechanism Quinolones and fluoroquinolones are bactericidal drugs, actively killing bacteria. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV. # Adverse effects Quinolone antibiotics were once considered relatively safe, but several side-effects have become evident with experience. For example, numerous case reports have implicated their use since 1965 in spontaneous tendon ruptures or damage, especially with the concurrent use of a systemic corticosteroid. In the fall of 2004, the Food and Drug Administration upgraded the warnings found within the package inserts for all drugs within this class regarding such serious adverse reactions. It is important to note, however, that the incidence of this is quite rare, with occurrences at less than one per ten thousand person-years. - Peripheral neuropathy (nerve damage): "Rare cases of sensory or sensor motor axonal polyneuropathy affecting small and or large axons resulting in paresthesias, hypoaesthesias, dysesthesias, and weakness have been reported in patients taking quinolones. Therapy should be discontinued if the patient experiences symptoms of neuropathy, including pain, burning, tingling, numbness and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition." - Tendon damage: "Ruptures of the shoulder, hand, Achilles tendon, or other tendons that require surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Fluoroquinolone therapy should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until diagnosis of tendinitis or tendon rupture had been excluded. Tendon rupture can occur during or after therapy with quinolones." Other problems include: - Heart problems (prolonged QT Interval / Torsades de pointes) - Pseudomembranous colitis - Rhabdomyolysis (breakdown of muscle tissue) - Stevens-Johnson syndrome - Lowered seizure threshold - Hypoglycemia - Kidney stones due to loss of Oxalobacter formigenes # Resistance Resistance to quinolones can develop rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide. Widespread veterinary usage of quinolones, in particular in Europe, has been implicated. There are three known mechanisms of resistance. Efflux pumps can be used to decrease intracellular drug concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug effectiveness. # Generations The quinolones are divided into generations based on their antibacterial spectrum. The earlier generation agents are, in general, more narrow spectrum than the later ones. ## 1st generation - cinoxacin (Cinoxacin®) - flumequine (Flubactin®) (Veterinary use) - nalidixic acid (NegGam®, Wintomylon®) - oxolinic acid - piromidic acid - pipemidic acid (Dolcol®) ## 2nd generation - ciprofloxacin (Ciprobay®, Cipro®, Ciproxin®) - enoxacin (Enroxil®, Penetrex®) - fleroxacin (Megalone®) (withdrawn) - lomefloxacin (Maxaquin®) - nadifloxacin - norfloxacin (Lexinor®, Noroxin®, Quinabic®, Janacin®) - ofloxacin (Floxin®, Oxaldin®, Tarivid®) - pefloxacin - rufloxacin (Uroflox®) ## 3rd generation - balofloxacin - grepafloxacin (Raxar®) (withdrawn) - levofloxacin (Cravit®, Levaquin®) - pazufloxacin Mesilate - sparfloxacin (Zagam®) - temafloxacin (Omniflox®) (withdrawn) - tosufloxacin ## 4th generation - clinafloxacin - gemifloxacin (Factive®) - moxifloxacin (Avelox®) - gatifloxacin (Tequin® (withdrawn), Zymar®) - sitafloxacin - trovafloxacin (Trovan®) (withdrawn) ## In development - ecinofloxacin - prulifloxacin # Veterinary use The quinolones have been widely used in agriculture and several agents exist which have veterinary but not human use. - danofloxacin (Advocin, Advocid) (for veterinary use) - difloxacin (Dicural, Vetequinon) - enrofloxacin (Baytril) (for veterinary use) - marbofloxacin (Marbocyl, Zenequin) (for veterinary use) - orbifloxacin (Orbax, Victas) (for veterinary use) - sarafloxacin (Floxasol, Saraflox, Sarafin) (for veterinary use)	Quinolone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview The quinolones are a family of broad-spectrum antibiotics. The parent of the group is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluoro group attached the central ring system, typically at the 6-position. # Mechanism Quinolones and fluoroquinolones are bactericidal drugs, actively killing bacteria. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV. # Adverse effects Quinolone antibiotics were once considered relatively safe, but several side-effects have become evident with experience. For example, numerous case reports have implicated their use since 1965 in spontaneous tendon ruptures or damage, especially with the concurrent use of a systemic corticosteroid. In the fall of 2004, the Food and Drug Administration upgraded the warnings found within the package inserts for all drugs within this class regarding such serious adverse reactions. It is important to note, however, that the incidence of this is quite rare, with occurrences at less than one per ten thousand person-years.[1] - Peripheral neuropathy (nerve damage): "Rare cases of sensory or sensor motor axonal polyneuropathy affecting small and or large axons resulting in paresthesias, hypoaesthesias, dysesthesias, and weakness have been reported in patients taking quinolones. Therapy should be discontinued if the patient experiences symptoms of neuropathy, including pain, burning, tingling, numbness and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition." - Tendon damage: "Ruptures of the shoulder, hand, Achilles tendon, or other tendons that require surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Fluoroquinolone therapy should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until diagnosis of tendinitis or tendon rupture had been excluded. Tendon rupture can occur during or after therapy with quinolones." Other problems include: - Heart problems (prolonged QT Interval / Torsades de pointes) - Pseudomembranous colitis - Rhabdomyolysis (breakdown of muscle tissue) - Stevens-Johnson syndrome - Lowered seizure threshold - Hypoglycemia - Kidney stones due to loss of Oxalobacter formigenes[2] # Resistance Resistance to quinolones can develop rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.[3] Widespread veterinary usage of quinolones, in particular in Europe, has been implicated. There are three known mechanisms of resistance.[4] Efflux pumps can be used to decrease intracellular drug concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug effectiveness. # Generations The quinolones are divided into generations based on their antibacterial spectrum. The earlier generation agents are, in general, more narrow spectrum than the later ones. ## 1st generation - cinoxacin (Cinoxacin®) - flumequine (Flubactin®) (Veterinary use) - nalidixic acid (NegGam®, Wintomylon®) - oxolinic acid - piromidic acid - pipemidic acid (Dolcol®) ## 2nd generation - ciprofloxacin (Ciprobay®, Cipro®, Ciproxin®) - enoxacin (Enroxil®, Penetrex®) - fleroxacin (Megalone®) (withdrawn) - lomefloxacin (Maxaquin®) - nadifloxacin - norfloxacin (Lexinor®, Noroxin®, Quinabic®, Janacin®) - ofloxacin (Floxin®, Oxaldin®, Tarivid®) - pefloxacin - rufloxacin (Uroflox®) ## 3rd generation - balofloxacin - grepafloxacin (Raxar®) (withdrawn) - levofloxacin (Cravit®, Levaquin®) - pazufloxacin Mesilate - sparfloxacin (Zagam®) - temafloxacin (Omniflox®) (withdrawn) - tosufloxacin ## 4th generation - clinafloxacin - gemifloxacin (Factive®) - moxifloxacin (Avelox®) - gatifloxacin (Tequin® (withdrawn), Zymar®) - sitafloxacin - trovafloxacin (Trovan®) (withdrawn) ## In development - ecinofloxacin - prulifloxacin # Veterinary use The quinolones have been widely used in agriculture and several agents exist which have veterinary but not human use. - danofloxacin (Advocin, Advocid) (for veterinary use) - difloxacin (Dicural, Vetequinon) - enrofloxacin (Baytril) (for veterinary use) - marbofloxacin (Marbocyl, Zenequin) (for veterinary use) - orbifloxacin (Orbax, Victas) (for veterinary use) - sarafloxacin (Floxasol, Saraflox, Sarafin) (for veterinary use) # External links - Fact Sheet: Quinolones - The Flox Report An investigative approach to the true toxicity of quinolone antibiotics. - Research on Adverse Effects of Fluoroquinolones - Fluoroquinolone-Induced Tendinopathy: What do we know? Richard M. Harrell, MD. - Fluoroquinolones "Family Practice Notebook" entry page for Fluoroquinolones - Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD	https://www.wikidoc.org/index.php/Fluoroquinolone
c8854ecb2270d9df2e18d40a837031652df7881b	wikidoc	Halothane	Halothane # Overview Halothane (trademarked as Fluothane) is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic containing a bromine atom; several other halogenated anesthesia agents lack the bromine atom and do contain the fluorine and chlorine atoms present in halothane. It is colorless and pleasant-smelling, but unstable in light. It is packaged in dark-colored bottles and contains 0.01% thymol as a stabilizing agent. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. Its use in developed countries, however, has been almost entirely superseded by newer inhalational anaesthetic agents such as sevoflurane, isoflurane, and desflurane. # Anesthetic properties It is a potent anesthetic with a minimum alveolar concentration of 0.74%. Its blood/gas partition coefficient of 2.4 makes it an agent with moderate induction and recovery time. It is not a good analgesic and its muscle relaxation effect is moderate. # Availability It is available as a volatile liquid, at 30, 50, 200, and 250 ml per container. # Side effects Repeated exposure to halothane in adults was noted in rare cases to result in severe liver injury. This occurred in about one in 10,000 exposures. The resulting syndrome was referred to as halothane hepatitis, and is thought to result from the metabolism of halothane to trifluoroacetic acid via oxidative reactions in the liver. About 20% of inhaled halothane is metabolized by the liver and these products are excreted in the urine. The hepatitis syndrome had a mortality rate of 30% to 70%. Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults. It was replaced in the 1980s by enflurane and isoflurane. By 2005, the common volatile anesthetics in use were isoflurane, sevoflurane, and desflurane. Since the risk of halothane hepatitis in children was substantially lower than in adults, halothane continued to be used in pediatrics in the 1990s. However, by 2000, sevoflurane had largely replaced the use of halothane in children. Halothane sensitises the heart to catecholamines, so it is liable to cause cardiac arrhythmias, occasionally fatal, particularly if hypercapnia has been allowed to develop. This seems to be especially problematic in dental anaesthesia. Like all the potent inhalational anaesthetic agents, it is a potent trigger for malignant hyperthermia. Similarly, it relaxes uterine smooth muscle and this may increase blood loss during delivery or termination of pregnancy. # Pharmacology Halothane activates GABAA and glycine receptors. It also acts as an NMDA receptor antagonist, inhibits nACh and voltage-gated sodium channels, and activates 5-HT3 and twin-pore K+ channels. It does not affect the AMPA or kainate receptors. # Chemical and physical properties Chemically, halothane is an alkyl halide (not an ether like many other anesthetics). The structure has one stereocenter, so (R)- and (S)-optical isomers occur. # Synthesis The commercial synthesis of halothane starts from trichloroethylene, which is reacted with hydrogen fluoride in the presence of antimony trichloride at 130°C to form 2-chloro-1,1,1-trifluoroethane. This is then reacted with bromine at 450°C to produce halothane. File:Halothane synth.png # Related substances Attempts to find anesthetics with less metabolism led to halogenated ethers such as enflurane and isoflurane. The incidence of hepatic reactions with these agents is lower. The exact degree of hepatotoxic potential of enflurane is debated, although it is minimally metabolized. Isoflurane is essentially not metabolized and reports of associated liver injury are quite rare. Small amounts of trifluoroacetic acid can be formed from both halothane and isoflurane metabolism and possibly accounts for cross sensitization of patients between these agents. The main advantage of the more modern agents is lower blood solubility, resulting in faster induction of and recovery from anaesthesia. # History This halogenated hydrocarbon was first synthesized by C. W. Suckling of Imperial Chemical Industries in 1951 and was first used clinically by M. Johnstone in Manchester in 1956. Halothane became popular as a nonflammable general anasthetic replacing other volatile anesthetics such as diethyl ether and cyclopropane. Use of the anesthetic was phased out during the 1980s and 1990s as newer anesthetic agents became popular. Halothane retains some use in veterinary surgery and in the Third World because of its lower cost. Halothane was given to many millions of adult and pediatric patients worldwide from its introduction in 1956 through the 1980s. Its properties include cardiac depression at high levels, cardiac sensitization to catecholamines such as norepinephrine, and potent bronchial relaxation. Its lack of airway irritation made it a common inhalation induction agent in pediatric anesthesia. Due to its cardiac depressive effect, it was contraindicated in patients with cardiac failure. Halothane was also contraindicated in patients susceptible to cardiac arrhythmias, or in situations related to high catecholamine levels such as pheochromocytoma.	Halothane Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Halothane (trademarked as Fluothane) is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic containing a bromine atom; several other halogenated anesthesia agents lack the bromine atom and do contain the fluorine and chlorine atoms present in halothane. It is colorless and pleasant-smelling, but unstable in light. It is packaged in dark-colored bottles and contains 0.01% thymol as a stabilizing agent. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[2] Its use in developed countries, however, has been almost entirely superseded by newer inhalational anaesthetic agents such as sevoflurane, isoflurane, and desflurane. # Anesthetic properties It is a potent anesthetic with a minimum alveolar concentration of 0.74%. Its blood/gas partition coefficient of 2.4 makes it an agent with moderate induction and recovery time. It is not a good analgesic and its muscle relaxation effect is moderate.[3] # Availability It is available as a volatile liquid, at 30, 50, 200, and 250 ml per container.[4] # Side effects Repeated exposure to halothane in adults was noted in rare cases to result in severe liver injury. This occurred in about one in 10,000 exposures. The resulting syndrome was referred to as halothane hepatitis, and is thought to result from the metabolism of halothane to trifluoroacetic acid via oxidative reactions in the liver. About 20% of inhaled halothane is metabolized by the liver and these products are excreted in the urine. The hepatitis syndrome had a mortality rate of 30% to 70%. Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults. It was replaced in the 1980s by enflurane and isoflurane. By 2005, the common volatile anesthetics in use were isoflurane, sevoflurane, and desflurane. Since the risk of halothane hepatitis in children was substantially lower than in adults, halothane continued to be used in pediatrics in the 1990s. However, by 2000, sevoflurane had largely replaced the use of halothane in children. Halothane sensitises the heart to catecholamines, so it is liable to cause cardiac arrhythmias, occasionally fatal, particularly if hypercapnia has been allowed to develop. This seems to be especially problematic in dental anaesthesia. Like all the potent inhalational anaesthetic agents, it is a potent trigger for malignant hyperthermia. Similarly, it relaxes uterine smooth muscle and this may increase blood loss during delivery or termination of pregnancy. # Pharmacology Halothane activates GABAA and glycine receptors.[5][6] It also acts as an NMDA receptor antagonist,[6] inhibits nACh and voltage-gated sodium channels,[7][5] and activates 5-HT3 and twin-pore K+ channels.[8][5] It does not affect the AMPA or kainate receptors.[6] # Chemical and physical properties Chemically, halothane is an alkyl halide (not an ether like many other anesthetics).[9] The structure has one stereocenter, so (R)- and (S)-optical isomers occur. # Synthesis The commercial synthesis of halothane starts from trichloroethylene, which is reacted with hydrogen fluoride in the presence of antimony trichloride at 130°C to form 2-chloro-1,1,1-trifluoroethane. This is then reacted with bromine at 450°C to produce halothane.[10] File:Halothane synth.png # Related substances Attempts to find anesthetics with less metabolism led to halogenated ethers such as enflurane and isoflurane. The incidence of hepatic reactions with these agents is lower. The exact degree of hepatotoxic potential of enflurane is debated, although it is minimally metabolized. Isoflurane is essentially not metabolized and reports of associated liver injury are quite rare. Small amounts of trifluoroacetic acid can be formed from both halothane and isoflurane metabolism and possibly accounts for cross sensitization of patients between these agents. The main advantage of the more modern agents is lower blood solubility, resulting in faster induction of and recovery from anaesthesia. # History This halogenated hydrocarbon was first synthesized by C. W. Suckling of Imperial Chemical Industries in 1951 and was first used clinically by M. Johnstone in Manchester in 1956. Halothane became popular as a nonflammable general anasthetic replacing other volatile anesthetics such as diethyl ether and cyclopropane. Use of the anesthetic was phased out during the 1980s and 1990s as newer anesthetic agents became popular. Halothane retains some use in veterinary surgery and in the Third World because of its lower cost. Halothane was given to many millions of adult and pediatric patients worldwide from its introduction in 1956 through the 1980s.[11] Its properties include cardiac depression at high levels, cardiac sensitization to catecholamines such as norepinephrine, and potent bronchial relaxation. Its lack of airway irritation made it a common inhalation induction agent in pediatric anesthesia. Due to its cardiac depressive effect, it was contraindicated in patients with cardiac failure. Halothane was also contraindicated in patients susceptible to cardiac arrhythmias, or in situations related to high catecholamine levels such as pheochromocytoma.	https://www.wikidoc.org/index.php/Fluothane
43f264735b9b83e0e36eb028ff19ad2a067b519d	wikidoc	Flutamide	Flutamide # 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 Flutamide is an androgen antagonist that is FDA approved for the treatment of carcinoma of prostate, stage B2, C or D2, in combination with an LHRH agonist. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, hot sweats, diarrhea, nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Flutamide capsules are indicated for use in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate. - Treatment with flutamide capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy. - To achieve benefit from treatment, flutamide capsules should be initiated with the LHRH agonist and continued until progression. ### Dosing Information - 250 mg ORALLY every 8 hr in conjunction with a luteinizing hormone-releasing hormone (LHRH) agonist; begin 8 weeks prior to initiating radiation therapy and continue during radiation therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Flutamide in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Flutamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Flutamide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Flutamide in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Flutamide in pediatric patients. # Contraindications - Flutamide capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation. - Flutamide capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment). # Warnings - See BOXED WARNINGS. - Flutamide capsules are for use only in men. This product has no indication for women and should not be used in this population, particularly for nonserious or non-life threatening conditions. - Flutamide may cause fetal harm when administered to a pregnant woman (see Pregnancy). - One metabolite of flutamide is 4-nitro-3-fluoro-methylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after flutamide administration. In patients susceptible to aniline toxicity (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered. ### PRECAUTIONS= - In clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration. # Adverse Reactions ## Clinical Trials Experience - Treatment with flutamide capsules and the goserelin acetate implant did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + goserelin acetate implant + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below. - Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). - The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + LHRH agonist versus placebo + LHRH agonist. - The most frequently reported (greater than 5%) adverse experiences during treatment with flutamide capsules in combination with an LHRH agonist are listed in the table below. For comparison, adverse experiences seen with an LHRH agonist and placebo are also listed in the following table. - As shown in the table, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, impotence, loss of libido) were those known to be associated with low serum androgen levels and known to occur with LHRH agonists alone. - The only notable difference was the higher incidence of diarrhea in the flutamide + LHRH agonist group (12%), which was severe in 5% as opposed to the placebo + LHRH agonist (4%), which was severe in less than 1%. - In addition, the following adverse reactions were reported during treatment with flutamide + LHRH agonist. - Hypertension in 1% of patients - CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients - Anorexia 4%, and other GI disorders occurred in 6% of patients - Anemia occurred in 6%, leukopenia in 3%, and thrombocytopenia in 1% of patients - Hepatitis and jaundice in less than 1% of patients ### =Skin - Irritation at the injection site and rash occurred in 3% of patients - Edema occurred in 4%, genitourinary and neuromuscular symptoms in 2%, and pulmonary symptoms in less than 1% of patients. - In addition, the following spontaneous adverse experiences have been reported during the marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions (including erythema, ulceration, bullous eruptions, and epidermal necrolysis), and urine discoloration. The urine was noted to change to an amber or yellow-green appearance which can be attributed to the flutamide and/or its metabolites. Also reported were cholestatic jaundice, hepatic encephalopathy, and hepatic necrosis. The hepatic conditions were often reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide. - Malignant breast neoplasms have occurred rarely in male patients being treated with flutamide. - Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported. ## Postmarketing Experience There is limited information regarding Flutamide Postmarketing Experience in the drug label. # Drug Interactions - Regular assessment of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise significantly and consistently during flutamide therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen while continuing the LHRH analogue may be considered. - Increases in prothrombin time have been noted in patients receiving long-term warfarin therapy after flutamide was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide capsules are administered concomitantly with warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - There was decreased 24 hour survival in the offspring of pregnant rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose). A slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of cats treated with two higher doses. Feminization of the male cats also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flutamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Flutamide during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Flutamide with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Flutamide with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Flutamide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Flutamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Flutamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Flutamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Flutamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Flutamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Flutamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dosage is 2 capsules 3 times a day at 8-hour intervals for a total daily dose of 750 mg. ### Monitoring There is limited information regarding Monitoring of Flutamide in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Flutamide in the drug label. # Overdosage - In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia. - Clinical trials have been conducted with flutamide in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness, and some increases in SGOT. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established. - Flutamide is highly protein bound and is not cleared by hemodialysis. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. # Pharmacology ## Mechanism of Action - In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration. ## Structure - Flutamide Capsules USP contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, α,α,α-Trifluoro-2-methyl-4’-nitro-m-propionotoluidide and has the following structural formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Flutamide in the drug label. ## Pharmacokinetics - Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide. - In male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 hours. Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL, is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins. - The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol. - Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours. ### Special Populations - Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8.1 hours and at steady state in 9.6 hours. - There are no known alterations in flutamide absorption, distribution, metabolism, or excretion due to race. - Following a single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmax or AUC of flutamide. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of flutamide. In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted. - No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury). - Flutamide has not been studied in women or pediatric patients. - Interactions between flutamide capsules and LHRH agonists have not occurred. Increases in prothrombin have been noted in patients receiving warfarin therapy. ## Nonclinical Toxicology - In a 1-year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily oral doses of 10, 30, and 50 mg/kg/day were administered). These produce plasma Cmax values that are 1, 2 to 3, and 4 fold, respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for 1 year, tumors were still present after 1 year of a drug-free period, but the incidences were 43% to 47%. In a 2 year carcinogenicity study in male rats, daily administration of flutamide at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were 1 to 4 fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with flutamide capsules (see ADVERSE REACTIONS section). - Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/Microsome Mutagenesis Assay. Dominant lethal tests in rats were negative. - Reduced sperm counts were observed during a 6 week study of flutamide monotherapy in normal human volunteers. - Flutamide did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose. - Serious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for 2 to 4 years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were 1 to 12 fold greater than those observed in humans at therapeutic levels. # Clinical Studies - Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion. - The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated flutamide and an LHRH agonist as the sole therapy in stage D2 metastatic carcinoma. - The effects of hormonal treatment combined with radiation were studied in 466 patients (231 flutamide capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement. - In this multicentered, controlled trial, administration of flutamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, P < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, P = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs. 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, P < 0.001). - To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + flutamide, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial. - Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9 months for patients treated with leuprolide alone. This 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo. # How Supplied - Flutamide Capsules USP, 125 mg are available as light brown opaque oblong hard gelatin capsules, spin printed with Company logo and “4960” in black ink containing 125 mg flutamide packaged in bottles of 180 and 500 capsules. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. ## Storage - Store at 20° to 25°C (68° to 77°F) . # Images ## Drug Images ## Package and Label Display Panel Flutamide Capsules USP 125 mg 180s Label Text NDC 0172-4960-58 FLUTAMIDE Capsules USP 125 mg PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET Rx only 180 CAPSULES TEVA # Patient Counseling Information - Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician. # Precautions with Alcohol - Alcohol-Flutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Eulexin® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Flutamide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, 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 Flutamide is an androgen antagonist that is FDA approved for the treatment of carcinoma of prostate, stage B2, C or D2, in combination with an LHRH agonist. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, hot sweats, diarrhea, nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Flutamide capsules are indicated for use in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate. - Treatment with flutamide capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy. - To achieve benefit from treatment, flutamide capsules should be initiated with the LHRH agonist and continued until progression. ### Dosing Information - 250 mg ORALLY every 8 hr in conjunction with a luteinizing hormone-releasing hormone (LHRH) agonist; begin 8 weeks prior to initiating radiation therapy and continue during radiation therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Flutamide in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Flutamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Flutamide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Flutamide in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Flutamide in pediatric patients. # Contraindications - Flutamide capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation. - Flutamide capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment). # Warnings - See BOXED WARNINGS. - Flutamide capsules are for use only in men. This product has no indication for women and should not be used in this population, particularly for nonserious or non-life threatening conditions. - Flutamide may cause fetal harm when administered to a pregnant woman (see Pregnancy). - One metabolite of flutamide is 4-nitro-3-fluoro-methylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after flutamide administration. In patients susceptible to aniline toxicity (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered. ### PRECAUTIONS= - In clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration. # Adverse Reactions ## Clinical Trials Experience - Treatment with flutamide capsules and the goserelin acetate implant did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + goserelin acetate implant + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below. - Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). - The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + LHRH agonist versus placebo + LHRH agonist. - The most frequently reported (greater than 5%) adverse experiences during treatment with flutamide capsules in combination with an LHRH agonist are listed in the table below. For comparison, adverse experiences seen with an LHRH agonist and placebo are also listed in the following table. - As shown in the table, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, impotence, loss of libido) were those known to be associated with low serum androgen levels and known to occur with LHRH agonists alone. - The only notable difference was the higher incidence of diarrhea in the flutamide + LHRH agonist group (12%), which was severe in 5% as opposed to the placebo + LHRH agonist (4%), which was severe in less than 1%. - In addition, the following adverse reactions were reported during treatment with flutamide + LHRH agonist. - Hypertension in 1% of patients - CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients - Anorexia 4%, and other GI disorders occurred in 6% of patients - Anemia occurred in 6%, leukopenia in 3%, and thrombocytopenia in 1% of patients - Hepatitis and jaundice in less than 1% of patients ### =Skin - Irritation at the injection site and rash occurred in 3% of patients - Edema occurred in 4%, genitourinary and neuromuscular symptoms in 2%, and pulmonary symptoms in less than 1% of patients. - In addition, the following spontaneous adverse experiences have been reported during the marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions (including erythema, ulceration, bullous eruptions, and epidermal necrolysis), and urine discoloration. The urine was noted to change to an amber or yellow-green appearance which can be attributed to the flutamide and/or its metabolites. Also reported were cholestatic jaundice, hepatic encephalopathy, and hepatic necrosis. The hepatic conditions were often reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide. - Malignant breast neoplasms have occurred rarely in male patients being treated with flutamide. - Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported. ## Postmarketing Experience There is limited information regarding Flutamide Postmarketing Experience in the drug label. # Drug Interactions - Regular assessment of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise significantly and consistently during flutamide therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen while continuing the LHRH analogue may be considered. - Increases in prothrombin time have been noted in patients receiving long-term warfarin therapy after flutamide was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide capsules are administered concomitantly with warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - There was decreased 24 hour survival in the offspring of pregnant rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose). A slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of cats treated with two higher doses. Feminization of the male cats also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flutamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Flutamide during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Flutamide with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Flutamide with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Flutamide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Flutamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Flutamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Flutamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Flutamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Flutamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Flutamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dosage is 2 capsules 3 times a day at 8-hour intervals for a total daily dose of 750 mg. ### Monitoring There is limited information regarding Monitoring of Flutamide in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Flutamide in the drug label. # Overdosage - In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia. - Clinical trials have been conducted with flutamide in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness, and some increases in SGOT. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established. - Flutamide is highly protein bound and is not cleared by hemodialysis. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. # Pharmacology ## Mechanism of Action - In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration. ## Structure - Flutamide Capsules USP contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, α,α,α-Trifluoro-2-methyl-4’-nitro-m-propionotoluidide and has the following structural formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Flutamide in the drug label. ## Pharmacokinetics - Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide. - In male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 hours. Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL, is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins. - The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol. - Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours. ### Special Populations - Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8.1 hours and at steady state in 9.6 hours. - There are no known alterations in flutamide absorption, distribution, metabolism, or excretion due to race. - Following a single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmax or AUC of flutamide. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of flutamide. In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted. - No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury). - Flutamide has not been studied in women or pediatric patients. - Interactions between flutamide capsules and LHRH agonists have not occurred. Increases in prothrombin have been noted in patients receiving warfarin therapy. ## Nonclinical Toxicology - In a 1-year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily oral doses of 10, 30, and 50 mg/kg/day were administered). These produce plasma Cmax values that are 1, 2 to 3, and 4 fold, respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for 1 year, tumors were still present after 1 year of a drug-free period, but the incidences were 43% to 47%. In a 2 year carcinogenicity study in male rats, daily administration of flutamide at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were 1 to 4 fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with flutamide capsules (see ADVERSE REACTIONS section). - Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/Microsome Mutagenesis Assay. Dominant lethal tests in rats were negative. - Reduced sperm counts were observed during a 6 week study of flutamide monotherapy in normal human volunteers. - Flutamide did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose. - Serious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for 2 to 4 years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were 1 to 12 fold greater than those observed in humans at therapeutic levels. # Clinical Studies - Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion. - The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated flutamide and an LHRH agonist as the sole therapy in stage D2 metastatic carcinoma. - The effects of hormonal treatment combined with radiation were studied in 466 patients (231 flutamide capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement. - In this multicentered, controlled trial, administration of flutamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, P < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, P = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs. 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, P < 0.001). - To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + flutamide, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial. - Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9 months for patients treated with leuprolide alone. This 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo. # How Supplied - Flutamide Capsules USP, 125 mg are available as light brown opaque oblong hard gelatin capsules, spin printed with Company logo and “4960” in black ink containing 125 mg flutamide packaged in bottles of 180 and 500 capsules. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel Flutamide Capsules USP 125 mg 180s Label Text NDC 0172-4960-58 FLUTAMIDE Capsules USP 125 mg PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET Rx only 180 CAPSULES TEVA # Patient Counseling Information - Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician. # Precautions with Alcohol - Alcohol-Flutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Eulexin® # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Flutamide
000249194cd887078cbf60b83cd7e56ea8505ce4	wikidoc	Foldamers	Foldamers # Overview A foldamer is a discrete chain molecule or oligomer that adopts a secondary structure stabilized by non-covalent interactions . They are artificial molecules that mimic the ability of proteins, nucleic acids, and polysaccharides to fold into well-defined conformations, such as helices and β-sheets. Foldamers have been demonstrated to display a number of interesting supramolecular properties including molecular self-assembly, molecular recognition, and host-guest chemistry. They are studied as models of biological molecules and have been shown to display antimicrobial activity. They also have great potential application to the development of new functional materials. Examples: - m-Phenylene ethynylene oligomers are driven to fold into a helical conformation by solvophobic forces and aromatic stacking interactions. - β-peptides are composed of amino acids containing an additional methylene unit between the amine and carboxylic acid. They are more stable to enzymatic degradation and have been demonstrated to have antimicrobial activity. - Aedamers that fold in aqueous solutions driven by hydrophobic and aromatic stacking interactions.	Foldamers # Overview A foldamer is a discrete chain molecule or oligomer that adopts a secondary structure stabilized by non-covalent interactions [1] [2]. They are artificial molecules that mimic the ability of proteins, nucleic acids, and polysaccharides to fold into well-defined conformations, such as helices and β-sheets. Foldamers have been demonstrated to display a number of interesting supramolecular properties including molecular self-assembly, molecular recognition, and host-guest chemistry. They are studied as models of biological molecules and have been shown to display antimicrobial activity. They also have great potential application to the development of new functional materials. Examples: - m-Phenylene ethynylene oligomers are driven to fold into a helical conformation by solvophobic forces and aromatic stacking interactions. - β-peptides are composed of amino acids containing an additional methylene unit between the amine and carboxylic acid. They are more stable to enzymatic degradation and have been demonstrated to have antimicrobial activity. - Aedamers that fold in aqueous solutions driven by hydrophobic and aromatic stacking interactions.	https://www.wikidoc.org/index.php/Foldamer
ce3ff4c05aa79043ff3fa7beb16907ce694013a8	wikidoc	Font size	Font size The fonts come in sizes from 1 to 7. The standard size is 3, unless otherwise specified in the or other tags. Changing the font size can be performed by placing and around your text. For example, creates a bigger font size of size 4: your text Also, typing this: creates text with size 1 bigger than the standard: your text Typing this: creates text with size 1 smaller than the standard: your text	Font size The fonts come in sizes from 1 to 7. The standard size is 3, unless otherwise specified in the <body> or other tags. Changing the font size can be performed by placing <font size="desired size"> and </font> around your text. For example, creates a bigger font size of size 4: your text Also, typing this: creates text with size 1 bigger than the standard: your text Typing this: creates text with size 1 smaller than the standard: your text	https://www.wikidoc.org/index.php/Font_size
a6aa9e2db7e2f4eb8bf5075606b3ac8ec9130dc1	wikidoc	Foot drop	Foot drop # Overview Foot drop is a deficit in turning the ankle and toes upward (dorsiflexion). Conditions leading to foot drop may be neurologic, muscular or anatomic in origin, often with significant overlap. # Features Foot drop is characterized by steppage gait. When the person with foot drop walks, the foot slaps down onto the floor. To compensate for the toe drop, the patient must raise the thigh excessively, as if walking upstairs. Individuals with foot drop are unable to walk on their heel, flex their ankle, or walk with the normal heel-toe pattern . Patients with painful disorders of sensation (dysesthesia) of the soles of the feet may have a similar gait, but do not have foot drop. Because of the extreme pain evoked by even the slightest pressure on the feet, the patient walks as if walking barefoot on hot sand. # Pathophysiology ## Conditions affecting the nervous system - Amyotrophic lateral sclerosis (Lou Gehrig's disease) - Lumbar radiculopathy (L4 and L5 nerve roots) - Spinal disc herniation - Multiple Sclerosis - Peripheral neuropathies: Multifocal motor neuropathy (foot drop may be the presenting symptom), diabetic neuropathy - Common peroneal nerve palsy - Charcot-Marie-Tooth disease (peroneal muscular atrophy) - Progressive spinal muscular atrophy - Poliomyelitis - Leprosy - Compartment syndrome - Human monocytic ehrlichiosis (long term manifestation) - Cryoglobulinemia ## Conditions affecting the musculature - Different kinds of muscular dystrophy (Duchenne muscular dystrophy, Facioscapulohumeral dystrophy, scapuloperoneal muscular dystrophy, Myotonic dystrophy, desmin myopathy, - Inclusion body myositis ## Drugs - Vincristine (adults more severely affected than children) (Adams and Victor) - Auranofin - Allopurinol (causal relationship not established) - Glatiramer (uncommon) - Chymopapain (uncommon) - Thalidomide (uncommon) ## Toxins - Lead neuropathy (usually presents with wrist and finger drop, foot drop less common) (Adams and Victor) # Treatment The underlying disorder must be treated. For example, if a spinal disc herniation in the low back is impinging on the nerve that goes to the leg and causing symptoms of foot drop, then the herniated disc should be treated. Ankles can be stabilized by lightweight orthoses, and shoes can be fit with springs to prevent foot drop while walking. Regular exercise is usually prescribed. The latest treatments include stimulation of the peroneal nerve that lifts the foot when you step. Many stroke and multiple sclerosis patients with foot drop have had success with it. Devices have also been designed to regulate walking.	Foot drop Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] # Overview Foot drop is a deficit in turning the ankle and toes upward (dorsiflexion). Conditions leading to foot drop may be neurologic, muscular or anatomic in origin, often with significant overlap. # Features Foot drop is characterized by steppage gait. When the person with foot drop walks, the foot slaps down onto the floor. To compensate for the toe drop, the patient must raise the thigh excessively, as if walking upstairs. Individuals with foot drop are unable to walk on their heel, flex their ankle, or walk with the normal heel-toe pattern [3]. Patients with painful disorders of sensation (dysesthesia) of the soles of the feet may have a similar gait, but do not have foot drop. Because of the extreme pain evoked by even the slightest pressure on the feet, the patient walks as if walking barefoot on hot sand. # Pathophysiology ## Conditions affecting the nervous system - Amyotrophic lateral sclerosis (Lou Gehrig's disease) - Lumbar radiculopathy (L4 and L5 nerve roots) - Spinal disc herniation - Multiple Sclerosis - Peripheral neuropathies: Multifocal motor neuropathy (foot drop may be the presenting symptom), diabetic neuropathy - Common peroneal nerve palsy - Charcot-Marie-Tooth disease (peroneal muscular atrophy) - Progressive spinal muscular atrophy - Poliomyelitis - Leprosy - Compartment syndrome - Human monocytic ehrlichiosis (long term manifestation) - Cryoglobulinemia ## Conditions affecting the musculature - Different kinds of muscular dystrophy (Duchenne muscular dystrophy, Facioscapulohumeral dystrophy, scapuloperoneal muscular dystrophy, Myotonic dystrophy, desmin myopathy, - Inclusion body myositis ## Drugs - Vincristine (adults more severely affected than children) (Adams and Victor) - Auranofin - Allopurinol (causal relationship not established) - Glatiramer (uncommon) - Chymopapain (uncommon) - Thalidomide (uncommon) ## Toxins - Lead neuropathy (usually presents with wrist and finger drop, foot drop less common) (Adams and Victor) # Treatment The underlying disorder must be treated. For example, if a spinal disc herniation in the low back is impinging on the nerve that goes to the leg and causing symptoms of foot drop, then the herniated disc should be treated. Ankles can be stabilized by lightweight orthoses, and shoes can be fit with springs to prevent foot drop while walking. Regular exercise is usually prescribed. The latest treatments include stimulation of the peroneal nerve that lifts the foot when you step. Many stroke and multiple sclerosis patients with foot drop have had success with it. Devices have also been designed to regulate walking.	https://www.wikidoc.org/index.php/Foot_drop
33e1d2b5de57af882c11295f6f8f5ba2cfc87bdf	wikidoc	Footprint	Footprint Footprints are the impressions or images left behind by a person walking. Hoofprints and pawprints are those left by animals with hooves or paws rather than feet, while "shoeprints" is the specific term for prints made by shoes. They may either be indentations in the ground or something placed onto the surface that was stuck to the bottom of the foot. A "trackway" is set of footprints in soft earth left by a life-form; animal tracks are the footprints, hoofprints, or pawprints of an animal. Footprints can be followed when tracking during a hunt or can provide evidence of activities. Some footprints remain unexplained, with several famous stories from mythology and legend. Others have provided evidence of prehistoric life and behaviours. # Footprints in detective work The print left behind at a crime scene can give vital evidence to the perpetrator of the crime. Shoes have different prints based on the sole design and the wear that it has received – this can help to identify suspects. Photographs or castings of footprints can be taken to preserve the finding. Analysis of footprints and shoeprints is a specialist part of forensic science. Some detective work is relatively immediate, with criminals being tracked by the footprints they left in the snow leading from the crime scene to their home or hiding place. This is usually reported as a humorous story in news publications. # Ancient footprints Footprints have been preserved as fossils and provide evidence of prehistoric life. Known as "ichnites", these trace fossils can give clues to the behaviour of specific species of dinosaur. The study of such fossils is known as ichnology and species known only by such evidence are known as ichnospecies. The Grallator is one example of a genus that has left no fossils other than ichnites. The finding of footprints in the limestone beds of the Paluxy River near Glen Rose, Texas show what some people have interpreted as human footprints alongside those of dinosaurs. This sparked the man track controversy, believed by some Creationists to show that humans and dinosaurs coexisted. ## Other footprint findings - Siwa Oasis– World's oldest footprint discovered over 3 million years old - Laetoli – human footprints from the Pliocene era (3.7 million years ago) preserved in volcanic ash. - Acahualinca – 6000 year old human footprints fossilized in volcanic ash and mud in Nicaragua. - Uskmouth – human footprints carbon dated to 4200BC preserved in clay. # Footprints in myth and legend The appearance of footprints, or marks interpreted as footprints, have led to numerous myths and legends. Some locations use such imprints as tourist attractions. Examples of footprints in myth and legend include: - Buddha footprint – an aniconic and symbolic representation of the Buddha. - The Devil's Footprints – an unexplained series of hoof-like marks that appeared in Devon, England on 8 February 1855 after a light snowfall during the night. - Golden calf – in Islam dust from the hoofprints of Haizum, the winged horse of archangel Gabriel, is used to animate the Golden calf. - Moso's Footprint – a 1m by 3m rock enclosure in Samoa made when the giant Moso stepped over to Samoa from Fiji, and the other footprint can be found on Viti Levu, the largest island of Fiji. - Footprints of Bigfoot, a cryptozoological animal, are said to give proof to its existence. - Sri Pada, or Adam's Peak, a mountain in Sri Lanka, has a large footprint-shaped impression in the rock at its summit, said by various religious adherents to be that of the Buddha, Shiva or Adam. - A set of Jesus's footprints, according to legend, are preserved at the Church of Domine Quo Vadis outside of Rome. - A mark in stone of the paving of the Munich Frauenkirche is known as the Teufelstritt ("Devil's Footstep"). # Footprints in popular culture The imagery of footprints has been used in many areas of popular culture. Several poems and songs have been written about them, with the religious poem Footprints being one of the best known. Prints or impressions of a child's feet can be kept as a memento by parents. Usually this is done using paint. The impressions of celebrity's feet, usually in concrete, may be kept in a collection such as that outside Grauman's Chinese Theatre. Footprints can be seen in some films when not intended, becoming a goof. When filming scenes in snow, sand or other easily-markable ground it is easy for the signs of previous takes or of crew movement to make it through to the finished film, such as in Touching the Void and Casino. Alternatively, the wrong type of footprints might appear, such as bootprints instead of hoofprints as in The Chronicles of Narnia: The Lion, the Witch and the Wardrobe.	Footprint Footprints are the impressions or images left behind by a person walking. Hoofprints and pawprints are those left by animals with hooves or paws rather than feet, while "shoeprints" is the specific term for prints made by shoes. They may either be indentations in the ground or something placed onto the surface that was stuck to the bottom of the foot. A "trackway" is set of footprints in soft earth left by a life-form; animal tracks are the footprints, hoofprints, or pawprints of an animal. Footprints can be followed when tracking during a hunt or can provide evidence of activities. Some footprints remain unexplained, with several famous stories from mythology and legend. Others have provided evidence of prehistoric life and behaviours. # Footprints in detective work The print left behind at a crime scene can give vital evidence to the perpetrator of the crime. Shoes have different prints based on the sole design and the wear that it has received – this can help to identify suspects.[1] Photographs or castings of footprints can be taken to preserve the finding. Analysis of footprints and shoeprints is a specialist part of forensic science. Some detective work is relatively immediate, with criminals being tracked by the footprints they left in the snow leading from the crime scene to their home or hiding place. This is usually reported as a humorous story in news publications.[2][3] # Ancient footprints Footprints have been preserved as fossils and provide evidence of prehistoric life. Known as "ichnites", these trace fossils can give clues to the behaviour of specific species of dinosaur. The study of such fossils is known as ichnology and species known only by such evidence are known as ichnospecies. The Grallator is one example of a genus that has left no fossils other than ichnites. The finding of footprints in the limestone beds of the Paluxy River near Glen Rose, Texas show what some people have interpreted as human footprints alongside those of dinosaurs. This sparked the man track controversy, believed by some Creationists to show that humans and dinosaurs coexisted.[4][5] ## Other footprint findings - Siwa Oasis– World's oldest footprint discovered over 3 million years old[6] - Laetoli – human footprints from the Pliocene era (3.7 million years ago) preserved in volcanic ash.[7] - Acahualinca – 6000 year old human footprints fossilized in volcanic ash and mud in Nicaragua. - Uskmouth – human footprints carbon dated to 4200BC preserved in clay.[8] # Footprints in myth and legend The appearance of footprints, or marks interpreted as footprints, have led to numerous myths and legends. Some locations use such imprints as tourist attractions. Examples of footprints in myth and legend include: - Buddha footprint – an aniconic and symbolic representation of the Buddha.[9] - The Devil's Footprints – an unexplained series of hoof-like marks that appeared in Devon, England on 8 February 1855 after a light snowfall during the night.[10] - Golden calf – in Islam dust from the hoofprints of Haizum, the winged horse of archangel Gabriel, is used to animate the Golden calf.[11] - Moso's Footprint – a 1m by 3m rock enclosure in Samoa made when the giant Moso stepped over to Samoa from Fiji, and the other footprint can be found on Viti Levu, the largest island of Fiji. - Footprints of Bigfoot, a cryptozoological animal, are said to give proof to its existence. - Sri Pada, or Adam's Peak, a mountain in Sri Lanka, has a large footprint-shaped impression in the rock at its summit, said by various religious adherents to be that of the Buddha, Shiva or Adam. - A set of Jesus's footprints, according to legend, are preserved at the Church of Domine Quo Vadis outside of Rome. - A mark in stone of the paving of the Munich Frauenkirche is known as the Teufelstritt ("Devil's Footstep"). # Footprints in popular culture The imagery of footprints has been used in many areas of popular culture. Several poems and songs have been written about them, with the religious poem Footprints being one of the best known. Prints or impressions of a child's feet can be kept as a memento by parents. Usually this is done using paint. The impressions of celebrity's feet, usually in concrete, may be kept in a collection such as that outside Grauman's Chinese Theatre. Footprints can be seen in some films when not intended, becoming a goof. When filming scenes in snow, sand or other easily-markable ground it is easy for the signs of previous takes or of crew movement to make it through to the finished film, such as in Touching the Void[12] and Casino.[13] Alternatively, the wrong type of footprints might appear, such as bootprints instead of hoofprints as in The Chronicles of Narnia: The Lion, the Witch and the Wardrobe.[14]	https://www.wikidoc.org/index.php/Footprint
b22ac017a6688717b2bc54ea5135d04e997847bc	wikidoc	Granuloma	Granuloma # Overview In medicine (anatomical pathology), a granuloma is a group of epithelioid macrophages surrounded by a lymphocyte cuff. Granulomas are small nodules that are seen in a variety of diseases such as Crohn's disease, tuberculosis, Leprosy, sarcoidosis, berylliosis and syphilis. It is also a feature of Wegener's granulomatosis and Churg-Strauss syndrome, two related autoimmune disorders. An important aspect of granulomas is whether they are caseating or not. Caseation (literally: turning to cheese) is a form of necrosis at the centre of a granuloma and is a feature of the granulomas of tuberculosis. # Diagnosis ## Tuberculous granuloma The tuberculous granuloma (caseating tubercule): central caseous necrosis bordered by giant multinucleated cells (Langhans giant cell), and surrounded by epithelioid cells aggregates, lymphocytes and fibroblasts. Granulomatous tubercules tend to confluence. Multinucleated giant cell (Langhans giant cell): 50-100 micrometres, numerous small nuclei (over 20) disposed at the periphery of the cell (crown or horseshoe), abundant eosinophilic cytoplasm. It results when activated macrophages merge. Epithelioid cells are activated macrophages resembling epithelial cells: elongated, with finely granular, pale eosinophilic (pink) cytoplasm and central, ovoid nucleus. They have indistinct shape contour and form aggregates. At the periphery are the lymphocytes (T cells) and rare plasma cells and fibroblasts. Caseous necrosis is a central area, amorphous, finely granular, eosinophilic (pink). If recent, it may contain nuclear fragments. The caseum is the result of the accumulated destruction of giant cells and epithelioid cells. ## Chronic granulomatous disease In the rare condition chronic granulomatous disease, neutrophil granulocyte function is impaired and granulomas form in various organs in response to infection, as the infection is not being contained through normal means. ## Granulomas of Sarcoidosis Granulomas seen in Sarcoidosis are nodal aggregates of epithelioid cells, similar to epithelioid tubercules of tuberculosis. However, the quantity of necrosis is low and it is noncaseating. Multinucleated giant cells of Langhans cell type and foreign-body type giant cells are present, however they are less numerous and can be star-shaped (asteroid bodies) or lamellar (Schaumann bodies). These inclusions are not sarcoidose-specific. Some fibrous tissue and lymphocytes are present on the periphery. These granulomas can resorb or heal with a scar. In the lungs this can cause disseminated pulmonary fibrosis; in cardiac tissue they may cause impaired heart function and possibly death by heart failure. ## Rheumatic myocarditis Rheumatic fever affects all the heart tissue (rheumatic pancarditis). From all the pathological changes, only the granulomas, called Aschoff granulomas, are pathognomonic, often located perivascularly. In the centre, fibrinoid necrosis is visible. It is encompassed by lymphocytes, plasma cells, fibroblasts and individual neutrophils. Also mononuclear Anitschkow's cells (histiocytes) and characteristic Aschoff giant cells are present (these latter represent multinucleated macrophages). Anitschkow's cells appear like an owl's eye and have abundant pale eosinophilic cytoplasm with a characteristic "caterpillar" or lacy nucleole in the bright nucleus. They are often arranged in a palisade around the center. Aschoff cells have a single or multiple bean-shaped nuclei. Peripherally, fibroblasts and sclerotic fibrous tissue can be seen. The granuloma sometimes immediately borders partially fragmented muscle fibers. Ultimately, Rheumatic heart disease results in a "fish mouth" appearing stenosis of the mitral valve, causing left atrial dilation, right ventricular hypertrophy, and mural thrombi. Patients are predisposed endocarditis and CHF. ## Gumma hepatitis The less common form of the third stage of syphilis. Gummas are of different sizes: smaller ones are miliary and more numerous, while the larger ones that are more common, are solitary and elastic. Gumma can develop in different tissues and organs, especially in bones, brain, liver, skin, testis and elsewhere. Contrary to the tuberculous granuloma, in the elastic coagulative central necrosis of the gumma, which is eosinophilic and of grey yellowish colour, there is still some silhouette of the previous tissue visible. The granuloma is encompassed by the grey whitish fibrous envelope, that sometimes sends radial ribbons in the surrounding area. In between, there are lymphocytes, plasma cells and giant cells from capillaries and rare epitheloid cells, and on the periphery lymphocytes and plasma cells are present. By healing, gumma transforms in a large scar that can for example disfigure liver with deep furrows (hepar lobar syphiliticum). ## Pathology - Caseating Granuloma (TB) - H&E section of non-caseating granuloma seen in the colon of a patient with ] # Related Chapters - Granuloma annulare - Navel - Peripheral giant cell granuloma	Granuloma Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In medicine (anatomical pathology), a granuloma is a group of epithelioid macrophages surrounded by a lymphocyte cuff. Granulomas are small nodules that are seen in a variety of diseases such as Crohn's disease, tuberculosis, Leprosy, sarcoidosis, berylliosis and syphilis. It is also a feature of Wegener's granulomatosis and Churg-Strauss syndrome, two related autoimmune disorders. An important aspect of granulomas is whether they are caseating or not. Caseation (literally: turning to cheese) is a form of necrosis at the centre of a granuloma and is a feature of the granulomas of tuberculosis. # Diagnosis ## Tuberculous granuloma The tuberculous granuloma (caseating tubercule): central caseous necrosis bordered by giant multinucleated cells (Langhans giant cell), and surrounded by epithelioid cells aggregates, lymphocytes and fibroblasts. Granulomatous tubercules tend to confluence. Multinucleated giant cell (Langhans giant cell): 50-100 micrometres, numerous small nuclei (over 20) disposed at the periphery of the cell (crown or horseshoe), abundant eosinophilic cytoplasm. It results when activated macrophages merge. Epithelioid cells are activated macrophages resembling epithelial cells: elongated, with finely granular, pale eosinophilic (pink) cytoplasm and central, ovoid nucleus. They have indistinct shape contour and form aggregates. At the periphery are the lymphocytes (T cells) and rare plasma cells and fibroblasts. Caseous necrosis is a central area, amorphous, finely granular, eosinophilic (pink). If recent, it may contain nuclear fragments. The caseum is the result of the accumulated destruction of giant cells and epithelioid cells. ## Chronic granulomatous disease In the rare condition chronic granulomatous disease, neutrophil granulocyte function is impaired and granulomas form in various organs in response to infection, as the infection is not being contained through normal means. ## Granulomas of Sarcoidosis Granulomas seen in Sarcoidosis are nodal aggregates of epithelioid cells, similar to epithelioid tubercules of tuberculosis. However, the quantity of necrosis is low and it is noncaseating. Multinucleated giant cells of Langhans cell type and foreign-body type giant cells are present, however they are less numerous and can be star-shaped (asteroid bodies) or lamellar (Schaumann bodies). These inclusions are not sarcoidose-specific. Some fibrous tissue and lymphocytes are present on the periphery. These granulomas can resorb or heal with a scar. In the lungs this can cause disseminated pulmonary fibrosis; in cardiac tissue they may cause impaired heart function and possibly death by heart failure. ## Rheumatic myocarditis Rheumatic fever affects all the heart tissue (rheumatic pancarditis). From all the pathological changes, only the granulomas, called Aschoff granulomas, are pathognomonic, often located perivascularly. In the centre, fibrinoid necrosis is visible. It is encompassed by lymphocytes, plasma cells, fibroblasts and individual neutrophils. Also mononuclear Anitschkow's cells (histiocytes) and characteristic Aschoff giant cells are present (these latter represent multinucleated macrophages). Anitschkow's cells appear like an owl's eye and have abundant pale eosinophilic cytoplasm with a characteristic "caterpillar" or lacy nucleole in the bright nucleus. They are often arranged in a palisade around the center. Aschoff cells have a single or multiple bean-shaped nuclei. Peripherally, fibroblasts and sclerotic fibrous tissue can be seen. The granuloma sometimes immediately borders partially fragmented muscle fibers. Ultimately, Rheumatic heart disease results in a "fish mouth" appearing stenosis of the mitral valve, causing left atrial dilation, right ventricular hypertrophy, and mural thrombi. Patients are predisposed endocarditis and CHF. ## Gumma hepatitis The less common form of the third stage of syphilis. Gummas are of different sizes: smaller ones are miliary and more numerous, while the larger ones that are more common, are solitary and elastic. Gumma can develop in different tissues and organs, especially in bones, brain, liver, skin, testis and elsewhere. Contrary to the tuberculous granuloma, in the elastic coagulative central necrosis of the gumma, which is eosinophilic and of grey yellowish colour, there is still some silhouette of the previous tissue visible. The granuloma is encompassed by the grey whitish fibrous envelope, that sometimes sends radial ribbons in the surrounding area. In between, there are lymphocytes, plasma cells and giant cells from capillaries and rare epitheloid cells, and on the periphery lymphocytes and plasma cells are present. By healing, gumma transforms in a large scar that can for example disfigure liver with deep furrows (hepar lobar syphiliticum). ## Pathology - Caseating Granuloma (TB) [1] - H&E section of non-caseating granuloma seen in the colon of a patient with [Crohn's disease]] # Related Chapters - Granuloma annulare - Navel - Peripheral giant cell granuloma # External links - Pathology Images of Granulomatous Diseases - Microscopy of caseating granuloma	https://www.wikidoc.org/index.php/Foreign_body_granulomatous
15a5a198879cbefaf95c699cb9b6231f33482bff	wikidoc	Form 1572	Form 1572 # Statement of Investigator (Form FDA 1572) This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. This guidance applies to clinical investigations conducted under 21 CFR Part 312 (Investigational New Drug Applications or IND regulations). It describes how to complete the Statement of Investigator form (Form FDA 1572). # I. GENERAL ## 1. What is the Statement of Investigator, Form FDA 1572? The Statement of Investigator, Form FDA 1572 (1572), is an agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic. The most recent version of the 1572 is available online at . ## 2. Why does this form need to be completed by an investigator? The 1572 has two purposes: 1) to provide the sponsor with information about the investigator’s qualifications and the clinical site that will enable the sponsor to establish and document that the investigator is qualified and the site is an appropriate location at which to conduct the clinical investigation. 2) to inform the investigator of his/her obligations and obtain the investigator’s commitment to follow pertinent FDA regulations. Investigators should complete the form as accurately as they can. Investigators should be aware that making a willfully false statement is a criminal offense under 18 U.S.C. 1001. Further, submission of a deliberately false statement to the sponsor or to the agency can be taken into consideration in a disqualification proceeding. ## 3. When must this form be completed and signed by an investigator? Whenever a sponsor selects a new investigator to participate in a clinical investigation that is being conducted under an investigational new drug application (IND), the sponsor must obtain a completed and signed 1572 before permitting the investigator to begin participation in the clinical investigation (21 CFR 312.53(c)). The investigator should sign the form only after being given enough information to be informed about the clinical investigation and to understand the commitments described in Section #9 of the 1572. Having enough information about the study typically means that the investigator has received copies of, has read, and understands the protocol and investigator’s brochure (if required), and is familiar with the regulations governing the conduct of clinical studies. The investigator’s signature on this form constitutes the investigator’s affirmation that he or she is qualified to conduct the clinical investigation and constitutes the investigator’s written commitment to abide by FDA regulations in the conduct of the clinical investigation. ## 4. Must the investigator be a physician? The regulations do not require that the investigator be a physician. Sponsors are required to select only investigators qualified by training and experience as appropriate experts to investigate the drug (21 CFR 312.53(a)). In the event the clinical investigator is a nonphysician, a qualified physician (or dentist, when appropriate) should be listed as a subinvestigator for the trial and should be responsible for all trial-related medical (or dental) decisions. (ICH E6 section 4.3.1; ). ## 5. What are the minimum qualifications of an investigator? As stated in #4, the regulations require that sponsors select investigators who are qualified by training and experience as appropriate experts to investigate the drug. The regulations do not specify the minimum requirements nor do the regulations specify what qualifications an investigator must have in order to be considered qualified by training and experience to conduct a clinical investigation. Sponsors have discretion in determining what qualifications, training, and experience will be needed, based on the general recognition that this would include familiarity with human subject protection (HSP) regulations (i.e., 21 CFR Parts 50 and 56) and practices as well as good clinical practice (GCP) regulations (see 21 CFR Part 312) and standards (e.g., ICH E6) for the conduct of clinical studies. ## 6. Does the 1572 need to be submitted to FDA? No. Although the sponsor is required to collect the 1572 from the investigator, FDA does not require the form to be submitted to the agency. Many sponsors submit the 1572 to FDA, however, because it collects, in one place, information that must be submitted to FDA under 21 CFR 312.23(a)(6)(iii)(b). ## 7. When must a 1572 be updated or a new 1572 completed and signed by an investigator to reflect new or changed information? There are two instances when it is necessary for an investigator to complete and sign a new 1572: when an investigator is participating in a new protocol that has been added to the IND and when a new investigator is added to the study (21 CFR 312.53(c)). If there are other changes to information contained on a signed and dated 1572 (e.g., an IRB address change, the addition of new subinvestigators, the addition of a clinical research lab), the investigator should document the changes in the clinical study records and inform the sponsor of these changes, so that the sponsor can appropriately update the IND. The 1572 itself does not need to be revised and a new 1572 need not be completed and signed by the investigator. The sponsor can accumulate certain changes and submit this information to the IND in, for example, an information amendment or a protocol amendment. ## 8. If a clinical investigation is not conducted under an IND or is for a medical device, must investigators sign a 1572? No. Under the regulations, a 1572 is only required for studies of investigational drugs and biologics conducted under an IND. It is not required for studies that are not done under an IND, and is not applicable to investigational device studies. Sponsors of device studies must obtain a signed investigator agreement (containing information similar to that requested on the 1572) from each participating investigator, per 21 CFR 812.43(c). ## 9. Must a sponsor conduct a foreign clinical study under an IND? No. A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived (see #12 and #13 below). When the foreign clinical study is not conducted under an IND, the sponsor must ensure that this study complies with 21 CFR 312.120, “Foreign clinical studies not conducted under an IND,” if the sponsor intends to submit the study to FDA to support clinical investigations conducted in the United States and/or marketing approval. An application based solely on foreign clinical data must meet criteria listed in 21 CFR 314.106. ## 10. Must investigators who conduct studies outside of the United States sign a 1572? If a foreign clinical study is conducted under an IND, then all FDA IND regulations, including the requirement to obtain a signed 1572, must be met. If a clinical study is conducted outside of the U.S. and is not conducted under an IND, then the investigator need not sign a 1572. If local laws or regulations prohibit the signing of a 1572, FDA would expect the sites to operate as non-IND sites and the study conducted as a non-IND study. If the study data is to be submitted to support a marketing application (e.g., a new drug application (NDA)), the study must be conducted in compliance with 21 CFR 312.120. ## 11. If a foreign clinical study is being conducted under an IND, what are the investigator’s responsibilities with respect to local laws and regulations? Investigators are responsible for complying with the applicable laws and regulations of the country in which the study is being conducted, regardless of whether the study is being conducted under an IND. We recommend that sponsors obtain signed, written statements from investigators acknowledging their commitment to comply with local laws and requirements. In addition, if a foreign clinical study is being conducted under an IND, the investigator must sign Form FDA 1572 (investigator statement) and ensure that the study is conducted in accordance with the investigator statement and all other applicable regulations under 21 CFR Part 312. ## 12. For foreign clinical studies conducted under an IND, how can an investigator sign the 1572 when the investigator knows he/she cannot commit to all of the requirements on the form, specifically IRB membership (21 CFR 56.107)? IRB review and approval is required before a clinical study can be initiated under an IND (21 CFR 56.103(a)). FDA may waive any of the IRB requirements for specific research activities or for classes of research activities otherwise covered by the IRB regulations (21 CFR 56.105), but FDA uses the waiver provision only when alternative mechanisms for ensuring protection of the rights and welfare of human subjects are acceptable. The most common circumstance for which FDA receives a waiver request is when a sponsor wishes to conduct a foreign clinical study under an IND. In this case, typically an Independent Ethics Committee (IEC) that operates in accordance with Good Clinical Practice (GCP) is utilized instead of a U.S. IRB. Although its membership and functions for assuring human subject protection are comparable to an IRB, an IEC may not meet all of the IRB requirements contained in 21 CFR Part 56. For a foreign study, an IRB waiver request should contain a description of alternative mechanisms for assuring human subject protection. It would generally be acceptable for a waiver request to state the intention to use an IEC that complies with GCP (e.g., ICH E6) instead of an IRB that complies with 21 CFR Part 56. The sponsor should submit the waiver request to the IND under which the study will be conducted. The IND will have been submitted to the appropriate review division in either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). The sponsor will be informed by the agency in writing whether the waiver request is denied or granted. If a waiver is granted, the sponsor should have investigators attach a copy of the letter granting the waiver to the signed 1572 in the investigator’s record. ## 13. If a sponsor chooses to conduct a foreign clinical study (or operate non-US sites in a multinational study) under an IND and the investigators at these non-US sites comply with the ICH E6 Good Clinical Practice Consolidated Guidance, would the non-US investigators also be in compliance with FDA’s IND requirements under 21 CFR Part 312? Yes, with two exceptions. The first is that the FDA requirements for IRBs under 21 CFR Part 56 are slightly different with respect to membership and function. To address this issue, as described in #12 above, FDA can provide a specific waiver from the Part 56 IRB requirements, allowing an IEC that complies with good clinical practice to substitute for the IRB.4 The second exception is that the requirements for informed consent under 21 CFR Part 50 for particular clinical trials (e.g., emergency research under 21 CFR 50.24, clinical investigations involving pediatric subjects under Subpart D) are more extensive with respect to IRB responsibilities. Because these types of trials are uncommon, our experience has not revealed that this has caused a conflict; but in the event of one, we would be willing to discuss a resolution with the sponsor on a case-by-case basis. If the investigator or sponsor believes that there are other conflicting requirements, the sponsor may request a waiver from FDA from the specific requirement under 21 CFR 312.10. ## 14. Must foreign clinical study sites in a multinational study that includes domestic sites be conducted under an IND? No. A multinational study may include domestic sites under the IND and foreign sites not under the IND. Investigational drug and biologics studies conducted in the U.S. must be conducted in compliance with the IND requirements contained in 21 CFR 312, which includes the requirement that investigators sign the 1572. If a study also involves foreign clinical sites, the sponsor may choose, but is not required, to include the foreign clinical sites under the IND. The investigators from the U.S. sites and any foreign sites included under the IND would be required to sign the 1572. The investigators from the foreign sites that are not included under the IND are not required to sign the 1572. If the sponsor chooses to conduct a multinational study with U.S. and some foreign sites under the IND, and other foreign sites not under the IND, the sponsor can submit a single protocol to the IND and all sites would follow this protocol. Alternatively, the sponsor can conduct a multinational study with one protocol for sites under the IND (U.S. sites and some foreign sites) and a different protocol(s) for foreign sites not under the IND. If the intent is to pool the data from U.S. and foreign sites, the protocols would ordinarily be very similar or identical. The U.S. sites and any foreign sites included under the IND must follow the protocol that was submitted to the IND. For foreign sites that are not included under the IND, the protocol(s) does not need to be submitted to the IND. In general, if the sponsor intends to submit the data in an application for marketing approval, we recommend that the sponsor identify the foreign sites that will not be conducted under the IND and discuss plans to pool the data from U.S. and foreign sites with the appropriate FDA review division. Note, however, that 21 CFR 312.32(b) requires sponsors to promptly review information about the safety of the investigational drug obtained or otherwise received by the sponsor from any source, foreign or domestic. Under 21 CFR 312.32(c), sponsors must also notify FDA and all participating investigators in an IND safety report of any adverse experience associated with the use of the drug that is both serious and unexpected. This means that FDA and all participating investigators under the IND would be informed of such an adverse experience, even if it occurred in a foreign study not conducted under the IND. ## 15. How does a sponsor submit information to FDA about a foreign clinical study that was not conducted under an IND? Under 21 CFR 312.120, the sponsor can submit information to FDA from a foreign clinical study that was not conducted under an IND to support clinical investigations in the United States and/or marketing approval. When submitting information about a foreign clinical study, it is helpful to clearly identify in the cover letter that the material is being submitted in accordance with 21 CFR 312.120. The submission requirements for supporting documentation can be found at 21 CFR 312.120(b). ===16. Should a new form be prepared and signed when the OMB expiration date is reached?=== No. There is no need to prepare and sign a new 1572 when the OMB expiration date has been reached. ===17. Does FDA expect a double-sided 1572, or is a two-page document printed from the FDA website acceptable?=== Either is acceptable; however, FDA recommends that a two-page document be stapled so that there is no question about what form the investigator signed. ## 18. How should the 1572 be completed? The 1572 on FDA’s website may be completed by typing the information directly into the fillable form and printing the completed form. Alternatively, it is acceptable to print the blank form from FDA’s website and hand-write or type the information onto the form. Typed forms are preferable because they are usually more legible. The completed form must be signed and dated by the investigator (either by hand or using an acceptable electronic method). ## 19. How should an investigator’s name appear on the 1572? Section #1 should contain the investigator’s full legal name (e.g., name on the investigator’s birth certificate or marriage certificate). Titles, degrees, and/or professional qualifications may follow the investigator’s legal name, if desired. ## 20. What address should be entered into Section #1? The address where the investigator can be reached by mail or in person should be entered in Section #1 of the 1572. Usually, this corresponds to the investigator’s work or business address. ===21. Should co-investigators be listed on the 1572 in Section #1? Is it acceptable to have more than one investigator at a single site?=== The term co-investigator is not defined in FDA regulations. As commonly used, the term is meant to indicate that each co-investigator is fully responsible for fulfilling all of the -bligations of an investigator as identified in 21 CFR 312.60. Thus under 21 CFR 312.3(b), each co-investigator is an investigator, and as such must sign a separate 1572. In some situations, it is preferable to have more than one investigator responsible for a clinical investigation. For example, when a study is conducted at multiple research facilities that are not in close proximity, FDA expects an investigator who has signed a # QUALIFY THE INVESTIGATOR AS AN EXPERT IN THE CLINICAL INVESTIGATION ## 22. What is the purpose of Section #2? Section #2 requires the investigator to attach a curriculum vitae (CV) or other statement -f qualifications, showing the education, training and experience that qualifies the investigator as an expert in the clinical investigation of the drug/biologic for the use under investigation. Information identified in this section and attached to the 1572 enables the sponsor to assess an investigator's qualifications. ===23. Does the CV or other statement of qualifications need to be updated during a clinical study?=== No. FDA regulations do not require a CV or other statement of qualifications to be updated during a clinical study. ## 24. Are CVs required to be signed and dated? No. FDA regulations do not require a CV to be signed and dated. The investigator's dated signature on the 1572 is sufficient to attest to the accuracy of the CV or other statement of qualifications submitted with the 1572. ==IV. SECTION #3: NAME AND ADDRESS OF ANY MEDICAL SCHOOL, HOSPITAL, OR OTHER RESEARCH FACILITY WHERE THE CLINICAL INVESTIGATION(S) WILL BE CONDUCTED== ===25. What address(es) should be entered in Section #3? The address(es) of the location(s) where the investigation will be conducted and to where the test articles will be shipped, if different from the investigator's address of record, should be entered in Section #3. ## 26. What qualifies as a research facility for Section #3? Section #3 is intended to identify facilities where study activities will be conducted and clinical data will be generated or collected. This includes facilities where subjects will be seen and study procedures performed. For example, this might include locations such as health care facilities where the test article will be administered, or where physical exams will be performed. Facilities where other important clinical investigation functions are performed may also be identified in Section #3. For example, a research laboratory where the test article is prepared, a special storage facility where the test article will be kept, or a location where tissue specimens are collected should be listed in this section. ===27. If an investigator sees study subjects at more than one site, should the investigator list all sites on the 1572?=== Yes. The names and addresses of each of the study sites should be identified in Section - 3. However, if the protocol specifies that the investigative product can be administered at a subject’s home (for example, the protocol allows for daily injections to be administered by a registered nurse in the subject’s home), the subjects' home addresses do not have to be listed on the 1572. Study records should reflect that the test article was administered at subjects' homes per the protocol. ==V. SECTION #4: NAME AND ADDRESS OF CLINICAL LABORATORY FACILITIES TO BE USED IN THIS STUDY== 28. What qualifies as a clinical laboratory facility for Section #4? Section #4 is intended to identify clinical laboratories or testing facilities directly contributing to or supporting the clinical study (for example, diagnostic labs performing blood work, imaging centers, cardiology labs, etc.). This may include analytical labs that provide pharmacokinetic analysis, and laboratories supplying efficacy data for clinical investigations conducted under an IND. 29. If a laboratory is sending samples to satellite or other contract labs for additional testing, should these labs be identified in Section #4? It is only necessary to list the primary laboratory, provided that laboratory can trace the samples to each of the satellite and/or contract labs where the tests were performed. VI. SECTION #5: NAME AND ADDRESS OF THE INSTITUTIONAL REVIEW BOARD (IRB) RESPONSIBLE FOR THE REVIEW AND APPROVAL OF THE STUDY(IES) Contains Nonbinding Recommendations 30. Does the IRB reviewing and approving the clinical study have to be at the same location as where the research is conducted? The regulations permit review of research by IRBs at locations other than where the research is being performed (e.g. independent or non-institutional IRB; use of a cooperative IRB review process; see 21 CFR 56.114). Therefore an IRB may review clinical studies that are not performed on-site as long as requirements in 21 CFR Parts 50 and 56 are met. For more information on cooperative research arrangements, see the FDA Guidance for Industry-Using a Centralized IRB Review Process in Multicenter Clinical Trials (). VII. SECTION #6: NAMES OF THE SUBINVESTIGATORS WHO WILL BE ASSISTING THE INVESTIGATOR IN THE CONDUCT OF THE INVESTIGATION(S) 31. Who should be listed as a subinvestigator in Section #6? FDA's regulation at 21 CFR 312.3(b) states: "In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. ‘Subinvestigator’ includes any other individual member of that team." 21 CFR 312.53(c)(1)(viii) requires the investigator to provide "a list of the names of the subinvestigators (e.g., research fellows, residents) who will be assisting the investigator in the conduct of the investigation(s)." The purpose of Section #6 is to capture information about individuals who, as part of an investigative team, will assist the investigator and make a direct and significant contribution to the data. The decision to list an individual in Section #6 depends on his/her level of responsibility (i.e., whether he/she is performing significant clinical investigation-related duties). In general, if an individual is directly involved in the performance of procedures required by the protocol, and the collection of data, that person should be listed on the 1572. For example, if the protocol notes that each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the clinical investigation, that internist should be listed in Section #6. 32. Should research nurses, other nurses, residents, fellows, office staff, or other hospital staff be listed in Section #6? Hospital staff, including nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make a direct and significant contribution to the clinical data, do not need to be listed individually. It is not necessary to include in this section a person with only an occasional role in the conduct of the research, e.g., an -n-call physician who temporarily dealt with a possible adverse effect or a temporary substitute for any research staff (see ICH E3, Section 6) ances/ucm073113.pdf). Contains Nonbinding Recommendations Concerning staff residents on rotation, it may be difficult to prospectively identify those individuals who might perform specified protocol procedures or collect clinical data. Specific names of the rotational staff do not have to be listed in Section #6. Instead, to successfully address this scenario, the names of rotational individuals and the procedures they are expected to perform should be included in the clinical study records. This information should also be sent to the sponsor for submission to FDA in, for example, an information amendment. 33. Should pharmacists or research coordinators be listed in Section #6? The decision about whether to list a pharmacist or research coordinator on the 1572 is a matter of judgment, dependent upon the contribution that the individual makes to the study. For example, a research pharmacist may prepare test articles and maintain drug accountability for many clinical studies that are ongoing concurrently at an institution. Because the pharmacist would not be making a direct and significant contribution to the data for a particular study, it would not be necessary to list the pharmacist as a subinvestigator in Section #6, but he/she should be listed in the investigator’s study records. Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 34. Is a statement of qualifications required for subinvestigators? No. The regulations at 21 CFR 312.53(c)(1)(viii) require only that subinvestigators’ names be listed in Section #6 of the 1572. It is the responsibility of the sponsor to select investigators qualified by training and experience, as appropriate experts, to investigate the drug. The investigator must ensure that all associates, colleagues, and employees assisting with the conduct of the clinical investigation are aware of their obligations including complying with the IND regulations. 35. Do individuals who are listed in Section #6 on the 1572 have to submit information about their financial interests? Yes. Under 21 CFR Part 54 (Disclosure of Financial Interests by Clinical Investigators), a person listed or identified as an investigator or subinvestigator who is directly involved in the treatment or evaluation of research subjects must submit financial disclosure information to the sponsor. For purposes of this financial disclosure regulation, the term investigator also includes the spouse and each dependent child of the investigator and subinvestigator. (21 CFR 54.2(d) and 54.4). For additional information about financial disclosure, see FDA’s Guidance for Industry Financial Disclosure by Clinical Investigators () Contains Nonbinding Recommendations VIII. SECTION #7: NAME AND CODE NUMBER, IF ANY, OF THE PROTOCOL(S) IN THE IND FOR STUDY(IES) TO BE CONDUCTED BY THE INVESTIGATOR 36. What information should be included in this section? List the name and code number (if any) of all the protocols under the IND that will be conducted by the investigator signing the 1572. A code number is an identifying number assigned by the sponsor. As a reminder, some investigators may be responsible for submitting certain clinical trial information to the National Institutes of Health clinical trials data bank under 42 U.S.C. 282(j), 402(j) of the Public Health Service Act. Although not all investigators will be expected to meet this requirement, go to www.clinicaltrials.gov for further information about potential responsibilities. IX. SECTION #8: CLINICAL PROTOCOL INFORMATION 37. How should Section #8 be completed for a phase 4 study? Phase 4 refers to the timing of a clinical study (i.e., postmarketing) rather than the characteristics of the study, which are described under 21 CFR 312.21, Phases of an investigation. A postmarketing clinical trial would meet the description of a phase 2 or 3 investigation and a full protocol would be submitted. The investigator does not need to mark either of the boxes in Section #8, but should identify in Section #7 that the study is a phase 4 study. 38. Can an investigator submit the study protocol instead of an outline of the study protocol? Yes. The protocol or a detailed description is required for any phase 2 or 3 clinical trial. Phase 1 studies can be supported by an outline (see 21 CFR 312.53).	Form 1572 # Statement of Investigator (Form FDA 1572) This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. This guidance applies to clinical investigations conducted under 21 CFR Part 312 (Investigational New Drug Applications or IND regulations). It describes how to complete the Statement of Investigator form (Form FDA 1572). # I. GENERAL ## 1. What is the Statement of Investigator, Form FDA 1572? The Statement of Investigator, Form FDA 1572 (1572), is an agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic. The most recent version of the 1572 is available online at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf. ## 2. Why does this form need to be completed by an investigator? The 1572 has two purposes: 1) to provide the sponsor with information about the investigator’s qualifications and the clinical site that will enable the sponsor to establish and document that the investigator is qualified and the site is an appropriate location at which to conduct the clinical investigation. 2) to inform the investigator of his/her obligations and obtain the investigator’s commitment to follow pertinent FDA regulations. Investigators should complete the form as accurately as they can. Investigators should be aware that making a willfully false statement is a criminal offense under 18 U.S.C. 1001. Further, submission of a deliberately false statement to the sponsor or to the agency can be taken into consideration in a disqualification proceeding. ## 3. When must this form be completed and signed by an investigator? Whenever a sponsor selects a new investigator to participate in a clinical investigation that is being conducted under an investigational new drug application (IND), the sponsor must obtain a completed and signed 1572 before permitting the investigator to begin participation in the clinical investigation (21 CFR 312.53(c)). The investigator should sign the form only after being given enough information to be informed about the clinical investigation and to understand the commitments described in Section #9 of the 1572. Having enough information about the study typically means that the investigator has received copies of, has read, and understands the protocol and investigator’s brochure (if required), and is familiar with the regulations governing the conduct of clinical studies. The investigator’s signature on this form constitutes the investigator’s affirmation that he or she is qualified to conduct the clinical investigation and constitutes the investigator’s written commitment to abide by FDA regulations in the conduct of the clinical investigation. ## 4. Must the investigator be a physician? The regulations do not require that the investigator be a physician. Sponsors are required to select only investigators qualified by training and experience as appropriate experts to investigate the drug (21 CFR 312.53(a)). In the event the clinical investigator is a nonphysician, a qualified physician (or dentist, when appropriate) should be listed as a subinvestigator for the trial and should be responsible for all trial-related medical (or dental) decisions. (ICH E6 section 4.3.1; http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf). ## 5. What are the minimum qualifications of an investigator? As stated in #4, the regulations require that sponsors select investigators who are qualified by training and experience as appropriate experts to investigate the drug. The regulations do not specify the minimum requirements nor do the regulations specify what qualifications an investigator must have in order to be considered qualified by training and experience to conduct a clinical investigation. Sponsors have discretion in determining what qualifications, training, and experience will be needed, based on the general recognition that this would include familiarity with human subject protection (HSP) regulations (i.e., 21 CFR Parts 50 and 56) and practices as well as good clinical practice (GCP) regulations (see 21 CFR Part 312) and standards (e.g., ICH E6) for the conduct of clinical studies. ## 6. Does the 1572 need to be submitted to FDA? No. Although the sponsor is required to collect the 1572 from the investigator, FDA does not require the form to be submitted to the agency. Many sponsors submit the 1572 to FDA, however, because it collects, in one place, information that must be submitted to FDA under 21 CFR 312.23(a)(6)(iii)(b). ## 7. When must a 1572 be updated or a new 1572 completed and signed by an investigator to reflect new or changed information? There are two instances when it is necessary for an investigator to complete and sign a new 1572: when an investigator is participating in a new protocol that has been added to the IND and when a new investigator is added to the study (21 CFR 312.53(c)). If there are other changes to information contained on a signed and dated 1572 (e.g., an IRB address change, the addition of new subinvestigators, the addition of a clinical research lab), the investigator should document the changes in the clinical study records and inform the sponsor of these changes, so that the sponsor can appropriately update the IND. The 1572 itself does not need to be revised and a new 1572 need not be completed and signed by the investigator. The sponsor can accumulate certain changes and submit this information to the IND in, for example, an information amendment or a protocol amendment. ## 8. If a clinical investigation is not conducted under an IND or is for a medical device, must investigators sign a 1572? No. Under the regulations, a 1572 is only required for studies of investigational drugs and biologics conducted under an IND. It is not required for studies that are not done under an IND, and is not applicable to investigational device studies. Sponsors of device studies must obtain a signed investigator agreement (containing information similar to that requested on the 1572) from each participating investigator, per 21 CFR 812.43(c). ## 9. Must a sponsor conduct a foreign clinical study under an IND? No. A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived (see #12 and #13 below). When the foreign clinical study is not conducted under an IND, the sponsor must ensure that this study complies with 21 CFR 312.120, “Foreign clinical studies not conducted under an IND,” if the sponsor intends to submit the study to FDA to support clinical investigations conducted in the United States and/or marketing approval. An application based solely on foreign clinical data must meet criteria listed in 21 CFR 314.106. ## 10. Must investigators who conduct studies outside of the United States sign a 1572? If a foreign clinical study is conducted under an IND, then all FDA IND regulations, including the requirement to obtain a signed 1572, must be met. If a clinical study is conducted outside of the U.S. and is not conducted under an IND, then the investigator need not sign a 1572. If local laws or regulations prohibit the signing of a 1572, FDA would expect the sites to operate as non-IND sites and the study conducted as a non-IND study. If the study data is to be submitted to support a marketing application (e.g., a new drug application (NDA)), the study must be conducted in compliance with 21 CFR 312.120. ## 11. If a foreign clinical study is being conducted under an IND, what are the investigator’s responsibilities with respect to local laws and regulations? Investigators are responsible for complying with the applicable laws and regulations of the country in which the study is being conducted, regardless of whether the study is being conducted under an IND. We recommend that sponsors obtain signed, written statements from investigators acknowledging their commitment to comply with local laws and requirements. In addition, if a foreign clinical study is being conducted under an IND, the investigator must sign Form FDA 1572 (investigator statement) and ensure that the study is conducted in accordance with the investigator statement and all other applicable regulations under 21 CFR Part 312. ## 12. For foreign clinical studies conducted under an IND, how can an investigator sign the 1572 when the investigator knows he/she cannot commit to all of the requirements on the form, specifically IRB membership (21 CFR 56.107)? IRB review and approval is required before a clinical study can be initiated under an IND (21 CFR 56.103(a)). FDA may waive any of the IRB requirements for specific research activities or for classes of research activities otherwise covered by the IRB regulations (21 CFR 56.105), but FDA uses the waiver provision only when alternative mechanisms for ensuring protection of the rights and welfare of human subjects are acceptable. The most common circumstance for which FDA receives a waiver request is when a sponsor wishes to conduct a foreign clinical study under an IND. In this case, typically an Independent Ethics Committee (IEC) that operates in accordance with Good Clinical Practice (GCP) is utilized instead of a U.S. IRB. Although its membership and functions for assuring human subject protection are comparable to an IRB, an IEC may not meet all of the IRB requirements contained in 21 CFR Part 56. For a foreign study, an IRB waiver request should contain a description of alternative mechanisms for assuring human subject protection. It would generally be acceptable for a waiver request to state the intention to use an IEC that complies with GCP (e.g., ICH E6) instead of an IRB that complies with 21 CFR Part 56. The sponsor should submit the waiver request to the IND under which the study will be conducted. The IND will have been submitted to the appropriate review division in either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). The sponsor will be informed by the agency in writing whether the waiver request is denied or granted. If a waiver is granted, the sponsor should have investigators attach a copy of the letter granting the waiver to the signed 1572 in the investigator’s record. ## 13. If a sponsor chooses to conduct a foreign clinical study (or operate non-US sites in a multinational study) under an IND and the investigators at these non-US sites comply with the ICH E6 Good Clinical Practice Consolidated Guidance, would the non-US investigators also be in compliance with FDA’s IND requirements under 21 CFR Part 312? Yes, with two exceptions. The first is that the FDA requirements for IRBs under 21 CFR Part 56 are slightly different with respect to membership and function. To address this issue, as described in #12 above, FDA can provide a specific waiver from the Part 56 IRB requirements, allowing an IEC that complies with good clinical practice to substitute for the IRB.4 The second exception is that the requirements for informed consent under 21 CFR Part 50 for particular clinical trials (e.g., emergency research under 21 CFR 50.24, clinical investigations involving pediatric subjects under Subpart D) are more extensive with respect to IRB responsibilities. Because these types of trials are uncommon, our experience has not revealed that this has caused a conflict; but in the event of one, we would be willing to discuss a resolution with the sponsor on a case-by-case basis. If the investigator or sponsor believes that there are other conflicting requirements, the sponsor may request a waiver from FDA from the specific requirement under 21 CFR 312.10. ## 14. Must foreign clinical study sites in a multinational study that includes domestic sites be conducted under an IND? No. A multinational study may include domestic sites under the IND and foreign sites not under the IND. Investigational drug and biologics studies conducted in the U.S. must be conducted in compliance with the IND requirements contained in 21 CFR 312, which includes the requirement that investigators sign the 1572. If a study also involves foreign clinical sites, the sponsor may choose, but is not required, to include the foreign clinical sites under the IND. The investigators from the U.S. sites and any foreign sites included under the IND would be required to sign the 1572. The investigators from the foreign sites that are not included under the IND are not required to sign the 1572. If the sponsor chooses to conduct a multinational study with U.S. and some foreign sites under the IND, and other foreign sites not under the IND, the sponsor can submit a single protocol to the IND and all sites would follow this protocol. Alternatively, the sponsor can conduct a multinational study with one protocol for sites under the IND (U.S. sites and some foreign sites) and a different protocol(s) for foreign sites not under the IND. If the intent is to pool the data from U.S. and foreign sites, the protocols would ordinarily be very similar or identical. The U.S. sites and any foreign sites included under the IND must follow the protocol that was submitted to the IND. For foreign sites that are not included under the IND, the protocol(s) does not need to be submitted to the IND. In general, if the sponsor intends to submit the data in an application for marketing approval, we recommend that the sponsor identify the foreign sites that will not be conducted under the IND and discuss plans to pool the data from U.S. and foreign sites with the appropriate FDA review division. Note, however, that 21 CFR 312.32(b) requires sponsors to promptly review information about the safety of the investigational drug obtained or otherwise received by the sponsor from any source, foreign or domestic. Under 21 CFR 312.32(c), sponsors must also notify FDA and all participating investigators in an IND safety report of any adverse experience associated with the use of the drug that is both serious and unexpected. This means that FDA and all participating investigators under the IND would be informed of such an adverse experience, even if it occurred in a foreign study not conducted under the IND. ## 15. How does a sponsor submit information to FDA about a foreign clinical study that was not conducted under an IND? Under 21 CFR 312.120, the sponsor can submit information to FDA from a foreign clinical study that was not conducted under an IND to support clinical investigations in the United States and/or marketing approval. When submitting information about a foreign clinical study, it is helpful to clearly identify in the cover letter that the material is being submitted in accordance with 21 CFR 312.120. The submission requirements for supporting documentation can be found at 21 CFR 312.120(b). ===16. Should a new form be prepared and signed when the OMB expiration date is reached?=== No. There is no need to prepare and sign a new 1572 when the OMB expiration date has been reached. ===17. Does FDA expect a double-sided 1572, or is a two-page document printed from the FDA website acceptable?=== Either is acceptable; however, FDA recommends that a two-page document be stapled so that there is no question about what form the investigator signed. ## 18. How should the 1572 be completed? The 1572 on FDA’s website may be completed by typing the information directly into the fillable form and printing the completed form. Alternatively, it is acceptable to print the blank form from FDA’s website and hand-write or type the information onto the form. Typed forms are preferable because they are usually more legible. The completed form must be signed and dated by the investigator (either by hand or using an acceptable electronic method). ## 19. How should an investigator’s name appear on the 1572? Section #1 should contain the investigator’s full legal name (e.g., name on the investigator’s birth certificate or marriage certificate). Titles, degrees, and/or professional qualifications may follow the investigator’s legal name, if desired. ## 20. What address should be entered into Section #1? The address where the investigator can be reached by mail or in person should be entered in Section #1 of the 1572. Usually, this corresponds to the investigator’s work or business address. ===21. Should co-investigators be listed on the 1572 in Section #1? Is it acceptable to have more than one investigator at a single site?=== The term co-investigator is not defined in FDA regulations. As commonly used, the term is meant to indicate that each co-investigator is fully responsible for fulfilling all of the obligations of an investigator as identified in 21 CFR 312.60. Thus under 21 CFR 312.3(b), each co-investigator is an investigator, and as such must sign a separate 1572. In some situations, it is preferable to have more than one investigator responsible for a clinical investigation. For example, when a study is conducted at multiple research facilities that are not in close proximity, FDA expects an investigator who has signed a # QUALIFY THE INVESTIGATOR AS AN EXPERT IN THE CLINICAL INVESTIGATION ## 22. What is the purpose of Section #2? Section #2 requires the investigator to attach a curriculum vitae (CV) or other statement of qualifications, showing the education, training and experience that qualifies the investigator as an expert in the clinical investigation of the drug/biologic for the use under investigation. Information identified in this section and attached to the 1572 enables the sponsor to assess an investigator's qualifications. ===23. Does the CV or other statement of qualifications need to be updated during a clinical study?=== No. FDA regulations do not require a CV or other statement of qualifications to be updated during a clinical study. ## 24. Are CVs required to be signed and dated? No. FDA regulations do not require a CV to be signed and dated. The investigator's dated signature on the 1572 is sufficient to attest to the accuracy of the CV or other statement of qualifications submitted with the 1572. ==IV. SECTION #3: NAME AND ADDRESS OF ANY MEDICAL SCHOOL, HOSPITAL, OR OTHER RESEARCH FACILITY WHERE THE CLINICAL INVESTIGATION(S) WILL BE CONDUCTED== ===25. What address(es) should be entered in Section #3? The address(es) of the location(s) where the investigation will be conducted and to where the test articles will be shipped, if different from the investigator's address of record, should be entered in Section #3. ## 26. What qualifies as a research facility for Section #3? Section #3 is intended to identify facilities where study activities will be conducted and clinical data will be generated or collected. This includes facilities where subjects will be seen and study procedures performed. For example, this might include locations such as health care facilities where the test article will be administered, or where physical exams will be performed. Facilities where other important clinical investigation functions are performed may also be identified in Section #3. For example, a research laboratory where the test article is prepared, a special storage facility where the test article will be kept, or a location where tissue specimens are collected should be listed in this section. ===27. If an investigator sees study subjects at more than one site, should the investigator list all sites on the 1572?=== Yes. The names and addresses of each of the study sites should be identified in Section - 3. However, if the protocol specifies that the investigative product can be administered at a subject’s home (for example, the protocol allows for daily injections to be administered by a registered nurse in the subject’s home), the subjects' home addresses do not have to be listed on the 1572. Study records should reflect that the test article was administered at subjects' homes per the protocol. ==V. SECTION #4: NAME AND ADDRESS OF CLINICAL LABORATORY FACILITIES TO BE USED IN THIS STUDY== 28. What qualifies as a clinical laboratory facility for Section #4? Section #4 is intended to identify clinical laboratories or testing facilities directly contributing to or supporting the clinical study (for example, diagnostic labs performing blood work, imaging centers, cardiology labs, etc.). This may include analytical labs that provide pharmacokinetic analysis, and laboratories supplying efficacy data for clinical investigations conducted under an IND. 29. If a laboratory is sending samples to satellite or other contract labs for additional testing, should these labs be identified in Section #4? It is only necessary to list the primary laboratory, provided that laboratory can trace the samples to each of the satellite and/or contract labs where the tests were performed. VI. SECTION #5: NAME AND ADDRESS OF THE INSTITUTIONAL REVIEW BOARD (IRB) RESPONSIBLE FOR THE REVIEW AND APPROVAL OF THE STUDY(IES) 12 Contains Nonbinding Recommendations 30. Does the IRB reviewing and approving the clinical study have to be at the same location as where the research is conducted? The regulations permit review of research by IRBs at locations other than where the research is being performed (e.g. independent or non-institutional IRB; use of a cooperative IRB review process; see 21 CFR 56.114). Therefore an IRB may review clinical studies that are not performed on-site as long as requirements in 21 CFR Parts 50 and 56 are met. For more information on cooperative research arrangements, see the FDA Guidance for Industry-Using a Centralized IRB Review Process in Multicenter Clinical Trials (http://www.fda.gov/RegulatoryInformation/Guidances/ucm127004.htm). VII. SECTION #6: NAMES OF THE SUBINVESTIGATORS WHO WILL BE ASSISTING THE INVESTIGATOR IN THE CONDUCT OF THE INVESTIGATION(S) 31. Who should be listed as a subinvestigator in Section #6? FDA's regulation at 21 CFR 312.3(b) states: "In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. ‘Subinvestigator’ includes any other individual member of that team." 21 CFR 312.53(c)(1)(viii) requires the investigator to provide "a list of the names of the subinvestigators (e.g., research fellows, residents) who will be assisting the investigator in the conduct of the investigation(s)." The purpose of Section #6 is to capture information about individuals who, as part of an investigative team, will assist the investigator and make a direct and significant contribution to the data. The decision to list an individual in Section #6 depends on his/her level of responsibility (i.e., whether he/she is performing significant clinical investigation-related duties). In general, if an individual is directly involved in the performance of procedures required by the protocol, and the collection of data, that person should be listed on the 1572. For example, if the protocol notes that each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the clinical investigation, that internist should be listed in Section #6. 32. Should research nurses, other nurses, residents, fellows, office staff, or other hospital staff be listed in Section #6? Hospital staff, including nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make a direct and significant contribution to the clinical data, do not need to be listed individually. It is not necessary to include in this section a person with only an occasional role in the conduct of the research, e.g., an on-call physician who temporarily dealt with a possible adverse effect or a temporary substitute for any research staff (see ICH E3, Section 6) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/ucm073113.pdf). 13 Contains Nonbinding Recommendations Concerning staff residents on rotation, it may be difficult to prospectively identify those individuals who might perform specified protocol procedures or collect clinical data. Specific names of the rotational staff do not have to be listed in Section #6. Instead, to successfully address this scenario, the names of rotational individuals and the procedures they are expected to perform should be included in the clinical study records. This information should also be sent to the sponsor for submission to FDA in, for example, an information amendment. 33. Should pharmacists or research coordinators be listed in Section #6? The decision about whether to list a pharmacist or research coordinator on the 1572 is a matter of judgment, dependent upon the contribution that the individual makes to the study. For example, a research pharmacist may prepare test articles and maintain drug accountability for many clinical studies that are ongoing concurrently at an institution. Because the pharmacist would not be making a direct and significant contribution to the data for a particular study, it would not be necessary to list the pharmacist as a subinvestigator in Section #6, but he/she should be listed in the investigator’s study records. Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572. 34. Is a statement of qualifications required for subinvestigators? No. The regulations at 21 CFR 312.53(c)(1)(viii) require only that subinvestigators’ names be listed in Section #6 of the 1572. It is the responsibility of the sponsor to select investigators qualified by training and experience, as appropriate experts, to investigate the drug. The investigator must ensure that all associates, colleagues, and employees assisting with the conduct of the clinical investigation are aware of their obligations including complying with the IND regulations. 35. Do individuals who are listed in Section #6 on the 1572 have to submit information about their financial interests? Yes. Under 21 CFR Part 54 (Disclosure of Financial Interests by Clinical Investigators), a person listed or identified as an investigator or subinvestigator who is directly involved in the treatment or evaluation of research subjects must submit financial disclosure information to the sponsor. For purposes of this financial disclosure regulation, the term investigator also includes the spouse and each dependent child of the investigator and subinvestigator. (21 CFR 54.2(d) and 54.4). For additional information about financial disclosure, see FDA’s Guidance for Industry Financial Disclosure by Clinical Investigators (http://www.fda.gov/RegulatoryInformation/Guidances/ucm126832.htm) 14 Contains Nonbinding Recommendations 15 VIII. SECTION #7: NAME AND CODE NUMBER, IF ANY, OF THE PROTOCOL(S) IN THE IND FOR STUDY(IES) TO BE CONDUCTED BY THE INVESTIGATOR 36. What information should be included in this section? List the name and code number (if any) of all the protocols under the IND that will be conducted by the investigator signing the 1572. A code number is an identifying number assigned by the sponsor. As a reminder, some investigators may be responsible for submitting certain clinical trial information to the National Institutes of Health clinical trials data bank under 42 U.S.C. 282(j), 402(j) of the Public Health Service Act. Although not all investigators will be expected to meet this requirement, go to www.clinicaltrials.gov for further information about potential responsibilities. IX. SECTION #8: CLINICAL PROTOCOL INFORMATION 37. How should Section #8 be completed for a phase 4 study? Phase 4 refers to the timing of a clinical study (i.e., postmarketing) rather than the characteristics of the study, which are described under 21 CFR 312.21, Phases of an investigation. A postmarketing clinical trial would meet the description of a phase 2 or 3 investigation and a full protocol would be submitted. The investigator does not need to mark either of the boxes in Section #8, but should identify in Section #7 that the study is a phase 4 study. 38. Can an investigator submit the study protocol instead of an outline of the study protocol? Yes. The protocol or a detailed description is required for any phase 2 or 3 clinical trial. Phase 1 studies can be supported by an outline (see 21 CFR 312.53). Template:WH Template:WS	https://www.wikidoc.org/index.php/Form_1572
7efff45eaedbb0e775b1a2fe133870a7631eafff	wikidoc	Metformin	Metformin # 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 Metformin is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cobalamin deficiency, diarrhea, flatulence, indigestion, malabsorption syndrome, nausea, vomiting, asthenia, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Metformin HCl Tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. - Dosing Information: - There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin HCl, USP or any other pharmacologic agent. Dosage of Metformin HCl, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Metformin HCl, USP is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age). - Metformin HCl, USP should be given in divided doses with meals. Metformin HCl, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. - During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to Metformin HCl, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Metformin HCl, USP, either when used as monotherapy or in combination with sulfonylurea or insulin. - Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. - Short-term administration of Metformin HCl, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. - Recommended Dosing Schedule - Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. - The usual starting dose of Metformin HCl Tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin HCl, USP may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals. - If higher doses of metformin are required, Metformin HCl, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. - Pediatrics - The usual starting dose of Metformin HCl, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. - Transfer From Other Antidiabetic Therapy - When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin HCl, USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant Metformin HCl, USP and Oral Sulfonylurea Therapy in Adult Patients - If patients have not responded to four weeks of the maximum dose of Metformin HCl, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin HCl, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). - With concomitant Metformin HCl, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Metformin HCl, USP 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of Metformin HCl, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Metformin HCl, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.) - If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of Metformin HCl, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin HCl, USP. Concomitant Metformin HCl, USP and Insulin Therapy in Adult Patients - The current insulin dose should be continued upon initiation of Metformin HCl, USP therapy. Metformin HCl, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Metformin HCl, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Metformin HCl, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin HCl, USP. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations - Metformin HCl, USP is not recommended for use in pregnancy. Metformin HCl, USP is not recommended in patients below the age of 10 years. - The initial and maintenance dosing of Metformin HCl, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin HCl, USP. - Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.) ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Metformin in adult patients. ### Non–Guideline-Supported Use ### Hyperinsulinar obesity ### Polycystic ovary syndrome - Dosing Information - The recommended metformin dose for the treatment of women with polycystic ovary syndrome is 1500 to 2000 mg/day orally in divided doses (guideline dose). # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Type 2 diabetes mellitus(10 years or older, immediate-release tablet and solution; 17 years or older, extended-release tablets (Glucophage XR(R) and Fortamet(TM) only) - Dosing Information - Immediate Release - The initial recommended dose of metformin for children, ages 10 to 16 years, is 500 mg twice daily, with meals. Dosage may be increased by 500 mg weekly, to a maximum of 2000 mg/day, in divided doses, if needed. Metformin is not recommended for children under 10 years of age. - In adolescents 17 years or older with type 2 diabetes mellitus, the initial recommended dosage of metformin is 500 mg twice daily or 850 mg once daily given with meals. When using the 500-mg tablet, the dose may be increased at intervals of 1 week depending on the blood glucose response; whereas, with the 850-mg tablet, the dose should be increased at intervals of 2 weeks, up to a maximum of 2550 mg daily. Doses up to 2000 mg daily may be divided into 2 equal doses, but higher doses are tolerated better if they are divided into 3 doses. - Extended-Release - Glucophage XR(R): - In adolescents 17 years or older with type 2 diabetes mellitus, the initial dose of metformin XR is 500 mg once daily with the evening meal. Dosage adjustments may be made weekly in increments of 500 mg to a maximum dose of 2000 mg daily. Patients who are receiving metformin may be switched to metformin XR at the same total daily dose, up to 2000 mg once daily. If metformin XR 2000 mg once daily does NOT achieve acceptable glycemic control, metformin XR 1000 mg twice daily may be tried. - Fortamet(TM) Extended-Release: - In adolescents 17 years or older, the initial dose of metformin extended-release (Fortamet(TM)) is 500 mg to 1000 mg once daily with the evening meal. Dosage adjustments may be made weekly in increments of 500 mg to a maximum of 2500 mg daily. Patients receiving immediate release metformin may be switched to extended release (Fortamet(TM)) once daily metformin at the same total daily dose. - Oral Solution: - The recommended initial dose of metformin oral solution in children 10 years or older is 500 mg orally twice daily. The dose may be titrated in 500 mg increments weekly to a maximum of 2000 mg/day in divided doses. - Guideline Dosing: - American Academy of Pediatrics guidelines recommend starting metformin at a dose 500 mg daily, with titration by 500 mg every 1 to 2 weeks to minimize gastrointestinal adverse effects. The ideal and maximum target dose is 2000 mg daily in divided doses. Extended-release metformin, dosed once in the evening, may be considered. Ideally, the target HbA1c in this patient population is less than 7%, but targets should be individualized to aid achievement with an ultimate goal of reaching the guideline target levels. In patients without hypoglycemic events and when otherwise appropriate, lower HbA1c targets may be considered. - The safety and efficacy of metformin oral solution or immediate-release oral tablets have not been established in pediatric patients younger than 10 years. - The safety and efficacy of extended-release Glumetza(TM) in pediatric patients, and Fortamet(TM) and Glucophage XR(R) in children younger than 17 years have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Metformin in pediatric patients. ### Non–Guideline-Supported Use - Hyperinsulinar obesity # Contraindications - Metformin HCl, USP is contraindicated in patients with: - Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL , ≥1.4 mg/dL or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia. - Known hypersensitivity to metformin HCl, USP. - Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. - Metformin HCl, USP should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. # Warnings ### PRECAUTIONS General - Macrovascular Outcomes—There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Metformin HCl or any other anti-diabetic drug. - Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCl. In patients with advanced age, Metformin HCl should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin HCl should not be titrated to the maximum dose. - Before initiation of Metformin HCl therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin HCl discontinued if evidence of renal impairment is present. - Use of concomitant medications that may affect renal function or metformin disposition—Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution. - Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)—Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Metformin HCl should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. - Hypoxic states—Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Metformin HCl therapy, the drug should be promptly discontinued. - Surgical procedures— Metformin HCl therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. - Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCl. - Impaired hepatic function—Since impaired hepatic function has been associated with some cases of lactic acidosis, Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. - Vitamin B12 levels—In controlled clinical trials of Metformin HCl of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Metformin HCl or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin HCl and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests). - Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful. - Change in clinical status of patients with previously controlled type 2 diabetes—A patient with type 2 diabetes previously well controlled on Metformin HCl who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Metformin HCl must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS). - Hypoglycemia—Hypoglycemia does not occur in patients receiving Metformin HCl alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. - Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. - Loss of control of blood glucose—When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin HCl and temporarily administer insulin. Metformin HCl may be reinstituted after the acute episode is resolved. - The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin HCl or sulfonylurea monotherapy, combined therapy with Metformin HCl and sulfonylurea may result in a response. Should secondary failure occur with combined Metformin HCl /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy. Laboratory Tests - Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control. - Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin HCl therapy, if this is suspected, Vitamin B12 deficiency should be excluded. # Adverse Reactions ## Clinical Trials Experience n a US double-blind clinical study of Metformin HCl in patients with type 2 diabetes, a total of 141 patients received Metformin HCl therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the Metformin HCl patients, and that were more common in Metformin HCl - than placebo-treated patients, are listed in Table 9. - Reactions that were more common in Metformin HCl -than placebo-treated patients. - Diarrhea led to discontinuation of study medication in 6% of patients treated with Metformin HCl. Additionally, the following adverse reactions were reported in ≥ 1.0 to ≤ 5.0% of Metformin HCl patients and were more commonly reported with Metformin HCl than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Pediatric Patients - In clinical trials with Metformin HCl in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults. ## Postmarketing Experience There is limited information regarding Metformin Postmarketing Experience in the drug label. # Drug Interactions Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin HCl) - Glyburide—In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. - Furosemide—A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically. - Nifedipine—A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. - Cationic drugs—Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Metformin HCl and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. - Other—Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Metformin HCl, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metformin HCl, the patient should be observed closely for hypoglycemia. - In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies. - Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed. - There are no adequate and well-controlled studies in pregnant women with Metformin HCl. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metformin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Metformin during labor and delivery. ### Nursing Mothers - Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, 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. If Metformin HCl is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use - The safety and effectiveness of Metformin HCl for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of Metformin HCl in this age group is supported by evidence from adequate and well-controlled studies of Metformin HCl in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. In this study, adverse effects were similar to those described in adults. A maximum daily dose of 2000 mg is recommended. ### Geriatic Use - Controlled clinical studies of Metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metformin HCl should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Metformin HCl should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Metformin HCl. ### Gender - There is no FDA guidance on the use of Metformin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Metformin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Metformin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Metformin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Metformin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Metformin in patients who are immunocompromised. # Administration and Monitoring ### Administration - There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin HCl, USP or any other pharmacologic agent. Dosage of Metformin HCl, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Metformin HCl, USP is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age). - Metformin HCl, USP should be given in divided doses with meals. Metformin HCl, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. - During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to Metformin HCl, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Metformin HCl, USP, either when used as monotherapy or in combination with sulfonylurea or insulin. - Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. - Short-term administration of Metformin HCl, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Recommended Dosing Schedule - Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. - The usual starting dose of Metformin HCl Tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin HCl, USP may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals. - If higher doses of metformin are required, Metformin HCl, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. - Pediatrics - The usual starting dose of Metformin HCl, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. Transfer From Other Antidiabetic Therapy - When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin HCl, USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant Metformin HCl, USP and Oral Sulfonylurea Therapy in Adult Patients - If patients have not responded to four weeks of the maximum dose of Metformin HCl, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin HCl, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). - With concomitant Metformin HCl, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Metformin HCl, USP 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of Metformin HCl, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Metformin HCl, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. - If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of Metformin HCl, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin HCl, USP. Concomitant Metformin HCl, USP and Insulin Therapy in Adult Patients - The current insulin dose should be continued upon initiation of Metformin HCl, USP therapy. Metformin HCl, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Metformin HCl, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Metformin HCl, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin HCl, USP. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations - Metformin HCl, USP is not recommended for use in pregnancy. Metformin HCl, USP is not recommended in patients below the age of 10 years. - The initial and maintenance dosing of Metformin HCl, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin HCl, USP. - Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.) ### Monitoring - Metformin HCl. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin HCl treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Metformin HCl should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. - Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCl. In patients with advanced age, Metformin HCl should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin HCl should not be titrated to the maximum dose. - Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control. - Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin HCl therapy, if this is suspected, Vitamin B12 deficiency should be excluded. # IV Compatibility There is limited information regarding the compatibility of Metformin and IV administrations. # Overdosage - Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. # Pharmacology ## Mechanism of Action - Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. ## Structure - Metformin Hydrochloride (HCl) Tablets, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin HCl, USP (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. - The structural formula is as shown: - Metformin HCl, USP is a white to off-white crystalline compound with a molecular formula of C4H11N5 - HCl and a molecular weight of 165.62. Metformin HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl, USP is 6.68. - Metformin HCl Tablets, USP, contains 500 mg, 850 mg, or 1000 mg of metformin HCl, USP. Each tablet contains the inactive ingredients povidone, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contain polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, gum acacia, maltodextrin, propylene glycol and natural flavors. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Metformin in the drug label. ## Pharmacokinetics Absorption and Bioavailability - The absolute bioavailability of a Metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of Metformin HCl 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. Distribution - The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin HCl 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Metformin HCl, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of Metformin HCl, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. Metabolism and Elimination - Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Patients with Type 2 Diabetes - In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses. Renal Insufficiency - In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS). Hepatic Insufficiency - No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. Geriatrics - Limited data from controlled pharmacokinetic studies of Metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin HCl Tablets treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. Pediatrics - After administration of a single oral Metformin HCl 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. Gender - Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of Metformin HCl was comparable in males and females. Race - No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of Metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24). Clinical Studies Metformin Hydrochloride - In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose of approximately 240 mg/dL), treatment with Metformin HCl (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2). - A 29-week, double-blind, placebo-controlled study of Metformin HCl and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with Metformin HCl 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of Metformin HCl increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed Metformin HCl 2500 mg. Patients in the Metformin HCl only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking Metformin HCl 2000 mg/glyburide 20 mg or Metformin HCl 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to Metformin HCl (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of Metformin HCl and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were –77 mg/dL, – 68 mg/dL, and –1.9%, respectively (see Table 3). - The magnitude of the decline in fasting blood glucose concentration following the institution of - Metformin HCl Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin. - In clinical studies, Metformin HCl, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4). - In contrast to sulfonylureas, body weight of individuals on Metformin HCl tended to remain stable or even decrease somewhat (see Tables 2 and 3). - A 24-week, double-blind, placebo-controlled study of Metformin HCl plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive Metformin HCl plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, Metformin HCl plus insulin versus insulin plus placebo, respectively, p=0.04. - A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of Metformin HCl maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for Metformin HCl plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for Metformin HCl plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of Metformin HCl plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01. Pediatric Clinical Studies - In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with Metformin HCl (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 8). ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. - These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. - There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. - Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. # Clinical Studies There is limited information regarding Clinical Studies of Metformin in the drug label. # How Supplied - Metformin HCl Tablets, USP 500 mg are blackberry flavored, white to off-white, round, biconvex, film-coated tablets debossed “IP 218” on obverse and “500” on the reverse. - They are available as follows: - Bottles of 100: NDC 65162-218-10 - Bottles of 500: NDC 65162-218-50 - Bottles of 1000: NDC 65162-218-11 - Metformin HCl Tablets, USP 850 mg are blackberry flavored, white to off-white, round, biconvex, film-coated tablets debossed “IP 219” on obverse and “850” on the reverse. - They are available as follows: - Bottles of 100: NDC 65162-219-10 - Bottles of 500: NDC 65162-219-50 - Bottles of 1000: NDC 65162-219-11 - Metformin HCl Tablets, USP 1000 mg are blackberry flavored, white to off-white, oval, biconvex, bisected, film-coated tablets debossed “IP 220” on obverse and “1000” on the reverse. - They are available as follows: - Bottles of 100: NDC 65162-220-10 - Bottles of 500: NDC 65162-220-50 - Bottles of 1000: NDC 65162-220-11 ## Storage - Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the potential risks and benefits of Metformin HCl and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. - The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Metformin HCl immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Metformin HCl, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. - Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Metformin HCl. - Metformin HCl alone does not usually cause hypoglycemia, although it may occur when Metformin HCl is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.) # Precautions with Alcohol - Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCl. # Brand Names Fortamet, Glucophage, Glucophage XR, Riomet, Glumetza. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Metformin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Metformin is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cobalamin deficiency, diarrhea, flatulence, indigestion, malabsorption syndrome, nausea, vomiting, asthenia, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Metformin HCl Tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. - Dosing Information: - There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin HCl, USP or any other pharmacologic agent. Dosage of Metformin HCl, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Metformin HCl, USP is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age). - Metformin HCl, USP should be given in divided doses with meals. Metformin HCl, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. - During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to Metformin HCl, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Metformin HCl, USP, either when used as monotherapy or in combination with sulfonylurea or insulin. - Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. - Short-term administration of Metformin HCl, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. - Recommended Dosing Schedule - Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. - The usual starting dose of Metformin HCl Tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin HCl, USP may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals. - If higher doses of metformin are required, Metformin HCl, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. - Pediatrics - The usual starting dose of Metformin HCl, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. - Transfer From Other Antidiabetic Therapy - When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin HCl, USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant Metformin HCl, USP and Oral Sulfonylurea Therapy in Adult Patients - If patients have not responded to four weeks of the maximum dose of Metformin HCl, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin HCl, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). - With concomitant Metformin HCl, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Metformin HCl, USP 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of Metformin HCl, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Metformin HCl, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.) - If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of Metformin HCl, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin HCl, USP. Concomitant Metformin HCl, USP and Insulin Therapy in Adult Patients - The current insulin dose should be continued upon initiation of Metformin HCl, USP therapy. Metformin HCl, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Metformin HCl, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Metformin HCl, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin HCl, USP. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations - Metformin HCl, USP is not recommended for use in pregnancy. Metformin HCl, USP is not recommended in patients below the age of 10 years. - The initial and maintenance dosing of Metformin HCl, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin HCl, USP. - Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.) ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Metformin in adult patients. ### Non–Guideline-Supported Use ### Hyperinsulinar obesity ### Polycystic ovary syndrome - Dosing Information - The recommended metformin dose for the treatment of women with polycystic ovary syndrome is 1500 to 2000 mg/day orally in divided doses (guideline dose). # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Type 2 diabetes mellitus(10 years or older, immediate-release tablet and solution; 17 years or older, extended-release tablets (Glucophage XR(R) and Fortamet(TM) only) - Dosing Information - Immediate Release - The initial recommended dose of metformin for children, ages 10 to 16 years, is 500 mg twice daily, with meals. Dosage may be increased by 500 mg weekly, to a maximum of 2000 mg/day, in divided doses, if needed. Metformin is not recommended for children under 10 years of age. - In adolescents 17 years or older with type 2 diabetes mellitus, the initial recommended dosage of metformin is 500 mg twice daily or 850 mg once daily given with meals. When using the 500-mg tablet, the dose may be increased at intervals of 1 week depending on the blood glucose response; whereas, with the 850-mg tablet, the dose should be increased at intervals of 2 weeks, up to a maximum of 2550 mg daily. Doses up to 2000 mg daily may be divided into 2 equal doses, but higher doses are tolerated better if they are divided into 3 doses. - Extended-Release - Glucophage XR(R): - In adolescents 17 years or older with type 2 diabetes mellitus, the initial dose of metformin XR is 500 mg once daily with the evening meal. Dosage adjustments may be made weekly in increments of 500 mg to a maximum dose of 2000 mg daily. Patients who are receiving metformin may be switched to metformin XR at the same total daily dose, up to 2000 mg once daily. If metformin XR 2000 mg once daily does NOT achieve acceptable glycemic control, metformin XR 1000 mg twice daily may be tried. - Fortamet(TM) Extended-Release: - In adolescents 17 years or older, the initial dose of metformin extended-release (Fortamet(TM)) is 500 mg to 1000 mg once daily with the evening meal. Dosage adjustments may be made weekly in increments of 500 mg to a maximum of 2500 mg daily. Patients receiving immediate release metformin may be switched to extended release (Fortamet(TM)) once daily metformin at the same total daily dose. - Oral Solution: - The recommended initial dose of metformin oral solution in children 10 years or older is 500 mg orally twice daily. The dose may be titrated in 500 mg increments weekly to a maximum of 2000 mg/day in divided doses. - Guideline Dosing: - American Academy of Pediatrics guidelines recommend starting metformin at a dose 500 mg daily, with titration by 500 mg every 1 to 2 weeks to minimize gastrointestinal adverse effects. The ideal and maximum target dose is 2000 mg daily in divided doses. Extended-release metformin, dosed once in the evening, may be considered. Ideally, the target HbA1c in this patient population is less than 7%, but targets should be individualized to aid achievement with an ultimate goal of reaching the guideline target levels. In patients without hypoglycemic events and when otherwise appropriate, lower HbA1c targets may be considered. - The safety and efficacy of metformin oral solution or immediate-release oral tablets have not been established in pediatric patients younger than 10 years. - The safety and efficacy of extended-release Glumetza(TM) in pediatric patients, and Fortamet(TM) and Glucophage XR(R) in children younger than 17 years have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Metformin in pediatric patients. ### Non–Guideline-Supported Use - Hyperinsulinar obesity # Contraindications - Metformin HCl, USP is contraindicated in patients with: - Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia. - Known hypersensitivity to metformin HCl, USP. - Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. - Metformin HCl, USP should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. # Warnings ### PRECAUTIONS General - Macrovascular Outcomes—There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Metformin HCl or any other anti-diabetic drug. - Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCl. In patients with advanced age, Metformin HCl should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin HCl should not be titrated to the maximum dose. - Before initiation of Metformin HCl therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin HCl discontinued if evidence of renal impairment is present. - Use of concomitant medications that may affect renal function or metformin disposition—Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution. - Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)—Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Metformin HCl should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. - Hypoxic states—Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Metformin HCl therapy, the drug should be promptly discontinued. - Surgical procedures— Metformin HCl therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. - Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCl. - Impaired hepatic function—Since impaired hepatic function has been associated with some cases of lactic acidosis, Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. - Vitamin B12 levels—In controlled clinical trials of Metformin HCl of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Metformin HCl or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin HCl and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests). - Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful. - Change in clinical status of patients with previously controlled type 2 diabetes—A patient with type 2 diabetes previously well controlled on Metformin HCl who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Metformin HCl must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS). - Hypoglycemia—Hypoglycemia does not occur in patients receiving Metformin HCl alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. - Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. - Loss of control of blood glucose—When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin HCl and temporarily administer insulin. Metformin HCl may be reinstituted after the acute episode is resolved. - The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin HCl or sulfonylurea monotherapy, combined therapy with Metformin HCl and sulfonylurea may result in a response. Should secondary failure occur with combined Metformin HCl /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy. Laboratory Tests - Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control. - Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin HCl therapy, if this is suspected, Vitamin B12 deficiency should be excluded. # Adverse Reactions ## Clinical Trials Experience n a US double-blind clinical study of Metformin HCl in patients with type 2 diabetes, a total of 141 patients received Metformin HCl therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the Metformin HCl patients, and that were more common in Metformin HCl - than placebo-treated patients, are listed in Table 9. - Reactions that were more common in Metformin HCl -than placebo-treated patients. - Diarrhea led to discontinuation of study medication in 6% of patients treated with Metformin HCl. Additionally, the following adverse reactions were reported in ≥ 1.0 to ≤ 5.0% of Metformin HCl patients and were more commonly reported with Metformin HCl than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Pediatric Patients - In clinical trials with Metformin HCl in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults. ## Postmarketing Experience There is limited information regarding Metformin Postmarketing Experience in the drug label. # Drug Interactions Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin HCl) - Glyburide—In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. - Furosemide—A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically. - Nifedipine—A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. - Cationic drugs—Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Metformin HCl and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. - Other—Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Metformin HCl, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metformin HCl, the patient should be observed closely for hypoglycemia. - In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies. - Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed. - There are no adequate and well-controlled studies in pregnant women with Metformin HCl. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metformin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Metformin during labor and delivery. ### Nursing Mothers - Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, 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. If Metformin HCl is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use - The safety and effectiveness of Metformin HCl for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of Metformin HCl in this age group is supported by evidence from adequate and well-controlled studies of Metformin HCl in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. In this study, adverse effects were similar to those described in adults. A maximum daily dose of 2000 mg is recommended. ### Geriatic Use - Controlled clinical studies of Metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metformin HCl should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Metformin HCl should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Metformin HCl. ### Gender - There is no FDA guidance on the use of Metformin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Metformin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Metformin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Metformin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Metformin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Metformin in patients who are immunocompromised. # Administration and Monitoring ### Administration - There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin HCl, USP or any other pharmacologic agent. Dosage of Metformin HCl, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Metformin HCl, USP is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age). - Metformin HCl, USP should be given in divided doses with meals. Metformin HCl, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. - During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to Metformin HCl, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Metformin HCl, USP, either when used as monotherapy or in combination with sulfonylurea or insulin. - Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. - Short-term administration of Metformin HCl, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Recommended Dosing Schedule - Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. - The usual starting dose of Metformin HCl Tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin HCl, USP may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals. - If higher doses of metformin are required, Metformin HCl, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. - Pediatrics - The usual starting dose of Metformin HCl, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. Transfer From Other Antidiabetic Therapy - When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin HCl, USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant Metformin HCl, USP and Oral Sulfonylurea Therapy in Adult Patients - If patients have not responded to four weeks of the maximum dose of Metformin HCl, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin HCl, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). - With concomitant Metformin HCl, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Metformin HCl, USP 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of Metformin HCl, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Metformin HCl, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. - If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of Metformin HCl, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin HCl, USP. Concomitant Metformin HCl, USP and Insulin Therapy in Adult Patients - The current insulin dose should be continued upon initiation of Metformin HCl, USP therapy. Metformin HCl, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Metformin HCl, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Metformin HCl, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin HCl, USP. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations - Metformin HCl, USP is not recommended for use in pregnancy. Metformin HCl, USP is not recommended in patients below the age of 10 years. - The initial and maintenance dosing of Metformin HCl, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin HCl, USP. - Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.) ### Monitoring - Metformin HCl. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin HCl treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Metformin HCl should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. - Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCl. In patients with advanced age, Metformin HCl should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin HCl should not be titrated to the maximum dose. - Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control. - Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin HCl therapy, if this is suspected, Vitamin B12 deficiency should be excluded. # IV Compatibility There is limited information regarding the compatibility of Metformin and IV administrations. # Overdosage - Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. # Pharmacology ## Mechanism of Action - Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. ## Structure - Metformin Hydrochloride (HCl) Tablets, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin HCl, USP (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. - The structural formula is as shown: - Metformin HCl, USP is a white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.62. Metformin HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl, USP is 6.68. - Metformin HCl Tablets, USP, contains 500 mg, 850 mg, or 1000 mg of metformin HCl, USP. Each tablet contains the inactive ingredients povidone, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contain polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, gum acacia, maltodextrin, propylene glycol and natural flavors. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Metformin in the drug label. ## Pharmacokinetics Absorption and Bioavailability - The absolute bioavailability of a Metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of Metformin HCl 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. Distribution - The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin HCl 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Metformin HCl, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of Metformin HCl, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. Metabolism and Elimination - Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Patients with Type 2 Diabetes - In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses. Renal Insufficiency - In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS). Hepatic Insufficiency - No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. Geriatrics - Limited data from controlled pharmacokinetic studies of Metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin HCl Tablets treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. Pediatrics - After administration of a single oral Metformin HCl 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. Gender - Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of Metformin HCl was comparable in males and females. Race - No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of Metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24). Clinical Studies Metformin Hydrochloride - In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with Metformin HCl (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2). - A 29-week, double-blind, placebo-controlled study of Metformin HCl and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with Metformin HCl 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of Metformin HCl increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed Metformin HCl 2500 mg. Patients in the Metformin HCl only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking Metformin HCl 2000 mg/glyburide 20 mg or Metformin HCl 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to Metformin HCl (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of Metformin HCl and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were –77 mg/dL, – 68 mg/dL, and –1.9%, respectively (see Table 3). - The magnitude of the decline in fasting blood glucose concentration following the institution of - Metformin HCl Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin. - In clinical studies, Metformin HCl, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4). - In contrast to sulfonylureas, body weight of individuals on Metformin HCl tended to remain stable or even decrease somewhat (see Tables 2 and 3). - A 24-week, double-blind, placebo-controlled study of Metformin HCl plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive Metformin HCl plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, Metformin HCl plus insulin versus insulin plus placebo, respectively, p=0.04. - A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of Metformin HCl maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for Metformin HCl plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for Metformin HCl plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of Metformin HCl plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01. Pediatric Clinical Studies - In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with Metformin HCl (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 8). ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. - These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. - There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. - Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. # Clinical Studies There is limited information regarding Clinical Studies of Metformin in the drug label. # How Supplied - Metformin HCl Tablets, USP 500 mg are blackberry flavored, white to off-white, round, biconvex, film-coated tablets debossed “IP 218” on obverse and “500” on the reverse. - They are available as follows: - Bottles of 100: NDC 65162-218-10 - Bottles of 500: NDC 65162-218-50 - Bottles of 1000: NDC 65162-218-11 - Metformin HCl Tablets, USP 850 mg are blackberry flavored, white to off-white, round, biconvex, film-coated tablets debossed “IP 219” on obverse and “850” on the reverse. - They are available as follows: - Bottles of 100: NDC 65162-219-10 - Bottles of 500: NDC 65162-219-50 - Bottles of 1000: NDC 65162-219-11 - Metformin HCl Tablets, USP 1000 mg are blackberry flavored, white to off-white, oval, biconvex, bisected, film-coated tablets debossed “IP 220” on obverse and “1000” on the reverse. - They are available as follows: - Bottles of 100: NDC 65162-220-10 - Bottles of 500: NDC 65162-220-50 - Bottles of 1000: NDC 65162-220-11 ## Storage - Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature.] # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the potential risks and benefits of Metformin HCl and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. - The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Metformin HCl immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Metformin HCl, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. - Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Metformin HCl. - Metformin HCl alone does not usually cause hypoglycemia, although it may occur when Metformin HCl is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.) # Precautions with Alcohol - Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCl. # Brand Names Fortamet, Glucophage, Glucophage XR, Riomet, Glumetza. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fortamet
33b04a723fca0f1a6ad2fa123e9aca0c955b055f	wikidoc	Gum greft	Gum greft # Overview A gum graft or gingival graft (Also called Periodontal Plastic Surgery) is a generic name for multiple periodontal procedures that all aim to cover an area of severe gum recession with grafted gum tissue. The purpose of covering the exposed root is not only cosmetic, but also to prevent further recession, tooth sensitivity due to exposed roots and tooth decay on exposed root surfaces. These procedures are usually performed by a periodontist, a dental specialist in treatment of diseases of the gingiva (gums), however some non-specialists dentists may also have training in this area. # Specific procedures (Periodontal Plastic Surgery) A free gingival graft is a dental procedure where a layer of tissue is removed from the palate of the patient's mouth and then relocated to the site of gum recession. It is stitched into place and will serve to protect the exposed root as living tissue. The donor site will heal without damage. This procedure is often used to increase the thickness of very thin gum tissue. A subepithelial connective tissue graft takes tissue from under healthy gum tissue in the palate, which may be placed at the area of gum recession. This procedure has the advantage of excellent predictability of root coverage , as well as decreased pain at the palatal donor site compared to the free gingival graft. The subepithelial connective tissue graft is a very common procedure for covering exposed roots. An Acellular Dermal Matrix (Alloderm) graft uses donated medically-processed human skin tissue as a source for the graft. The advantage of this procedure is no need for a palatal donor site, however some periodontists believe it may be less successful , while others believe it is equally successful as a subepithlial connective tissue graft. A lateral pedicle graft, also known as a "pedicle" graft, takes tissue from the area immediately adjacent to the damaged gum. This is not always an option, as the constraint that there must be sufficient tissue immediately lateral to the area of interest is an onerous one. When this procedure is performed, the transplant tissue is cut away and rotated over the damaged area. This can place the donor area at risk of recession as well. A coronally positioned flap is another form of a "pedicle" graft in which gingival (gum) tissue is freed up and simply moved upwards on the tooth to cover the recession. This requires adequate thickness and width of gum tissue at the base of the recession defect.	Gum greft Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A gum graft or gingival graft (Also called Periodontal Plastic Surgery) is a generic name for multiple periodontal procedures that all aim to cover an area of severe gum recession with grafted gum tissue. The purpose of covering the exposed root is not only cosmetic, but also to prevent further recession, tooth sensitivity due to exposed roots and tooth decay on exposed root surfaces. These procedures are usually performed by a periodontist, a dental specialist in treatment of diseases of the gingiva (gums), however some non-specialists dentists may also have training in this area. # Specific procedures (Periodontal Plastic Surgery) A free gingival graft is a dental procedure where a layer of tissue is removed from the palate of the patient's mouth and then relocated to the site of gum recession. It is stitched into place and will serve to protect the exposed root as living tissue. The donor site will heal without damage. This procedure is often used to increase the thickness of very thin gum tissue. A subepithelial connective tissue graft takes tissue from under healthy gum tissue in the palate, which may be placed at the area of gum recession. This procedure has the advantage of excellent predictability of root coverage [1], as well as decreased pain at the palatal donor site compared to the free gingival graft. The subepithelial connective tissue graft is a very common procedure for covering exposed roots. An Acellular Dermal Matrix (Alloderm) graft uses donated medically-processed human skin tissue as a source for the graft. The advantage of this procedure is no need for a palatal donor site, however some periodontists believe it may be less successful [2], while others believe it is equally successful as a subepithlial connective tissue graft. [3] A lateral pedicle graft, also known as a "pedicle" graft, takes tissue from the area immediately adjacent to the damaged gum. This is not always an option, as the constraint that there must be sufficient tissue immediately lateral to the area of interest is an onerous one. When this procedure is performed, the transplant tissue is cut away and rotated over the damaged area. This can place the donor area at risk of recession as well. A coronally positioned flap is another form of a "pedicle" graft in which gingival (gum) tissue is freed up and simply moved upwards on the tooth to cover the recession. This requires adequate thickness and width of gum tissue at the base of the recession defect.	https://www.wikidoc.org/index.php/Free_gingival_graft
bf423f321a1926dcca7445a23ec528c009279ea1	wikidoc	Frostbite	Frostbite # Overview Frostbite (congelatio in medical terminology) is a freezing, cold thermal injury, which occurs on being exposed to temperatures below the freezing point of typically −0.55°C to as high as 2°C for a sustained period of time. It is a condition characterized by the consequences in terms of functional morbidity among the panel of population that are often young, fit and healthy prior to sustaining thermal injury. Currently, the prevalence of frostbite is increasing within the civilian population, particularly among those who partake in winter sports such as skiing, hiking, mountain and ice climbing. The outdoor activities are more accessible so the individuals with limited experience or inadequate preparation and protection are highly prone to it. Additionally, vagrancy, homelessness, industrial injury and malfunctioning or misuse of equipment using NO or CO2 have also been causative factors. Cutaneous circulation plays an important role in thermoregulation by varying blood flow through peripheral structures to maintain core body temperature for survival. In a cold environment, maximal vasoconstriction is reached in hands and feet when their temperature drops to 15° C which is followed by local protective cycles of vasodilation on persistence of freezing temperature; but leads to progressive local ischemia if further exposure continues. However, thawing restores blood flow; but induces congestion, inflammation and thrombosis in the injured endothelium which may prompt erythrocyte extravasation due to distorted vessel wall. According to the depth of the skin damage, necrosis can be deeply severe which can results in spontaneous or surgical amputation. Frostbite can present with a wide spectrum of injury ranging from complete resolution without significant sequelae to major limb amputation and its functional consequences. Timely pre-hospital and definitive hospital management are important to minimize final tissue loss and maximize functionality of the affected limb. Once in the hospital setting, a multidisciplinary approach must be utilized to achieve the best outcomes. Either intravenous iloprost or thrombolysis with rTPA should be considered in all patients presenting within 24 h of sustaining an appropriately severe injury, and if the facility is capable of appropriate administration and monitoring. The treatment should be started with an immediate action to have a maximal output. Bone scanning is helpful to ascertain deep tissue injury and response to therapy. However, surgeons should avoid rushing to an early amputation; if case managed correctly in the earlier days, significant tissue can be salvaged for the final functional outcome. Prevention with education, behavior modification, following workplace guidelines, and appropriate use of modern equipment in most adventurous tourist destinations is important to reduce frostbite incidence. Once frostbite injury has occurred, little can be done to reverse the changes. Hence, a great preventive care should be taken to avoid its incidence. # Historical Perspective - 5,000 years ago: An earliest evidence of frostbite was documented among pre-Columbian mummy discovered in the Andes. - 218 BC: Hannibal lost nearly half his army of 46,000 to frostbite injuries over a two week period of crossing the Southern Alps to reach Italy. - 1778: Dr. James Thatcher reported that Washington lost 10% of his army to cold-related tissue casualties during the winter times of the Revolutionary War. - 1812–1813: Baron Dominique Jean Larrey, Surgeon-in-Chief to Napoleon's Army, reported the first systematic medical observations of frostbite during the ill-fated invasion of Moscow during the fall season, and the subsequent retreat in a harsh Russian winter. He noted the deleterious effects of the freeze–thaw–refreeze cycle by identifing the debilitating effects of daily refreezing that occurred with bonfire thawing and subsequent marching in frigid conditions. He further stated that warming was beneficial; however, not by using the excessive heat of fires. Hence, he concluded the friction massage with snow or ice which results in slow rewarming is an optimal therapeutic standard of care for frostbite in military medicine and practiced for more than 100 years. - 1930:During World War II, both German and Russian troops moved to a philosophy of rapid rewarming based on work conducted at the Kirov Institute. - 1941–1942: German troops sustained an estimated 250,000 frostbite injuries in the attempt to take over Moscow; and hence, constitutes the largest reported number of frostbite related injuries in history. Moreover, it was reported that the German army alone performed more than 15,000 amputations for cold related injuries on the Russian front during the winter season. - 1960: Mills published the first major clinical experience with rapid rewarming and included a concept of preventive care for frostbite with his report. # Classification - Frostbite has been divided into 4 tiers or degrees of injury based on acute physical findings and advanced imaging after rewarming following the classification scheme for thermal burn injury. However, these categories are difficult to use in the field and before rewarming as the still-frozen tissue is hard, pale, and anesthetic. Hence, an alternate 2-tiered classification has been proposed for the field use. Table 1: A two and four tiers classification scheme for Frostbite Table 2: Classification scheme for the frostbite injuries of the extremity # Pathophysiology - The rate of normal skin blood flow is about 250 ml/min, however; the flow drops to less than 20-50 ml/min during frostbite. As the temperature drops to below 0°C, the stasis of blood flow occurs especially in the slower venous system before the arterial system which subsequently leads to the cellular damage and results in reversible or irreversible injuries depending upon the extent of the exposure. - Normal physiological responses to the cold environment: Aim: To conserve the internal body core temperature and the viability of the extremities. Peripheral vasoconstriction: It is caused by sympathetic stimulation and catecholamine release which reduces the heat loss. Shivering: It is a muscular activity which maintain or augment the body heat; however, it cannot be sustained for more than a few hours because of the depletion of glycogen, which is the source of heat during shivering. Hunting reaction: It protects the extremities by the process of irregular 5 to 10-minute cycles of alternating vasoconstriction and vasodilation against excessive sustained peripheral vasoconstriction with minimal loss of internal body temperature. However, this mechanism fails when the body is exposed to freezing temperature of a magnitude or a duration that disrupt the internal body temperature maintenance because of the following reasons: - Aim: To conserve the internal body core temperature and the viability of the extremities. - Peripheral vasoconstriction: It is caused by sympathetic stimulation and catecholamine release which reduces the heat loss. - Shivering: It is a muscular activity which maintain or augment the body heat; however, it cannot be sustained for more than a few hours because of the depletion of glycogen, which is the source of heat during shivering. - Hunting reaction: It protects the extremities by the process of irregular 5 to 10-minute cycles of alternating vasoconstriction and vasodilation against excessive sustained peripheral vasoconstriction with minimal loss of internal body temperature. - However, this mechanism fails when the body is exposed to freezing temperature of a magnitude or a duration that disrupt the internal body temperature maintenance because of the following reasons: - Disruption of body core temperature is more deleterious than peripheral vasoconstriction; - Conservation of core temperature takes precedence over rewarming of the extremities; - The hunting response is replaced by continuous and more intense vasoconstriction resulting in frostbite via ice crystal formation, cellular dehydration, and microvasculature thrombosis. - Four pathophysiological phases: Frostbite occurs through four interconnected progressive processes depending upon the rate and duration of freezing, rate of rewarming, and anatomic extent of exposure. - Prefreeze phase: The tissue cooling leads to local vasoconstriction and ischemia which results in the neuronal effects of hyperesthesia and paresthesia. - Freeze thaw phase: The cellular changes observed during freezing include extracellular ice formation, intracellular ice formation, cell dehydration and crenation, abnormal electrolyte concentrations due to altered oncotic pressures, and perturbations in lipid–protein complexes. However, the body initially responds to tissue freezing with alternating cycles of vasodilation and vasoconstriction (the “hunting reaction”) which lead to cycles of partial thawing and a prothrombotic microenvironment. Subsequently, rewarming melts ice crystals, promotes edema from injured endothelium, forms epidermal blisters and free radicals which continues the insult further. Additionally, an elaboration of inflammatory mediators, prostaglandins, and thromboxanes induces vasoconstriction and causes the vascular stasis period. - Vascular stasis phase: The persistence of the local vasoconstriction causes hypoxia and acidotic damage to the endothelium; and promotes coagulation and interstitial edema. Since, the vascular endothelium is highly susceptible; it may be completely obliterated and replaced by fibrin deposition 72 hours after the phase of freezing and thawing. The electron microscopic further shows an evidence of perivascular fluid extravasation and endothelial swelling and lysis. - Ischemic phase: Finally, hypoxia, endothelial injury, and local thrombosis lead to the late ischemic phase, in which inflammatory mediators such as prostaglandins, thromboxanes, bradykinins, and histamine trigger additional vasoconstriction, platelet aggregation, and vessel thrombosis. As these inflammatory mediators peak during rewarming, the cycles of refreezing and rewarming can worsen the extent of tissue loss. Therefore, an initial frostbite treatment is targeted at restoring perfusion to the affected limb(s) and limiting tissue loss after rewarming. # Differentiating Frostbite from other Diseases - Various types of cold injury can mimic each other which are categorized into hypothermia, tissue-freezing injury (frostbite), non–tissue-freezing injury (frostnip, trenchfoot, chilblain, or pernio) in the following Table. Table 3: List of differential diagnosis for the Frostbite # Epidemiology and Demographics - Age: Although the elderly and young children are highly susceptible to the frostbite injury; however, the published epidemiological studies showed that frostbite is uncommon in these age groups and instead tends to affect adults between the ages of 30–49 years. - Anatomic location: The feet and the hands account for 90% of injuries reported. Other includes the face (nose, chin, earlobes, cheeks and lips), buttocks/perineum (from sitting on metal seats) and penis (joggers,runners and Nordic skiers). - A 12 year review on the inpatient frostbite injuries conducted in Saskatchewan, Canada revealed the incidence of predisposing factors in a decreasing order: Alcohol consumption (46%), psychiatric illness (17%), vehicular failure (19%), and drug misuse (4%). - Alcohol: It causes heat loss through peripheral vasodilatation and deranged judgement which may results in not seeking timely adequate shelter and consequently turns to a higher level of injury. # Risk Factors - Various behavioural, physiological and mechanical factors play an important roles in increasing the likelihood of its development and the extent of the damage. Table 4: Factors that increases risk for frostbite # Complications and late sequelae - Most common: Complex regional pain syndrome and arthritis - Late or chronic sequelae (70%): Infection, increased cold sensitivity, hyperhydrosis, numbness, skin pigmentation, abnormalities of the nails, joint stiffness, and premature closure of physeal growth plate in children. - Skin areas affected by frostbite are susceptible to chronic ulceration due to poor tissue quality after healing; and can undergo a malignant transformation akin to the formation of Marjolin's ulcers similar to old burn scars. - Frostbite Arthropathy: In the growing child, frostbite produces a characteristic growth stunting of the small bones through premature closure of physeal growth plate and acro-osteolysis. Additionally, secondary osteoarthritic changes may be seen in early adulthood. # Prognosis - Favourable prognostic factors: Retained sensation, normal skin colour, and clear rather than cloudy fluid in the blisters, early edema formation and clear blisters extending to the tips of the digits are considered favourable sign. - Poor prognostic factors: Non-blanching cyanosis, firm skin, lack of edema, and small, proximal, dark haemorrhagic vesicles indicates damage to the subdermal vascular plexus. - However, no prognostic features are entirely predictive; and weeks or months may pass before the demarcation between viable and non-viable tissue becomes visible. - Hence, patients should avoid cold exposure for up to a year after the initial injury. # Diagnosis ## Clinical Symptoms - Severity of symptoms is directly proportional to the severity of injury. - Initial presenting complaint: A cold numbness associated with a sensory loss, the extremities are cold to the touch, and patients complains of clumsiness, ‘‘like a block of wood’’. Thawing and reperfusion are often accompanied by intense pain. - At 2-3 days: A throbbing pain begins after rewarming and may persist for weeks or months even after the tissue becomes demarcated. - At a week: A residual tingling sensation appears probably due to an ischemic neuritis. However, a variable presentation can be seen with no painful sensation especially among diabetics with previous neuropathic damage. - Symptoms usually subside within 1 month in mild cases of no tissue loss; contrarily, in cases with severe tissue loss, disablement may exceed 6 months. Usually frostbite victims experience some degree of sensory loss for at least 4 years or indefinitely post injury. - Aggravating factor: Symptoms gets exacerbated by a warm environment. - Other sensory deficits: Spontaneous burning and electric current-like sensations in the affected body areas. ## Clinical Signs - Frostbite is a clinical diagnosis. - However, initial injuries appear similar and make it difficult to determine the severity or grade of injury until post rewarming. - The extent of the freezing and tissue loss may not be apparent for 4 to 5 days. - Frostbite injuries can be classified clinically as either superficial or deep. Superficial injuries: It may appear as either a numb central white plaque with surrounding erythema, or as blisters filled with clear or milky fluid with surrounding erythema and edema. Deep injuries: It is characterized by either hemorrhagic blisters that develop into a black eschar in 2 weeks or have a complete tissue loss and necrosis. Final tissue demarcation may take 3 to 4 weeks to establish. The appearance of the skin, sensation to pinprick, and whether the vesicles are clear or hemorrhagic should be noted. Identify signs of dehydration, hypothermia, altitude effects (pulmonary edema), and exhaustion. - Superficial injuries: It may appear as either a numb central white plaque with surrounding erythema, or as blisters filled with clear or milky fluid with surrounding erythema and edema. - Deep injuries: It is characterized by either hemorrhagic blisters that develop into a black eschar in 2 weeks or have a complete tissue loss and necrosis. Final tissue demarcation may take 3 to 4 weeks to establish. The appearance of the skin, sensation to pinprick, and whether the vesicles are clear or hemorrhagic should be noted. Identify signs of dehydration, hypothermia, altitude effects (pulmonary edema), and exhaustion. - Rewarming injuries: During rewarming, edema may start to appear within 3-5 hours and may last 7 days. Blisters tend to appear within 4-24 hours. Presence of eschar will be obvious at 10-15 days and mummification with a line of demarcation may develop in 3-8 weeks. ## Diagnostic modality - The primary role of imaging in frostbite injuries is to define the precisely the severity, depth, and extent of tissue injury to better direct nonsurgical and surgical treatment. Additionally, imaging plays an important role in monitoring response to the provided treatment. Table 5: Elaborates the different imaging modality used for Frostbite - Other miscellaneous tests: Infrared thermography, laser doppler studies, digital plethysmography and magnetic resonance imaging/ magnetic resonance angiography. # Treatment - Almost all patients should be admitted to hospital; considering alcohol intoxication, psychiatric illness, and homelessness as the common features of the frostbite patient; an immediate discharge is rarely prudent. Hence, treatment of frostbite can be divided into three phases: prethaw field care phase, immediate hospital care phase, and postthaw phase. ## Field Treatment - If a body part found frozen in the field area, it should be protected from further damage with the following measures: - The patient should be immediately moved out of the wind, provided with shelter and given warm fluids. - Remove boots but the problems of replacement can arise if swelling occurs, and replace wet gloves and socks with dry ones. Warm the cold extremity by placing them in a companion's armpit or groin for 10 min and then replace the boots/gloves. Rubbing the affected part is not recommended because of the potential for worsening direct tissue injury. - If sensation returns, the patient may mitigate the further risks and continue to walk. If there is no return of sensation, the injured should go to the nearest warm shelter (hut or base camp) and seek medical treatment. If at high altitude (>4,000 m), supplementary oxygen should be considered. - Aspirin 75 mg can be given for its rheologic effect. Ibuprofen 12 mg/kg/day divided into two daily doses (maximum of 2,400 mg/day) should be given for its prostaglandin effect. - Field rewarming should only be attempted if there is no further risk of refreezing as the cycle of thawing and refreezing results in a more extensive injury. - The decision to thaw the frostbitten tissue in the field may involve pain control, maintaining warm water baths at a constant temperature, protecting tissue from further injury during rewarming, and eventual transport. - In extreme scenarios, it may be better to let a casualty walk on a frozen limb to safety rather than risk refreezing. ## Immediate hospital care - The standard approach to the initial treatment of frostbite is the strategy originally outlined by McCauley and Heggers as mentioned below: - Admit frostbite patient to specialist unit if possible - Evaluate for hypothermia, concomitant injury, or complicating problems - On admission, rapidly rewarm the affected areas in warm water at 37–39°C (99–102°F) for 15–30 mins or until thawing is complete - Debride clear or white blisters and apply topical aloe vera (Dermaide aloe) every 6 h - Leave haemorrhagic blisters intact and apply topical aloe vera every 6 h - Splint and elevate the extremity - Administer antitetanus prophylaxis (toxoid or immunoglobulin (Ig)) - Analgesia: opiate (intravenously or intramuscularly) as indicated - Administer ibuprofen 400 mg orally every 12 h - Administer benzyl penicillin 500 000 U every 6 h for 48–72 h - Administer daily hydrotherapy in 40°C water for 30–45 mins. Do not towel dry affected tissue. - Prohibit smoking ## Fluids - Rehydration can be provided orally or intravenously depending upon severity and ability of the patient to accept the warm fluids. - Oral fluids should be given if the patient is alert and has no gastrointestinal symptoms. - In case of nausea, vomiting, or an altered mental status; IV normal saline should be given if available. - High altitude increases the risk of dehydration. A hypothermia in combination to dehydration may be compounded by cold diuresis due to suppression of antidiuretic hormone which mandates the replenishment with intravenous fluids. - Intravenous fluids should be warmed before infusion if possible; and should be infused in small boluses as slower infusion will result in fluid cooling as it passes through the IV tubing. - Volume status should be optimized as per the signs of clinical dehydration. ## Rewarming - Hypothermia and concomitant injury should be thoroughly evaluated. - Systemic hypothermia should be corrected to a core temperature of 34°C before frostbite management is initiated. - Rewarming should be carried out in a whirlpool of recirculating water with a mild antibacterial solutions (povidone-iodine or chlorhexidine). - The State of Alaska Cold-injury Guidelines recommend a lower temperature water bath of 37–39°C which decreases the patient pain with slightly slowing the rewarming process. - The time period recommended for rewarming varies from 15–30 mins up to 1 h. - Rewarming should continue until a red/purple color appears and the extremity becomes pliable. - Active motion during the rewarming period is beneficial but care should be taken to prevent the extremity from touching the sides of the whirlpool. - It is important to provide good analgesic cover by including narcotic medication. ## Blisters and dressings - Blisters containing clear or milky fluid should be debrided and covered every 6 h with aloe vera ointment, a potent anti-prostaglandin agent. - Splinting, elevating, and wrapping the affected part in a loose and protective dressing should follow the administration of the aloe vera cream. - Padding should be put between the patient’s toes if affected. - Haemorrhagic blisters should be left intact to prevent desiccation of the underlying tissue. If they restrict movement, they can be drained with their roofs left on. ## Antibiotics - Frostbite is not an inherently infection-prone injury. Therefore, the use of antibiotics specifically for preventing infection during or after frostbite injury is still controversial. - However, when associated with significant edema or malnutrition due to homelessness, chronic alcohol abuse or return from extreme altitude; penicillin is administered as edema deranges the skin bactericidal properties. - Additionally, systemic antibiotics are administered in the presence of proven infection, trauma or cellulitis. ## Tetanus toxoid - Tetanus prophylaxis should be done as per the standard guidelines. ## Analgesia and NSAIDs - Rewarming the extremities can be extremely painful process, so use of NSAID drugs or opiates should be administered. - Oral ibuprofen 12 mg/kg divided over two daily doses provides systemic anti-prostaglandin activity that limits the cascade of inflammatory damage. This dose can be increased to a maximum of 2,400 mg/day if the patient is still experiencing pain, and can be continued until wounds are healed or amputation occurs. A dose of 400 mg BID is a practical regime to start with the most patients, but it can be increased later on to 600 mg QDS as pain dictates. - If aspirin has not been given in the field, 300 mg once a day can be given provided no contraindications. However, aspirin is less useful as it prolongs blockade of all prostaglandin synthesis and some prostacyclins that are considered beneficial for wound healing. - The role of clopidogrel in frostbite has yet to be assessed. ## Definitive treatment Angiography and thrombolysis - rTPA delivery should be provided at a centre accustomed to performing thrombolysis and providing adequate monitoring in a critical care/high-dependency setting. - If the patient presents less than 24 h after injury to a hospital without these facilities, consider urgent transfer to avoid further delay in the commencement of therapy. - An initial selective diagnostic DSA should be performed in patients being considered for thrombolysis. - Intravenous vasodilators such as nitroglycerin or papaverine are useful in conjunction with rTPA to treat the vasospasm associated with a frostbite injury. - rTPA is used in combination with heparin which reduces the recurrence of microvascular thrombosis. - Repeat angiograms should be performed every 12–24 h to evaluate response to therapy. - rTPA treatment should be discontinued when perfusion is restored to distal vessels or at 48 h if no improvement is observed. Table 6: Enumuerates the protocol for intravenous rTPA Vasodilators: Iloprost - Iloprost is a prostacyclin analogue with vasodilatory properties that mimic the effects of a sympathectomy. Additionally, it may affect platelet aggregation and hence, decrease microvascular occlusion. Table 7: Protocol of intravenous prostacyclin ## Surgery Fasciotomies - Early surgical intervention in the form of fasciotomy in the immediate post-thaw phase is required if compartment syndrome compromises the reperfusion. Amputation - Angiography, technetium-99 bone scan and/or magnetic resonance imaging may be used to assist determination of surgical margins in conjunction with clinical findings. - An early amputation is indicated occasionally if liquefaction, moist gangrene, or overwhelming infection and sepsis develops. - Otherwise, amputation should be delayed until definitive demarcation occurs which takes around 6–12 weeks. - Negative pressure devices can aid in speeding up healing of amputation sites by secondary intention. - The healed affected limb is often insensate. Hence, an approach that addresses both protective footwear and orthotics to provide optimal limb function is essential. ## Tissue protection - The functional use of extremities following a partial amputation is variable and injury specific. - The biomechanics of the foot/hand can be radically altered and frostbite neuropathy can compound the problem; hence, liaison with orthotic/podiatry department to provide custom-made footwear may be required to optimize the long-term limb functional result and minimize secondary injuries. ## Adjuvant therapies Hyperbaric oxygen therapy (HBOT) - Benefits of HBOT in frostbite are as follows: It reverses vasoconstriction in ischemic tissue and the resulting hyperoxia from oxygen dissolved in plasma surpasses any potential blood flow reduction. It increases a diffusion distance and improves oxygenation in hypoxic tissue. Angiogenesis is also promoted by HBOT which further reduces edema and necrosis in hypoxic skeletal muscle by improving the blood supply. It increases the deformability of erythrocytes, has a bacteriostatic effect and may act as an antioxidant. It delineates the viable tissue from necrotic part and allows marginal tissue to be maintained until revascularization has been established. - It reverses vasoconstriction in ischemic tissue and the resulting hyperoxia from oxygen dissolved in plasma surpasses any potential blood flow reduction. - It increases a diffusion distance and improves oxygenation in hypoxic tissue. - Angiogenesis is also promoted by HBOT which further reduces edema and necrosis in hypoxic skeletal muscle by improving the blood supply. - It increases the deformability of erythrocytes, has a bacteriostatic effect and may act as an antioxidant. - It delineates the viable tissue from necrotic part and allows marginal tissue to be maintained until revascularization has been established. - However, HBOT showed mixed results with no level 1 evidence available. Hence, its role warrants further investigation as it is a relatively safe and inexpensive treatment. Sympathectomy - The role of sympathectomy, either surgical (via open or minimally invasive) or chemical, has yielded mixed results. - Early sympathectomy, performed within the first few hours of injury, has led to increase in edema formation and tissue destruction. - However, if performed 24–48 h after thawing, it is considered to hasten resolution of edema and decrease tissue loss. - Sympathectomy may prevent some long term sequelae such as pain due to vasospasm, paresthesias and hyperhidrosis. - However, since the advent of alternative therapies such as rTPA and Iloprost, and being irreversible nature of sympathectomy procedure, a great caution should be exercised while considering its use; and hence, some consider no role for its use in frostbite. ## Telemedicine - A recent development in accessing expert advice by the use of the internet and satellite phones has been driven both by the patients and the clinicians with a limited experience of frostbite. A virtual opinion can be sought from any remote or difficult situations in the world. - The UK based service can be accessed via the Diploma in Mountain Medicine or the British Mountaineering Council websites which is run by Diploma Faculty Members and is being increasingly used by climbers and physicians worldwide, often to obtain a second opinion or to seek more specialized advice. - Patients can be readily followed up in a ‘‘virtual clinic’’ by reviewing recent digital images and discussing management options either by phone or via email. # Primary Prevention - As in many instances, it can be prevented so the key is deterrence and patient education. Risk modification including proper clothing, access to shelter, and maintaining hydration and nutrition are vital for protection against frostbite. Patients should be advised to carry extra clothing supplies if they are into winter sports and avoid tight restrictive clothing. Emollients, although traditionally believed in Nordic countries to prevent frostbite, do not have protective effects in preventing frostbite and should be discouraged. Advise against the abuse of alcohol, illicit drugs, and tobacco. For those with medical conditions, it is important to ensure that their health is stable before venturing on an adventurous outdoor trip during winter. - Risk modification including proper clothing, access to shelter, and maintaining hydration and nutrition are vital for protection against frostbite. - Patients should be advised to carry extra clothing supplies if they are into winter sports and avoid tight restrictive clothing. - Emollients, although traditionally believed in Nordic countries to prevent frostbite, do not have protective effects in preventing frostbite and should be discouraged. - Advise against the abuse of alcohol, illicit drugs, and tobacco. - For those with medical conditions, it is important to ensure that their health is stable before venturing on an adventurous outdoor trip during winter. - Prolonged exposure to freezing cold temperatures may cause serious health problems so if signs related to it are observed, call for emergency help. - The Occupational Safety and Health Act (OSHA) Cold Stress Card provides a reference guide and recommendations to combat and prevent many illnesses and injuries. Available in English and Spanish, this laminated fold-up card is free to employers, workers and the public. - Tips include how to protect workers: Recognize the environmental and workplace conditions that may be dangerous. Learn the signs and symptoms of cold-induced illnesses and injuries and what to do to help workers. Train workers about cold-induced illnesses and injuries. Encourage workers to wear proper clothing for cold, wet and windy conditions, including layers that can be adjusted to changing conditions. Be sure workers in extreme conditions take a frequent short break in warm dry shelters to allow their bodies to warm up. Try to schedule work for the warmest part of the day. Avoid exhaustion or fatigue because energy is needed to keep muscles warm. Use the buddy-system, work in pairs so that one worker can recognize danger signs. Drink warm, sweet beverages (sugar water, sports-type drinks) and avoid drinks with caffeine (coffee, tea, sodas or hot chocolate) or alcohol. Eat warm, high-calorie foods such as hot pasta dishes. Remember, workers are at an increased risks who takes certain medications, are in poor physical condition or suffer from illnesses such as diabetes, hypertension or cardiovascular disease. - Recognize the environmental and workplace conditions that may be dangerous. - Learn the signs and symptoms of cold-induced illnesses and injuries and what to do to help workers. - Train workers about cold-induced illnesses and injuries. - Encourage workers to wear proper clothing for cold, wet and windy conditions, including layers that can be adjusted to changing conditions. - Be sure workers in extreme conditions take a frequent short break in warm dry shelters to allow their bodies to warm up. - Try to schedule work for the warmest part of the day. - Avoid exhaustion or fatigue because energy is needed to keep muscles warm. - Use the buddy-system, work in pairs so that one worker can recognize danger signs. - Drink warm, sweet beverages (sugar water, sports-type drinks) and avoid drinks with caffeine (coffee, tea, sodas or hot chocolate) or alcohol. - Eat warm, high-calorie foods such as hot pasta dishes. - Remember, workers are at an increased risks who takes certain medications, are in poor physical condition or suffer from illnesses such as diabetes, hypertension or cardiovascular disease.	Frostbite Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jaspinder Kaur, MBBS[2] # Overview Frostbite (congelatio in medical terminology) is a freezing, cold thermal injury, which occurs on being exposed to temperatures below the freezing point of typically −0.55°C to as high as 2°C for a sustained period of time. It is a condition characterized by the consequences in terms of functional morbidity among the panel of population that are often young, fit and healthy prior to sustaining thermal injury. Currently, the prevalence of frostbite is increasing within the civilian population, particularly among those who partake in winter sports such as skiing, hiking, mountain and ice climbing. The outdoor activities are more accessible so the individuals with limited experience or inadequate preparation and protection are highly prone to it. Additionally, vagrancy, homelessness, industrial injury and malfunctioning or misuse of equipment using NO or CO2 have also been causative factors. Cutaneous circulation plays an important role in thermoregulation by varying blood flow through peripheral structures to maintain core body temperature for survival. In a cold environment, maximal vasoconstriction is reached in hands and feet when their temperature drops to 15° C which is followed by local protective cycles of vasodilation on persistence of freezing temperature; but leads to progressive local ischemia if further exposure continues. However, thawing restores blood flow; but induces congestion, inflammation and thrombosis in the injured endothelium which may prompt erythrocyte extravasation due to distorted vessel wall. According to the depth of the skin damage, necrosis can be deeply severe which can results in spontaneous or surgical amputation. Frostbite can present with a wide spectrum of injury ranging from complete resolution without significant sequelae to major limb amputation and its functional consequences. Timely pre-hospital and definitive hospital management are important to minimize final tissue loss and maximize functionality of the affected limb. Once in the hospital setting, a multidisciplinary approach must be utilized to achieve the best outcomes. Either intravenous iloprost or thrombolysis with rTPA should be considered in all patients presenting within 24 h of sustaining an appropriately severe injury, and if the facility is capable of appropriate administration and monitoring. The treatment should be started with an immediate action to have a maximal output. Bone scanning is helpful to ascertain deep tissue injury and response to therapy. However, surgeons should avoid rushing to an early amputation; if case managed correctly in the earlier days, significant tissue can be salvaged for the final functional outcome. Prevention with education, behavior modification, following workplace guidelines, and appropriate use of modern equipment in most adventurous tourist destinations is important to reduce frostbite incidence. Once frostbite injury has occurred, little can be done to reverse the changes. Hence, a great preventive care should be taken to avoid its incidence. # Historical Perspective - 5,000 years ago: An earliest evidence of frostbite was documented among pre-Columbian mummy discovered in the Andes.[1] - 218 BC: Hannibal lost nearly half his army of 46,000 to frostbite injuries over a two week period of crossing the Southern Alps to reach Italy. [2] - 1778: Dr. James Thatcher reported that Washington lost 10% of his army to cold-related tissue casualties during the winter times of the Revolutionary War. [2] - 1812–1813: Baron Dominique Jean Larrey, Surgeon-in-Chief to Napoleon's Army, reported the first systematic medical observations of frostbite during the ill-fated invasion of Moscow during the fall season, and the subsequent retreat in a harsh Russian winter. He noted the deleterious effects of the freeze–thaw–refreeze cycle by identifing the debilitating effects of daily refreezing that occurred with bonfire thawing and subsequent marching in frigid conditions. He further stated that warming was beneficial; however, not by using the excessive heat of fires. Hence, he concluded the friction massage with snow or ice which results in slow rewarming is an optimal therapeutic standard of care for frostbite in military medicine and practiced for more than 100 years. [3] - 1930:During World War II, both German and Russian troops moved to a philosophy of rapid rewarming based on work conducted at the Kirov Institute.[4] [5] - 1941–1942: German troops sustained an estimated 250,000 frostbite injuries in the attempt to take over Moscow; and hence, constitutes the largest reported number of frostbite related injuries in history. Moreover, it was reported that the German army alone performed more than 15,000 amputations for cold related injuries on the Russian front during the winter season.[4] - 1960: Mills published the first major clinical experience with rapid rewarming and included a concept of preventive care for frostbite with his report.[6] # Classification - Frostbite has been divided into 4 tiers or degrees of injury based on acute physical findings and advanced imaging after rewarming following the classification scheme for thermal burn injury. However, these categories are difficult to use in the field and before rewarming as the still-frozen tissue is hard, pale, and anesthetic. Hence, an alternate 2-tiered classification has been proposed for the field use. [7] Table 1: A two and four tiers classification scheme for Frostbite Table 2: Classification scheme for the frostbite injuries of the extremity[8] # Pathophysiology - The rate of normal skin blood flow is about 250 ml/min, however; the flow drops to less than 20-50 ml/min during frostbite. As the temperature drops to below 0°C, the stasis of blood flow occurs especially in the slower venous system before the arterial system which subsequently leads to the cellular damage and results in reversible or irreversible injuries depending upon the extent of the exposure. - Normal physiological responses to the cold environment:[9] Aim: To conserve the internal body core temperature and the viability of the extremities. Peripheral vasoconstriction: It is caused by sympathetic stimulation and catecholamine release which reduces the heat loss. Shivering: It is a muscular activity which maintain or augment the body heat; however, it cannot be sustained for more than a few hours because of the depletion of glycogen, which is the source of heat during shivering. Hunting reaction: It protects the extremities by the process of irregular 5 to 10-minute cycles of alternating vasoconstriction and vasodilation against excessive sustained peripheral vasoconstriction with minimal loss of internal body temperature. However, this mechanism fails when the body is exposed to freezing temperature of a magnitude or a duration that disrupt the internal body temperature maintenance because of the following reasons: - Aim: To conserve the internal body core temperature and the viability of the extremities. - Peripheral vasoconstriction: It is caused by sympathetic stimulation and catecholamine release which reduces the heat loss. - Shivering: It is a muscular activity which maintain or augment the body heat; however, it cannot be sustained for more than a few hours because of the depletion of glycogen, which is the source of heat during shivering. - Hunting reaction: It protects the extremities by the process of irregular 5 to 10-minute cycles of alternating vasoconstriction and vasodilation against excessive sustained peripheral vasoconstriction with minimal loss of internal body temperature. - However, this mechanism fails when the body is exposed to freezing temperature of a magnitude or a duration that disrupt the internal body temperature maintenance because of the following reasons: - Disruption of body core temperature is more deleterious than peripheral vasoconstriction; - Conservation of core temperature takes precedence over rewarming of the extremities; - The hunting response is replaced by continuous and more intense vasoconstriction resulting in frostbite via ice crystal formation, cellular dehydration, and microvasculature thrombosis. - Four pathophysiological phases: Frostbite occurs through four interconnected progressive processes depending upon the rate and duration of freezing, rate of rewarming, and anatomic extent of exposure. [10] - Prefreeze phase: The tissue cooling leads to local vasoconstriction and ischemia which results in the neuronal effects of hyperesthesia and paresthesia.[11] - Freeze thaw phase: The cellular changes observed during freezing include extracellular ice formation, intracellular ice formation, cell dehydration and crenation, abnormal electrolyte concentrations due to altered oncotic pressures, and perturbations in lipid–protein complexes. However, the body initially responds to tissue freezing with alternating cycles of vasodilation and vasoconstriction (the “hunting reaction”) which lead to cycles of partial thawing and a prothrombotic microenvironment. Subsequently, rewarming melts ice crystals, promotes edema from injured endothelium, forms epidermal blisters and free radicals which continues the insult further. Additionally, an elaboration of inflammatory mediators, prostaglandins, and thromboxanes induces vasoconstriction and causes the vascular stasis period.[12] - Vascular stasis phase: The persistence of the local vasoconstriction causes hypoxia and acidotic damage to the endothelium; and promotes coagulation and interstitial edema. Since, the vascular endothelium is highly susceptible; it may be completely obliterated and replaced by fibrin deposition 72 hours after the phase of freezing and thawing. The electron microscopic further shows an evidence of perivascular fluid extravasation and endothelial swelling and lysis.[11] [13] - Ischemic phase: Finally, hypoxia, endothelial injury, and local thrombosis lead to the late ischemic phase, in which inflammatory mediators such as prostaglandins, thromboxanes, bradykinins, and histamine trigger additional vasoconstriction, platelet aggregation, and vessel thrombosis. As these inflammatory mediators peak during rewarming, the cycles of refreezing and rewarming can worsen the extent of tissue loss. Therefore, an initial frostbite treatment is targeted at restoring perfusion to the affected limb(s) and limiting tissue loss after rewarming.[11] [12] [13] # Differentiating Frostbite from other Diseases - Various types of cold injury can mimic each other which are categorized into hypothermia, tissue-freezing injury (frostbite), non–tissue-freezing injury (frostnip, trenchfoot, chilblain, or pernio) in the following Table. Table 3: List of differential diagnosis for the Frostbite # Epidemiology and Demographics - Age: Although the elderly and young children are highly susceptible to the frostbite injury; however, the published epidemiological studies showed that frostbite is uncommon in these age groups and instead tends to affect adults between the ages of 30–49 years.[13] - Anatomic location: The feet and the hands account for 90% of injuries reported. Other includes the face (nose, chin, earlobes, cheeks and lips), buttocks/perineum (from sitting on metal seats) and penis (joggers,runners and Nordic skiers). [13] - A 12 year review on the inpatient frostbite injuries conducted in Saskatchewan, Canada revealed the incidence of predisposing factors in a decreasing order: Alcohol consumption (46%), psychiatric illness (17%), vehicular failure (19%), and drug misuse (4%). [20] - Alcohol: It causes heat loss through peripheral vasodilatation and deranged judgement which may results in not seeking timely adequate shelter and consequently turns to a higher level of injury.[13] # Risk Factors - Various behavioural, physiological and mechanical factors play an important roles in increasing the likelihood of its development and the extent of the damage. Table 4: Factors that increases risk for frostbite[10] [13][20] # Complications and late sequelae - Most common: Complex regional pain syndrome and arthritis - Late or chronic sequelae (70%): Infection, increased cold sensitivity, hyperhydrosis, numbness, skin pigmentation, abnormalities of the nails, joint stiffness, and premature closure of physeal growth plate in children.[9] - Skin areas affected by frostbite are susceptible to chronic ulceration due to poor tissue quality after healing; and can undergo a malignant transformation akin to the formation of Marjolin's ulcers similar to old burn scars.[21] - Frostbite Arthropathy: In the growing child, frostbite produces a characteristic growth stunting of the small bones through premature closure of physeal growth plate and acro-osteolysis. Additionally, secondary osteoarthritic changes may be seen in early adulthood.[22] # Prognosis - Favourable prognostic factors: Retained sensation, normal skin colour, and clear rather than cloudy fluid in the blisters, early edema formation and clear blisters extending to the tips of the digits are considered favourable sign. - Poor prognostic factors: Non-blanching cyanosis, firm skin, lack of edema, and small, proximal, dark haemorrhagic vesicles indicates damage to the subdermal vascular plexus.[23] - However, no prognostic features are entirely predictive; and weeks or months may pass before the demarcation between viable and non-viable tissue becomes visible.[10] - Hence, patients should avoid cold exposure for up to a year after the initial injury. # Diagnosis ## Clinical Symptoms - Severity of symptoms is directly proportional to the severity of injury. - Initial presenting complaint: A cold numbness associated with a sensory loss, the extremities are cold to the touch, and patients complains of clumsiness, ‘‘like a block of wood’’. Thawing and reperfusion are often accompanied by intense pain. [13] - At 2-3 days: A throbbing pain begins after rewarming and may persist for weeks or months even after the tissue becomes demarcated. - At a week: A residual tingling sensation appears probably due to an ischemic neuritis. However, a variable presentation can be seen with no painful sensation especially among diabetics with previous neuropathic damage. [24] - Symptoms usually subside within 1 month in mild cases of no tissue loss; contrarily, in cases with severe tissue loss, disablement may exceed 6 months. Usually frostbite victims experience some degree of sensory loss for at least 4 years or indefinitely post injury. - Aggravating factor: Symptoms gets exacerbated by a warm environment. - Other sensory deficits: Spontaneous burning and electric current-like sensations in the affected body areas.[25] ## Clinical Signs - Frostbite is a clinical diagnosis. - However, initial injuries appear similar and make it difficult to determine the severity or grade of injury until post rewarming. - The extent of the freezing and tissue loss may not be apparent for 4 to 5 days. - Frostbite injuries can be classified clinically as either superficial or deep.[26] Superficial injuries: It may appear as either a numb central white plaque with surrounding erythema, or as blisters filled with clear or milky fluid with surrounding erythema and edema. Deep injuries: It is characterized by either hemorrhagic blisters that develop into a black eschar in 2 weeks or have a complete tissue loss and necrosis. Final tissue demarcation may take 3 to 4 weeks to establish. The appearance of the skin, sensation to pinprick, and whether the vesicles are clear or hemorrhagic should be noted. Identify signs of dehydration, hypothermia, altitude effects (pulmonary edema), and exhaustion. - Superficial injuries: It may appear as either a numb central white plaque with surrounding erythema, or as blisters filled with clear or milky fluid with surrounding erythema and edema. - Deep injuries: It is characterized by either hemorrhagic blisters that develop into a black eschar in 2 weeks or have a complete tissue loss and necrosis. Final tissue demarcation may take 3 to 4 weeks to establish. The appearance of the skin, sensation to pinprick, and whether the vesicles are clear or hemorrhagic should be noted. Identify signs of dehydration, hypothermia, altitude effects (pulmonary edema), and exhaustion. - Rewarming injuries: During rewarming, edema may start to appear within 3-5 hours and may last 7 days. Blisters tend to appear within 4-24 hours. Presence of eschar will be obvious at 10-15 days and mummification with a line of demarcation may develop in 3-8 weeks. [27] ## Diagnostic modality - The primary role of imaging in frostbite injuries is to define the precisely the severity, depth, and extent of tissue injury to better direct nonsurgical and surgical treatment. Additionally, imaging plays an important role in monitoring response to the provided treatment. Table 5: Elaborates the different imaging modality used for Frostbite[28] - Other miscellaneous tests: Infrared thermography, laser doppler studies, digital plethysmography and magnetic resonance imaging/ magnetic resonance angiography. [10] # Treatment - Almost all patients should be admitted to hospital; considering alcohol intoxication, psychiatric illness, and homelessness as the common features of the frostbite patient; an immediate discharge is rarely prudent. Hence, treatment of frostbite can be divided into three phases: prethaw field care phase, immediate hospital care phase, and postthaw phase. ## Field Treatment - If a body part found frozen in the field area, it should be protected from further damage with the following measures:[33] - The patient should be immediately moved out of the wind, provided with shelter and given warm fluids. - Remove boots but the problems of replacement can arise if swelling occurs, and replace wet gloves and socks with dry ones. Warm the cold extremity by placing them in a companion's armpit or groin for 10 min and then replace the boots/gloves. Rubbing the affected part is not recommended because of the potential for worsening direct tissue injury. - If sensation returns, the patient may mitigate the further risks and continue to walk. If there is no return of sensation, the injured should go to the nearest warm shelter (hut or base camp) and seek medical treatment. If at high altitude (>4,000 m), supplementary oxygen should be considered. [10] - Aspirin 75 mg can be given for its rheologic effect. Ibuprofen 12 mg/kg/day divided into two daily doses (maximum of 2,400 mg/day) should be given for its prostaglandin effect. - Field rewarming should only be attempted if there is no further risk of refreezing as the cycle of thawing and refreezing results in a more extensive injury.[34] [35] - The decision to thaw the frostbitten tissue in the field may involve pain control, maintaining warm water baths at a constant temperature, protecting tissue from further injury during rewarming, and eventual transport. - In extreme scenarios, it may be better to let a casualty walk on a frozen limb to safety rather than risk refreezing.[36] ## Immediate hospital care - The standard approach to the initial treatment of frostbite is the strategy originally outlined by McCauley and Heggers as mentioned below: [36] - Admit frostbite patient to specialist unit if possible - Evaluate for hypothermia, concomitant injury, or complicating problems - On admission, rapidly rewarm the affected areas in warm water at 37–39°C (99–102°F) for 15–30 mins or until thawing is complete - Debride clear or white blisters and apply topical aloe vera (Dermaide aloe) every 6 h - Leave haemorrhagic blisters intact and apply topical aloe vera every 6 h - Splint and elevate the extremity - Administer antitetanus prophylaxis (toxoid or immunoglobulin (Ig)) - Analgesia: opiate (intravenously or intramuscularly) as indicated - Administer ibuprofen 400 mg orally every 12 h - Administer benzyl penicillin 500 000 U every 6 h for 48–72 h - Administer daily hydrotherapy in 40°C water for 30–45 mins. Do not towel dry affected tissue. - Prohibit smoking ## Fluids[34] - Rehydration can be provided orally or intravenously depending upon severity and ability of the patient to accept the warm fluids. - Oral fluids should be given if the patient is alert and has no gastrointestinal symptoms. - In case of nausea, vomiting, or an altered mental status; IV normal saline should be given if available. - High altitude increases the risk of dehydration. A hypothermia in combination to dehydration may be compounded by cold diuresis due to suppression of antidiuretic hormone which mandates the replenishment with intravenous fluids. - Intravenous fluids should be warmed before infusion if possible; and should be infused in small boluses as slower infusion will result in fluid cooling as it passes through the IV tubing. - Volume status should be optimized as per the signs of clinical dehydration. ## Rewarming - Hypothermia and concomitant injury should be thoroughly evaluated. - Systemic hypothermia should be corrected to a core temperature of 34°C before frostbite management is initiated. - Rewarming should be carried out in a whirlpool of recirculating water with a mild antibacterial solutions (povidone-iodine or chlorhexidine). - The State of Alaska Cold-injury Guidelines recommend a lower temperature water bath of 37–39°C which decreases the patient pain with slightly slowing the rewarming process. [35] - The time period recommended for rewarming varies from 15–30 mins up to 1 h.[36] - Rewarming should continue until a red/purple color appears and the extremity becomes pliable. [34] - Active motion during the rewarming period is beneficial but care should be taken to prevent the extremity from touching the sides of the whirlpool. - It is important to provide good analgesic cover by including narcotic medication. [33] ## Blisters and dressings[10] - Blisters containing clear or milky fluid should be debrided and covered every 6 h with aloe vera ointment, a potent anti-prostaglandin agent. - Splinting, elevating, and wrapping the affected part in a loose and protective dressing should follow the administration of the aloe vera cream. - Padding should be put between the patient’s toes if affected. - Haemorrhagic blisters should be left intact to prevent desiccation of the underlying tissue. If they restrict movement, they can be drained with their roofs left on. ## Antibiotics - Frostbite is not an inherently infection-prone injury. Therefore, the use of antibiotics specifically for preventing infection during or after frostbite injury is still controversial. - However, when associated with significant edema or malnutrition due to homelessness, chronic alcohol abuse or return from extreme altitude; penicillin is administered as edema deranges the skin bactericidal properties.[12] - Additionally, systemic antibiotics are administered in the presence of proven infection, trauma or cellulitis. [13] ## Tetanus toxoid - Tetanus prophylaxis should be done as per the standard guidelines. ## Analgesia and NSAIDs - Rewarming the extremities can be extremely painful process, so use of NSAID drugs or opiates should be administered. - Oral ibuprofen 12 mg/kg divided over two daily doses provides systemic anti-prostaglandin activity that limits the cascade of inflammatory damage. This dose can be increased to a maximum of 2,400 mg/day if the patient is still experiencing pain, and can be continued until wounds are healed or amputation occurs. A dose of 400 mg BID is a practical regime to start with the most patients, but it can be increased later on to 600 mg QDS as pain dictates. [37] - If aspirin has not been given in the field, 300 mg once a day can be given provided no contraindications. However, aspirin is less useful as it prolongs blockade of all prostaglandin synthesis and some prostacyclins that are considered beneficial for wound healing. [37] - The role of clopidogrel in frostbite has yet to be assessed. ## Definitive treatment Angiography and thrombolysis - rTPA delivery should be provided at a centre accustomed to performing thrombolysis and providing adequate monitoring in a critical care/high-dependency setting. - If the patient presents less than 24 h after injury to a hospital without these facilities, consider urgent transfer to avoid further delay in the commencement of therapy. - An initial selective diagnostic DSA should be performed in patients being considered for thrombolysis. - Intravenous vasodilators such as nitroglycerin or papaverine are useful in conjunction with rTPA to treat the vasospasm associated with a frostbite injury.[38] [39] - rTPA is used in combination with heparin which reduces the recurrence of microvascular thrombosis. [39] - Repeat angiograms should be performed every 12–24 h to evaluate response to therapy. - rTPA treatment should be discontinued when perfusion is restored to distal vessels or at 48 h if no improvement is observed.[40] Table 6: Enumuerates the protocol for intravenous rTPA[41] Vasodilators: Iloprost - Iloprost is a prostacyclin analogue with vasodilatory properties that mimic the effects of a sympathectomy. Additionally, it may affect platelet aggregation and hence, decrease microvascular occlusion. Table 7: Protocol of intravenous prostacyclin[41] ## Surgery Fasciotomies - Early surgical intervention in the form of fasciotomy in the immediate post-thaw phase is required if compartment syndrome compromises the reperfusion. [42] Amputation - Angiography, technetium-99 bone scan and/or magnetic resonance imaging may be used to assist determination of surgical margins in conjunction with clinical findings. - An early amputation is indicated occasionally if liquefaction, moist gangrene, or overwhelming infection and sepsis develops. - Otherwise, amputation should be delayed until definitive demarcation occurs which takes around 6–12 weeks. [43] - Negative pressure devices can aid in speeding up healing of amputation sites by secondary intention.[44] - The healed affected limb is often insensate. Hence, an approach that addresses both protective footwear and orthotics to provide optimal limb function is essential. [43] ## Tissue protection - The functional use of extremities following a partial amputation is variable and injury specific. - The biomechanics of the foot/hand can be radically altered and frostbite neuropathy can compound the problem; hence, liaison with orthotic/podiatry department to provide custom-made footwear may be required to optimize the long-term limb functional result and minimize secondary injuries. [45] ## Adjuvant therapies Hyperbaric oxygen therapy (HBOT) - Benefits of HBOT in frostbite are as follows:[46] It reverses vasoconstriction in ischemic tissue and the resulting hyperoxia from oxygen dissolved in plasma surpasses any potential blood flow reduction. It increases a diffusion distance and improves oxygenation in hypoxic tissue. Angiogenesis is also promoted by HBOT which further reduces edema and necrosis in hypoxic skeletal muscle by improving the blood supply. It increases the deformability of erythrocytes, has a bacteriostatic effect and may act as an antioxidant. It delineates the viable tissue from necrotic part and allows marginal tissue to be maintained until revascularization has been established. - It reverses vasoconstriction in ischemic tissue and the resulting hyperoxia from oxygen dissolved in plasma surpasses any potential blood flow reduction. - It increases a diffusion distance and improves oxygenation in hypoxic tissue. - Angiogenesis is also promoted by HBOT which further reduces edema and necrosis in hypoxic skeletal muscle by improving the blood supply. - It increases the deformability of erythrocytes, has a bacteriostatic effect and may act as an antioxidant. - It delineates the viable tissue from necrotic part and allows marginal tissue to be maintained until revascularization has been established. - However, HBOT showed mixed results with no level 1 evidence available. Hence, its role warrants further investigation as it is a relatively safe and inexpensive treatment. [33] Sympathectomy - The role of sympathectomy, either surgical (via open or minimally invasive) or chemical, has yielded mixed results. - Early sympathectomy, performed within the first few hours of injury, has led to increase in edema formation and tissue destruction.[47] - However, if performed 24–48 h after thawing, it is considered to hasten resolution of edema and decrease tissue loss. - Sympathectomy may prevent some long term sequelae such as pain due to vasospasm, paresthesias and hyperhidrosis. - However, since the advent of alternative therapies such as rTPA and Iloprost, and being irreversible nature of sympathectomy procedure, a great caution should be exercised while considering its use; and hence, some consider no role for its use in frostbite. [10] ## Telemedicine - A recent development in accessing expert advice by the use of the internet and satellite phones has been driven both by the patients and the clinicians with a limited experience of frostbite. A virtual opinion can be sought from any remote or difficult situations in the world. [48] - The UK based service can be accessed via the Diploma in Mountain Medicine or the British Mountaineering Council websites which is run by Diploma Faculty Members and is being increasingly used by climbers and physicians worldwide, often to obtain a second opinion or to seek more specialized advice. [49] - Patients can be readily followed up in a ‘‘virtual clinic’’ by reviewing recent digital images and discussing management options either by phone or via email. # Primary Prevention - As in many instances, it can be prevented so the key is deterrence and patient education. Risk modification including proper clothing, access to shelter, and maintaining hydration and nutrition are vital for protection against frostbite. Patients should be advised to carry extra clothing supplies if they are into winter sports and avoid tight restrictive clothing. Emollients, although traditionally believed in Nordic countries to prevent frostbite, do not have protective effects in preventing frostbite and should be discouraged.[50] Advise against the abuse of alcohol, illicit drugs, and tobacco. For those with medical conditions, it is important to ensure that their health is stable before venturing on an adventurous outdoor trip during winter. - Risk modification including proper clothing, access to shelter, and maintaining hydration and nutrition are vital for protection against frostbite. - Patients should be advised to carry extra clothing supplies if they are into winter sports and avoid tight restrictive clothing. - Emollients, although traditionally believed in Nordic countries to prevent frostbite, do not have protective effects in preventing frostbite and should be discouraged.[50] - Advise against the abuse of alcohol, illicit drugs, and tobacco. - For those with medical conditions, it is important to ensure that their health is stable before venturing on an adventurous outdoor trip during winter. - Prolonged exposure to freezing cold temperatures may cause serious health problems so if signs related to it are observed, call for emergency help. - The Occupational Safety and Health Act (OSHA) Cold Stress Card provides a reference guide and recommendations to combat and prevent many illnesses and injuries. Available in English and Spanish, this laminated fold-up card is free to employers, workers and the public. [51] - Tips include how to protect workers: Recognize the environmental and workplace conditions that may be dangerous. Learn the signs and symptoms of cold-induced illnesses and injuries and what to do to help workers. Train workers about cold-induced illnesses and injuries. Encourage workers to wear proper clothing for cold, wet and windy conditions, including layers that can be adjusted to changing conditions. Be sure workers in extreme conditions take a frequent short break in warm dry shelters to allow their bodies to warm up. Try to schedule work for the warmest part of the day. Avoid exhaustion or fatigue because energy is needed to keep muscles warm. Use the buddy-system, work in pairs so that one worker can recognize danger signs. Drink warm, sweet beverages (sugar water, sports-type drinks) and avoid drinks with caffeine (coffee, tea, sodas or hot chocolate) or alcohol. Eat warm, high-calorie foods such as hot pasta dishes. Remember, workers are at an increased risks who takes certain medications, are in poor physical condition or suffer from illnesses such as diabetes, hypertension or cardiovascular disease. - Recognize the environmental and workplace conditions that may be dangerous. - Learn the signs and symptoms of cold-induced illnesses and injuries and what to do to help workers. - Train workers about cold-induced illnesses and injuries. - Encourage workers to wear proper clothing for cold, wet and windy conditions, including layers that can be adjusted to changing conditions. - Be sure workers in extreme conditions take a frequent short break in warm dry shelters to allow their bodies to warm up. - Try to schedule work for the warmest part of the day. - Avoid exhaustion or fatigue because energy is needed to keep muscles warm. - Use the buddy-system, work in pairs so that one worker can recognize danger signs. - Drink warm, sweet beverages (sugar water, sports-type drinks) and avoid drinks with caffeine (coffee, tea, sodas or hot chocolate) or alcohol. - Eat warm, high-calorie foods such as hot pasta dishes. - Remember, workers are at an increased risks who takes certain medications, are in poor physical condition or suffer from illnesses such as diabetes, hypertension or cardiovascular disease.	https://www.wikidoc.org/index.php/Frostbite
e1f2aa526de69a28fa46bea98a9f5384adc54c4b	wikidoc	Frusemide	Frusemide Furosemide (INN) or frusemide (former BAN) is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also been used to prevent Thoroughbred and Standardbred race horses from bleeding through the nose during races. Along with some other diuretics, furosemide is also included on the World Anti-Doping Agency's banned drug list due to its alleged use as a masking agent for other drugs. # Medical uses Furosemide is primarily used for the treatment of two conditions: hypertension and edema. It is the first line agent in most people with edema due to congestive heart failure. - Edema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome - Hypertension - Adjunct in cerebral/pulmonary edema where rapid diuresis, i.e. lowering body water content by inducing urination, is required (IV injection) It is also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration. # Adverse effects Although disputed, it is considered ototoxic: "usually with large parenteral doses and rapid administration and in renal impairment" Furosemide also can lead to gout due to hyperuricemia. Hyperglycemia is also a common side effect. The tendency, as for all loop diuretics, to cause low potassium levels (hypokalemia) has given rise to combination products, either with potassium itself (e.g. Lasix-K) or with the potassium sparing diuretic of amiloride (Co-amilofruse). ## Interactions Furosemide has potential interactions with the following medications: - Aminoglycoside antibiotics such as gentamicin - Aspirin and other salicylates - Other diuretics (e.g. ethacrynic acid, hydrochlorothiazide) - Indomethacin - Lithium - Synergistic effects with other antihypertensives (e.g. doxazosin) - Sucralfate # Mechanism of action Furosemide, like other loop diuretics, acts by inhibiting NKCC2, the luminal Na-K-2Cl symporter in the thick ascending limb of the loop of Henle. The action on the distal tubules is independent of any inhibitory effect on carbonic anhydrase or aldosterone; it also abolishes the corticomedullary osmotic gradient and blocks negative as well as positive free water clearance. Due to the large NaCl absorptive capacity of the loop of Henle, diuresis is not limited by development of acidosis, as it is with the carbonic anhydrase inhibitors. By inhibiting the transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that derives from K+ recycling. This electrical potential normally drives divalent cation reabsorbtion in the loop, and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since Ca2+ is actively reabsorbed in the distal convoluted tubule, loop diuretics do not generally cause hypocalcemia. Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors. Furosemide has been reported to reversibly antagonize GABA-evoked currents of α6β2γ2 receptors at µM concentrations, but not α1β2γ2 receptors. During development, the α6β2γ2 receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide. # Brand names Some of the brand names under which furosemide is marketed include: Aisemide, Apo-Furosemide, Beronald, Desdemin, Discoid, Diural, Diurapid, Dryptal, Durafurid, Edemid, Errolon, Eutensin, Flusapex, Frudix, Frusetic, Frusid, Fulsix, Fuluvamide, Furesis, Furix, Furo-Puren, Furosedon, Fusid.frusone, Hydro-rapid, Impugan, Katlex, Lasilix, Lasix, Lodix, Lowpston, Macasirool, Mirfat, Nicorol, Odemase, Oedemex, Profemin, Rosemide, Rusyde, Salix, Trofurit, Uremide and Urex. The name Lasix is derived from the phrase "lasts six (hours)" — referring to its duration of action. Intravenous and oral Lasix lasts two to four hours. # Veterinary uses The diuretic effects are put to use most commonly in horses to prevent bleeding during a race. Sometime in the early 1970s, furosemide's ability to prevent, or at least greatly reduce, the incidence of bleeding (EIPH) by horses during races was discovered accidentally. Pursuant to the racing rules of most states, horses that bleed from the nostrils three times are permanently barred from racing (for their own protection). Clinical trials followed, and by decade's end, racing commissions in some states began legalizing its use on race horses. On September 1, 1995, New York became the last state in the United States to approve such use, after years of refusing to consider doing so. Some states allow its use for all racehorses; some allow it only for confirmed "bleeders." However, its use for this purpose is still prohibited in many other countries, and veterinarians dispute its use for this problem. Furosemide is also used in horses for pulmonary edema, congestive heart failure (in combination with other drugs), and allergic reactions. Despite the fact it increases circulation to the kidneys, it does not help kidney function, and is not recommended for kidney disease. It is also used to treat congestive heart failure in canines (who experience fluid on the lungs) due to complications from heartworms. It can be used in conjunction with an antibiotic and anti-inflammatory to treat this condition. ## Precautions, side effects, and administration for horses Furosemide is injected either intramuscularly (IM) or intravenously (IV), usually 0.5-1.0 mg/kg 2x/day, although less before a horse is raced. As with many diuretics, it can cause dehydration and electrolyte imbalance, including loss of potassium, calcium, sodium, and magnesium. It is especially important to prevent potassium loss. Excessive use of furosemide will most likely lead to a metabolic alkalosis due to hypochloremia and hypokalemia. The drug should therefore not be used in horses that are dehydrated or experiencing kidney failure. It should be used with caution in horses with liver problems or electrolyte abnormalities. Overdose may lead to dehydration, change in drinking patterns and urination, seizures, GI problems, kidney damage, lethargy, collapse, and coma. Furosemide should be used with caution when combined with corticosteroids (as this increases the risk of electrolyte imbalance), aminoglycoside antibiotics (increases risk of kidney or ear damage), and trimethoprim sulfa (causes decreased platelet count). It may also cause interactions with anesthesics, so its use should be related to the veterinarian if the animal is going into surgery, and it decreases the kidney's ability to excrete aspirin, so dosages will need to be adjusted if combined with that drug Furosemide may increase the risk of digoxin toxicity due to hypokalemia. The drug is best not used during pregnancy or in a lactating mare, as it has been shown to be passed through the placenta and milk in studies with other species. It should not be used in horses with pituitary pars intermedia dysfunction (Cushings). Furosemide is detectable in urine 36–72 hours following injection. Its use is prohibited by most equestrian organizations.	Frusemide Furosemide (INN) or frusemide (former BAN) is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also been used to prevent Thoroughbred and Standardbred race horses from bleeding through the nose during races. Along with some other diuretics, furosemide is also included on the World Anti-Doping Agency's banned drug list due to its alleged use as a masking agent for other drugs. # Medical uses Furosemide is primarily used for the treatment of two conditions: hypertension and edema.[1] It is the first line agent in most people with edema due to congestive heart failure.[1] - Edema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome - Hypertension - Adjunct in cerebral/pulmonary edema where rapid diuresis, i.e. lowering body water content by inducing urination, is required (IV injection) It is also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration.[2] # Adverse effects Although disputed,[3] it is considered ototoxic: "usually with large parenteral doses and rapid administration and in renal impairment"[4] Furosemide also can lead to gout due to hyperuricemia. Hyperglycemia is also a common side effect. The tendency, as for all loop diuretics, to cause low potassium levels (hypokalemia) has given rise to combination products, either with potassium itself (e.g. Lasix-K) or with the potassium sparing diuretic of amiloride (Co-amilofruse). ## Interactions Furosemide has potential interactions with the following medications:[5] - Aminoglycoside antibiotics such as gentamicin - Aspirin and other salicylates - Other diuretics (e.g. ethacrynic acid, hydrochlorothiazide) - Indomethacin - Lithium - Synergistic effects with other antihypertensives (e.g. doxazosin) - Sucralfate # Mechanism of action Furosemide, like other loop diuretics, acts by inhibiting NKCC2, the luminal Na-K-2Cl symporter in the thick ascending limb of the loop of Henle. The action on the distal tubules is independent of any inhibitory effect on carbonic anhydrase or aldosterone; it also abolishes the corticomedullary osmotic gradient and blocks negative as well as positive free water clearance. Due to the large NaCl absorptive capacity of the loop of Henle, diuresis is not limited by development of acidosis, as it is with the carbonic anhydrase inhibitors. By inhibiting the transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that derives from K+ recycling. This electrical potential normally drives divalent cation reabsorbtion in the loop, and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since Ca2+ is actively reabsorbed in the distal convoluted tubule, loop diuretics do not generally cause hypocalcemia. Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors.[6][7][8] Furosemide has been reported to reversibly antagonize GABA-evoked currents of α6β2γ2 receptors at µM concentrations, but not α1β2γ2 receptors.[6][8] During development, the α6β2γ2 receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide.[7] # Brand names Some of the brand names under which furosemide is marketed include: Aisemide, Apo-Furosemide, Beronald, Desdemin, Discoid, Diural, Diurapid, Dryptal, Durafurid, Edemid, Errolon, Eutensin, Flusapex, Frudix, Frusetic, Frusid, Fulsix, Fuluvamide, Furesis, Furix, Furo-Puren, Furosedon, Fusid.frusone, Hydro-rapid, Impugan, Katlex, Lasilix, Lasix, Lodix, Lowpston, Macasirool, Mirfat, Nicorol, Odemase, Oedemex, Profemin, Rosemide, Rusyde, Salix, Trofurit, Uremide and Urex. The name Lasix is derived from the phrase "lasts six (hours)" — referring to its duration of action.[9] Intravenous and oral Lasix lasts two to four hours.[10] # Veterinary uses The diuretic effects are put to use most commonly in horses to prevent bleeding during a race. Sometime in the early 1970s, furosemide's ability to prevent, or at least greatly reduce, the incidence of bleeding (EIPH) by horses during races was discovered accidentally. Pursuant to the racing rules of most states, horses that bleed from the nostrils three times are permanently barred from racing (for their own protection). Clinical trials followed, and by decade's end, racing commissions in some states began legalizing its use on race horses. On September 1, 1995, New York became the last state in the United States to approve such use, after years of refusing to consider doing so. Some states allow its use for all racehorses; some allow it only for confirmed "bleeders." However, its use for this purpose is still prohibited in many other countries, and veterinarians dispute its use for this problem. Furosemide is also used in horses for pulmonary edema, congestive heart failure (in combination with other drugs), and allergic reactions. Despite the fact it increases circulation to the kidneys, it does not help kidney function, and is not recommended for kidney disease. It is also used to treat congestive heart failure in canines (who experience fluid on the lungs) due to complications from heartworms. It can be used in conjunction with an antibiotic and anti-inflammatory to treat this condition. ## Precautions, side effects, and administration for horses Furosemide is injected either intramuscularly (IM) or intravenously (IV), usually 0.5-1.0 mg/kg 2x/day, although less before a horse is raced. As with many diuretics, it can cause dehydration and electrolyte imbalance, including loss of potassium, calcium, sodium, and magnesium. It is especially important to prevent potassium loss. Excessive use of furosemide will most likely lead to a metabolic alkalosis due to hypochloremia and hypokalemia. The drug should therefore not be used in horses that are dehydrated or experiencing kidney failure. It should be used with caution in horses with liver problems or electrolyte abnormalities. Overdose may lead to dehydration, change in drinking patterns and urination, seizures, GI problems, kidney damage, lethargy, collapse, and coma. Furosemide should be used with caution when combined with corticosteroids (as this increases the risk of electrolyte imbalance), aminoglycoside antibiotics (increases risk of kidney or ear damage), and trimethoprim sulfa (causes decreased platelet count). It may also cause interactions with anesthesics, so its use should be related to the veterinarian if the animal is going into surgery, and it decreases the kidney's ability to excrete aspirin, so dosages will need to be adjusted if combined with that drug Furosemide may increase the risk of digoxin toxicity due to hypokalemia. The drug is best not used during pregnancy or in a lactating mare, as it has been shown to be passed through the placenta and milk in studies with other species. It should not be used in horses with pituitary pars intermedia dysfunction (Cushings). Furosemide is detectable in urine 36–72 hours following injection. Its use is prohibited by most equestrian organizations.	https://www.wikidoc.org/index.php/Frusemide
10d8357c36139a0e8cf4cb1512e991836598436d	wikidoc	Fuel cell	Fuel cell A fuel cell is an electrochemical energy conversion device. It produces electricity from various external quantities of fuel (on the anode side) and an oxidant (on the cathode side). These react in the presence of an electrolyte. Generally, the reactants flow in and reaction products flow out while the electrolyte remains in the cell. Fuel cells can operate virtually continuously as long as the necessary flows are maintained. Fuel cells are different from batteries in that they consume reactant, which must be replenished, whereas batteries store electrical energy chemically in a closed system. Additionally, while the electrodes within a battery react and change as a battery is charged or discharged, a fuel cell's electrodes are catalytic and relatively stable. Many combinations of fuel and oxidant are possible. A hydrogen cell uses hydrogen as fuel and oxygen as oxidant. Other fuels include hydrocarbons and alcohols. Other oxidants include air, chlorine and chlorine dioxide. # Fuel cell design In essence, a fuel cell works by catalysis, separating the component electrons and protons of the reactant fuel, and forcing the electrons to travel though a circuit, hence converting them to electrical power. The catalyst is typically comprised of a platinum group metal or alloy. Another catalytic process takes the electrons back in, combining them with the protons and the oxidant to form waste products (typically simple compounds like water and carbon dioxide). In the archetypal hydrogen–oxygen proton exchange membrane fuel cell (PEMFC) design, a proton-conducting polymer membrane, (the electrolyte), separates the anode and cathode sides. This was called a "solid polymer electrolyte fuel cell" (SPEFC) in the early 1970s, before the proton exchange mechanism was well-understood. (Notice that "polymer electrolyte membrane" and "proton exchange membrane" result in the same acronym.) On the anode side, hydrogen diffuses to the anode catalyst where it later dissociates into protons and electrons. These protons often react with oxidants causing them to become what is commonly reffered to as multi-facilitated proton membranes (MFPM). The protons are conducted through the membrane to the cathode, but the electrons are forced to travel in an external circuit (supplying power) because the membrane is electrically insulating. On the cathode catalyst, oxygen molecules react with the electrons (which have traveled through the external circuit) and protons to form water — in this example, the only waste product, either liquid or vapor. In addition to this pure hydrogen type, there are hydrocarbon fuels for fuel cells, including diesel, methanol (see: direct-methanol fuel cells) and chemical hydrides. The waste products with these types of fuel are carbon dioxide and water. The materials used in fuel cells differ by type. The electrode–bipolar plates are usually made of metal, nickel or carbon nanotubes, and are coated with a catalyst (like platinum, nano iron powders or palladium) for higher efficiency. Carbon paper separates them from the electrolyte. The electrolyte could be ceramic or a membrane. A typical PEM fuel cell produces a voltage from 0.6 V to 0.7 V at full rated load. Voltage decreases as current increases, due to several factors: - Activation loss - Ohmic loss (voltage drop due to resistance of the cell components and interconnects) - Mass transport loss (depletion of reactants at catalyst sites under high loads, causing rapid loss of voltage) To deliver the desired amount of energy, the fuel cells can be combined in series and parallel circuits, where series yield higher voltage, and parallel allows a stronger current to be drawn. Such a design is called a fuel cell stack. Further, the cell surface area can be increased, to allow stronger current from each cell. ## Fuel cell design issues - Costs. In 2002, typical cells had a catalyst content of US$1000 per kilowatt of electric power output. In 2008 UTC Power has 400kw Fuel cells for $1,000,000 per 400kW installed costs. The goal is to reduce the cost in order to compete with current market technologies including gasoline internal combustion engines. Many companies are working on techniques to reduce cost in a variety of ways including reducing the amount of platinum needed in each individual cell. Ballard Power Systems have experiments with a catalyst enhanced with carbon silk which allows a 30% reduction (1 mg/cm² to 0.7 mg/cm²) in platinum usage without reduction in performance. - The production costs of the PEM (proton exchange membrane). The Nafion® membrane currently costs €400/m². This, and the Toyota PEM and 3M PEM membrane can be replaced with the ITM Power membrane (a hydrocarbon polymer), resulting in a price of ~€4/m². in 2005 Ballard Power Systems announced that its fuel cells will use Solupor®, a porous polyethylene film patented by DSM. - Water and air management (in PEMFCs). In this type of fuel cell, the membrane must be hydrated, requiring water to be evaporated at precisely the same rate that it is produced. If water is evaporated too quickly, the membrane dries, resistance across it increases, and eventually it will crack, creating a gas "short circuit" where hydrogen and oxygen combine directly, generating heat that will damage the fuel cell. If the water is evaporated too slowly, the electrodes will flood, preventing the reactants from reaching the catalyst and stopping the reaction. Methods to manage water in cells are being developed like electroosmotic pumps focusing on flow control. Just as in a combustion engine, a steady ratio between the reactant and oxygen is necessary to keep the fuel cell operating efficiently. - Temperature management. The same temperature must be maintained throughout the cell in order to prevent destruction of the cell through thermal loading. This is particularly challenging as the 2H2 + O2 -> 2H2O reaction is highly exothermic, so a large quantity of heat is generated within the fuel cell. - Durability, service life, and special requirements for some type of cells. Stationary applications typically require more than 40,000 hours of reliable operation at a temperature of -35 °C to 40 °C, while automotive fuel cells require a 5,000 hour lifespan (the equivalent of 150,000 miles) under extreme temperatures. Automotive engines must also be able to start reliably at -30 °C and have a high power to volume ratio (typically 2.5 kW per liter). - Limited carbon monoxide tolerance of the anode. # History The principle of the fuel cell was discovered by German scientist Christian Friedrich Schönbein in 1838 and published in the January 1839 edition of the "Philosophical Magazine". Based on this work, the first fuel cell was developed by Welsh scientist Sir William Robert Grove in 1843. The fuel cell he made used similar materials to today's phosphoric-acid fuel cell. In 1955, W. Thomas Grubb, a chemist working for the General Electric Company (GE), further modified the original fuel cell design by using a sulphonated polystyrene ion-exchange membrane as the electrolyte. Three years later another GE chemist, Leonard Niedrach, devised a way of depositing platinum onto the membrane, which served as catalyst for the necessary hydrogen oxidation and oxygen reduction reactions. This became known as the 'Grubb-Niedrach fuel cell'. GE went on to develop this technology with NASA and McDonnell Aircraft, leading to its use during Project Gemini. This was the first commercial use of a fuel cell. It wasn't until 1959 that British engineer Francis Thomas Bacon successfully developed a 5 kW stationary fuel cell. In 1959, a team led by Harry Ihrig built a 15 kW fuel cell tractor for Allis-Chalmers which was demonstrated across the US at state fairs. This system used potassium hydroxide as the electrolyte and compressed hydrogen and oxygen as the reactants. Later in 1959, Bacon and his colleagues demonstrated a practical five-kilowatt unit capable of powering a welding machine. In the 1960s, Pratt and Whitney licensed Bacon's U.S. patents for use in the U.S. space program to supply electricity and drinking water (hydrogen and oxygen being readily available from the spacecraft tanks). United Technology Corp.'s UTC Power subsidiary was the first company to manufacture and commercialize a large, stationary fuel cell system for use as a co-generation power plant in hospitals, universities and large office buildings. UTC Power continues to market this fuel cell as the PureCell 200, a 200 kW system. UTC Power continues to be the sole supplier of fuel cells to NASA for use in space vehicles, having supplied the Apollo missions, and currently the Space Shuttle program, and is developing fuel cells for automobiles, buses, and cell phone towers; the company has demonstrated the first fuel cell capable of starting under freezing conditions with its proton exchange membrane automotive fuel cell. # Types of fuel cells # Efficiency ## Fuel cell efficiency The efficiency of a fuel cell is dependent on the amount of power drawn from it. Drawing more power means drawing more current, which increases the losses in the fuel cell. As a general rule, the more power (current) drawn, the lower the efficiency. Most losses manifest themselves as a voltage drop in the cell, so the efficiency of a cell is almost proportional to its voltage. For this reason, it is common to show graphs of voltage versus current (so-called polarization curves) for fuel cells. A typical cell running at 0.7 V has an efficiency of about 50%, meaning that 50% of the energy content of the hydrogen is converted into electrical energy; the remaining 50% will be converted into heat. (Depending on the fuel cell system design, some fuel might leave the system unreacted, constituting an additional loss.) For a hydrogen cell operating at standard conditions with no reactant leaks, the efficiency is equal to the cell voltage divided by 1.48 V, based on the enthalpy, or heating value, of the reaction. For the same cell, the second law efficiency is equal to cell voltage divided by 1.23 V. (This voltage varies with fuel used, and quality and temperature of the cell.) The difference between these number represents the difference between the reaction's enthalpy and Gibbs free energy. This difference always appears as heat, along with any losses in electrical conversion efficiency. Fuel cells are not constrained by the maximum Carnot cycle efficiency as combustion engines are, because they do not operate with a thermal cycle. At times this is misrepresented by saying that fuel cells are exempt from the laws of thermodynamics, because most people think of thermodynamics in terms of combustion processes (enthalpy of formation). The laws of thermodynamics also hold for chemical processes (Gibb's free energy) like fuel cells, but the maximum theoretical efficiency is higher (83% efficient at 298K ) than the Otto cycle thermal efficiency (60% for compression ratio of 10 and specific heat ratio of 1.4). Of course, comparing limits imposed by thermodynamics is not a good predictor of practically achievable efficiencies. Also, if propulsion is the goal, electrical output of the fuel cell has to still be converted into mechanical power with the corresponding inefficiency. In reference to the exemption claim, the correct claim is that the "limitations imposed by the second law of thermodynamics on the operation of fuel cells are much less severe than the limitations imposed on conventional energy conversion systems". Consequently, they can have very high efficiencies in converting chemical energy to electrical energy, especially when they are operated at low power density, and using pure hydrogen and oxygen as reactants. ## In practice For a fuel cell operated on air (rather than bottled oxygen), losses due to the air supply system must also be taken into account. This refers to the pressurization of the air and adding moisture to it. This reduces the efficiency significantly and brings it near to the efficiency of a compression ignition engine. Furthermore fuel cells have lower efficiencies at higher loads. The tank-to-wheel efficiency of a fuel cell vehicle is about 45% at low loads and shows average values of about 36% when a driving cycle like the NEDC (New European Driving Cycle) is used as test procedure. The comparable NEDC value for a Diesel vehicle is 22%. It is also important to take losses due to production, transportation, and storage into account. Fuel cell vehicles running on compressed hydrogen may have a power-plant-to-wheel efficiency of 22% if the hydrogen is stored as high-pressure gas, and 17% if it is stored as liquid hydrogen. Fuel cells cannot store energy like a battery, but in some applications, such as stand-alone power plants based on discontinuous sources such as solar or wind power, they are combined with electrolyzers and storage systems to form an energy storage system. The overall efficiency (electricity to hydrogen and back to electricity) of such plants (known as round-trip efficiency) is between 30 and 50%, depending on conditions. While a much cheaper lead-acid battery might return about 90%, the electrolyzer/fuel cell system can store indefinite quantities of hydrogen, and is therefore better suited for long-term storage. Solid-oxide fuel cells produce exothermic heat from the recombination of the oxygen and hydrogen. The ceramic can run as hot as 800 degrees Celsius. This heat can be captured and used to heat water in a micro combined heat and power (m-CHP) application. When the heat is captured, total efficiency can reach 80-90%. CHP units are being developed today for the European home market. # Fuel cell applications Fuel cells are very useful as power sources in remote locations, such as spacecraft, remote weather stations, large parks, rural locations, and in certain military applications. A fuel cell system running on hydrogen can be compact, lightweight and has no major moving parts. Because fuel cells have no moving parts and do not involve combustion, in ideal conditions they can achieve up to 99.9999% reliability. This equates to less than one minute of down time in a six year period. A new application is micro combined heat and power, which is cogeneration for family homes, office buildings and factories. This type of system generates constant electric power (selling excess power back to the grid when it is not consumed), and at the same time produces hot air and water from the waste heat. A lower fuel-to-electricity conversion efficiency is tolerated (typically 15-20%), because most of the energy not converted into electricity is utilized as heat. Some heat is lost with the exhaust gas just as in a normal furnace, so the combined heat and power efficiency is still lower than 100%, typically around 80%. In terms of exergy however, the process is inefficient, and one could do better by maximizing the electricity generated and then using the electricity to drive a heat pump. Phosphoric-acid fuel cells (PAFC) comprise the largest segment of existing CHP products worldwide and can provide combined efficiencies close to 90% (35-50% electric + remainder as thermal) Molten-carbonate fuel cells have also been installed in these applications, and solid-oxide fuel cell prototypes exist. However, since electrolyzer systems do not store fuel in themselves, but rather rely on external storage units, they can be successfully applied in large-scale energy storage, rural areas being one example. In this application, batteries would have to be largely oversized to meet the storage demand, but fuel cells only need a larger storage unit (typically cheaper than an electrochemical device). One such pilot program is operating on Stuart Island in Washington State. There the Stuart Island Energy Initiative has built a complete, closed-loop system: Solar panels power an electrolyzer which makes hydrogen. The hydrogen is stored in a 500 gallon tank at 200 PSI, and runs a ReliOn fuel cell to provide full electric back-up to the off-the-grid residence. The SIEI website gives extensive technical details. The world's first Fuel Cell operated and certified passenger ship was the "HYDRA" (see picture). Mr. Christian Machens was the founder of the company "etaing GmbH" and realised this project with a small team of young engineers in Leipzig. It was christened in June 2000 in Bonn. The Fuel Cell System (AFC type, 6,5 kWel net output) was built in Wurzen near Leipzig, the hull was built in Hamburg and it was certified by the Germanischer Lloyd (Hamburg). The boat has transported around 2.000 persons without any major technical problems. The main advantages of the AFC technology are that the system can start at freezing temperatures (-10°C) and is not sensitive to a salty environment. ## Suggested applications - Base load power plants - Electric and hybrid vehicles. - Auxiliary power - Off-grid power supply - Notebook computers for applications where AC charging may not be available for weeks at a time. - Portable charging docks for small electronics (e.g. a belt clip that charges your cell phone or PDA). ## Hydrogen transportation and refueling The first public hydrogen refueling station was opened in Reykjavík, Iceland in April 2003. This station serves three buses built by DaimlerChrysler that are in service in the public transport net of Reykjavík. The station produces the hydrogen it needs by itself, with an electrolyzing unit (produced by Norsk Hydro), and does not need refilling: all that enters is electricity and water. Royal Dutch Shell is also a partner in the project. The station has no roof, in order to allow any leaked hydrogen to escape to the atmosphere. The GM 1966 Electrovan was the automotive industry's first attempt at an automobile powered by a hydrogen fuel cell. The Electrovan, which weighed more than twice as much as a normal van, could travel up to 70mph for 30 seconds. The 2001 Chrysler Natrium used its own on-board hydrogen processor. It produces hydrogen for the fuel cell by reacting sodium borohydride fuel with Borax, both of which Chrysler claimed was naturally occurring in great quantity in the United States. The hydrogen produces electric power in the fuel cell for near-silent operation and a range of 300 miles without impinging on passenger space. Chrysler also developed vehicles which separated hydrogen from gasoline in the vehicle, the purpose being to reduce emissions without relying on a nonexistent hydrogen infrastructure and to avoid large storage tanks. In 2005 the British firm Intelligent Energy produced the first ever working hydrogen run motorcycle called the ENV (Emission Neutral Vehicle). The motorcycle holds enough fuel to run for four hours, and to travel 100 miles in an urban area. Its top speed is 50 miles per hour. Honda is also going to offer fuel-cell motorcycles. There are numerous prototype or production cars and buses based on fuel cell technology being researched or manufactured. Research is ongoing at a variety of motor car manufacturers. Honda has announced the release of a hydrogen vehicle in 2008. Type 212 submarines use fuel cells to remain submerged for weeks without the need to surface. Boeing researchers and industry partners throughout Europe are planning to conduct experimental flight tests in 2007 of a manned airplane powered only by a fuel cell and lightweight batteries. The Fuel Cell Demonstrator Airplane research project was completed recently and thorough systems integration testing is now under way in preparation for upcoming ground and flight testing. The Boeing demonstrator uses a Proton Exchange Membrane (PEM) fuel cell/lithium-ion battery hybrid system to power an electric motor, which is coupled to a conventional propeller. ## Market structure Not all geographic markets are ready for SOFC powered m-CHP appliances. Currently, the regions that lead the race in Distributed Generation and deployment of fuel cell m-CHP units are the EU and Japan. # Hydrogen economy Electrochemical extraction of energy from hydrogen via fuel cells is an especially clean method of meeting our power needs, but not an efficient one, due to the necessity of adding large amounts of energy to either water or hydrocarbon fuels in order to produce the hydrogen. Additionally, during the extraction of hydrogen from hydrocarbons, carbon monoxide is released. Although this gas is artificially converted into carbon dioxide, such a method of extracting hydrogen remains environmentally injurious. It must however be noted that regarding the concept of the hydrogen vehicle, burning/combustion of hydrogen in an internal combustion engine (IC/ICE) is often confused with the electrochemical process of generating electricity via fuel cells (FC) in which there is no combustion (though there is a small byproduct of heat in the reaction). Both processes require the establishment of a hydrogen economy before they may be considered commercially viable, and even then, the aforementioned energy costs make a hydrogen economy of questionable environmental value. Hydrogen combustion is similar to petroleum combustion, and like petroleum combustion, still results in nitrogen oxides as a by-product of the combustion, which lead to smog. Hydrogen combustion, like that of petroleum, is limited by the Carnot efficiency, but is completely different from the hydrogen fuel cell's chemical conversion process of hydrogen to electricity and water without combustion. Hydrogen fuel cells emit only water during use, while producing carbon dioxide emissions during the majority of hydrogen production, which comes from natural gas. Direct methane or natural gas conversion (whether IC or FC) also generate carbon dioxide emissions, but direct hydrocarbon conversion in high-temperature fuel cells produces lower carbon dioxide emissions than either combustion of the same fuel (due to the higher efficiency of the fuel cell process compared to combustion), and also lower carbon dioxide emissions than hydrogen fuel cells, which use methane less efficiently than high-temperature fuel cells by first converting it to high-purity hydrogen by steam reforming. Although hydrogen can also be produced by electrolysis of water using renewable energy, at present less than 3% of hydrogen is produced in this way. Hydrogen is an energy carrier, and not an energy source, because it is usually produced from other energy sources via petroleum combustion, wind power, or solar photovoltaic cells. Hydrogen may be produced from subsurface reservoirs of methane and natural gas by a combination of steam reforming with the water gas shift reaction, from coal by coal gasification, or from oil shale by oil shale gasification. Electrolysis, which requires electricity, and high-temperature electrolysis/thermochemical production, which requires high temperatures (ideal for nuclear reactors), are two primary methods for the extraction of hydrogen from water. As of 2005, 49.7% of the electricity produced in the United States comes from coal, 19.3% comes from nuclear, 18.7% comes from natural gas, 6.5% from hydroelectricity, 3% from petroleum and the remaining 2.8% mostly coming from geothermal, solar and biomass. When hydrogen is produced through electrolysis, the energy comes from these sources. Though the fuel cell itself will only emit heat and water as waste, pollution is often caused when generating the electricity required to produce the hydrogen that the fuel cell uses as its power source (for example, when coal, oil, or natural gas-generated electricity is used). This will be the case unless the hydrogen is produced using electricity generated by hydroelectric, geothermal, solar, wind or other clean power sources (which may or may not include nuclear power, depending on one's attitude to the nuclear waste byproducts); hydrogen is only as clean as the energy sources used to produce it. If fusion power were to become a viable energy source, then this would provide a clean method of producing abundant electricity. A holistic approach has to take into consideration the impacts of an extended hydrogen scenario, including the production, the use and the disposal of infrastructure and energy converters. Nowadays low temperature fuel cell stacks proton exchange membrane fuel cell (PEMFC), direct methanol fuel cell (DMFC) and phosphoric acid fuel cell (PAFC) make extensive use of catalysts. Impurities poison or foul the catalysts (reducing activity and efficiency), thus higher catalyst densities are required. Limited reserves of platinum quicken the synthesis of an inorganic complex very similar to the catalytic iron-sulfur core of bacterial hydrogenase to step in. Although platinum is seen by some as one of the major "showstoppers" to mass market fuel cell commercialization companies, most predictions of platinum running out and/or platinum prices soaring do not take into account effects of thrifting (reduction in catalyst loading) and recycling. Recent research at Brookhaven National Laboratory could lead to the replacement of platinum by a gold-palladium coating which may be less susceptible to poisoning and thereby improve fuel cell lifetime considerably. Current targets for a transport PEM fuel cells are 0.2 g/kW Pt – which is a factor of 5 decrease over current loadings – and recent comments from major original equipment manufacturers (OEMs) indicate that this is possible. Also it is fully anticipated that recycling of fuel cells components, including platinum, will kick-in. High-temperature fuel cells, including molten carbonate fuel cells (MCFC's) and solid oxide fuel cells (SOFC's), do not use platinum as catalysts, but instead use cheaper materials such as nickel and nickel oxide, which are considerably more abundant (for example, nickel is used in fairly large quantities in common stainless steel). # Research and development - August 2005: Georgia Institute of Technology researchers use triazole to raise the operating temperature of PEM fuel cells from below 100 °C to over 120 °C, claiming this will require less carbon-monoxide purification of the hydrogen fuel. - 2006:Staxon introduced an inexpensive OEM fuel cell module for system integration. In 2006 Angstrom Power, a British Columbia based company, began commercial sales of portable devices using proprietary hydrogen fuel cell technology, trademarked as "micro hydrogen."	Fuel cell A fuel cell is an electrochemical energy conversion device. It produces electricity from various external quantities of fuel (on the anode side) and an oxidant (on the cathode side). These react in the presence of an electrolyte. Generally, the reactants flow in and reaction products flow out while the electrolyte remains in the cell. Fuel cells can operate virtually continuously as long as the necessary flows are maintained. Fuel cells are different from batteries in that they consume reactant, which must be replenished, whereas batteries store electrical energy chemically in a closed system. Additionally, while the electrodes within a battery react and change as a battery is charged or discharged, a fuel cell's electrodes are catalytic and relatively stable. Many combinations of fuel and oxidant are possible. A hydrogen cell uses hydrogen as fuel and oxygen as oxidant. Other fuels include hydrocarbons and alcohols. Other oxidants include air, chlorine and chlorine dioxide.[1] # Fuel cell design In essence, a fuel cell works by catalysis, separating the component electrons and protons of the reactant fuel, and forcing the electrons to travel though a circuit, hence converting them to electrical power. The catalyst is typically comprised of a platinum group metal or alloy. Another catalytic process takes the electrons back in, combining them with the protons and the oxidant to form waste products (typically simple compounds like water and carbon dioxide). In the archetypal hydrogen–oxygen proton exchange membrane fuel cell (PEMFC) design, a proton-conducting polymer membrane, (the electrolyte), separates the anode and cathode sides. This was called a "solid polymer electrolyte fuel cell" (SPEFC) in the early 1970s, before the proton exchange mechanism was well-understood. (Notice that "polymer electrolyte membrane" and "proton exchange membrane" result in the same acronym.) On the anode side, hydrogen diffuses to the anode catalyst where it later dissociates into protons and electrons. These protons often react with oxidants causing them to become what is commonly reffered to as multi-facilitated proton membranes (MFPM). The protons are conducted through the membrane to the cathode, but the electrons are forced to travel in an external circuit (supplying power) because the membrane is electrically insulating. On the cathode catalyst, oxygen molecules react with the electrons (which have traveled through the external circuit) and protons to form water — in this example, the only waste product, either liquid or vapor. In addition to this pure hydrogen type, there are hydrocarbon fuels for fuel cells, including diesel, methanol (see: direct-methanol fuel cells) and chemical hydrides. The waste products with these types of fuel are carbon dioxide and water. The materials used in fuel cells differ by type. The electrode–bipolar plates are usually made of metal, nickel or carbon nanotubes, and are coated with a catalyst (like platinum, nano iron powders or palladium) for higher efficiency. Carbon paper separates them from the electrolyte. The electrolyte could be ceramic or a membrane. A typical PEM fuel cell produces a voltage from 0.6 V to 0.7 V at full rated load. Voltage decreases as current increases, due to several factors: - Activation loss - Ohmic loss (voltage drop due to resistance of the cell components and interconnects) - Mass transport loss (depletion of reactants at catalyst sites under high loads, causing rapid loss of voltage)[3] To deliver the desired amount of energy, the fuel cells can be combined in series and parallel circuits, where series yield higher voltage, and parallel allows a stronger current to be drawn. Such a design is called a fuel cell stack. Further, the cell surface area can be increased, to allow stronger current from each cell. ## Fuel cell design issues - Costs. In 2002, typical cells had a catalyst content of US$1000 per kilowatt of electric power output. In 2008 UTC Power has 400kw Fuel cells for $1,000,000 per 400kW installed costs. The goal is to reduce the cost in order to compete with current market technologies including gasoline internal combustion engines. Many companies are working on techniques to reduce cost in a variety of ways including reducing the amount of platinum needed in each individual cell. Ballard Power Systems have experiments with a catalyst enhanced with carbon silk which allows a 30% reduction (1 mg/cm² to 0.7 mg/cm²) in platinum usage without reduction in performance.[4] - The production costs of the PEM (proton exchange membrane). The Nafion® membrane currently costs €400/m². This, and the Toyota PEM and 3M PEM membrane can be replaced with the ITM Power membrane (a hydrocarbon polymer), resulting in a price of ~€4/m². in 2005 Ballard Power Systems announced that its fuel cells will use Solupor®, a porous polyethylene film patented by DSM.[5][6] - Water and air management[7] (in PEMFCs). In this type of fuel cell, the membrane must be hydrated, requiring water to be evaporated at precisely the same rate that it is produced. If water is evaporated too quickly, the membrane dries, resistance across it increases, and eventually it will crack, creating a gas "short circuit" where hydrogen and oxygen combine directly, generating heat that will damage the fuel cell. If the water is evaporated too slowly, the electrodes will flood, preventing the reactants from reaching the catalyst and stopping the reaction. Methods to manage water in cells are being developed like electroosmotic pumps focusing on flow control. Just as in a combustion engine, a steady ratio between the reactant and oxygen is necessary to keep the fuel cell operating efficiently. - Temperature management. The same temperature must be maintained throughout the cell in order to prevent destruction of the cell through thermal loading. This is particularly challenging as the 2H2 + O2 -> 2H2O reaction is highly exothermic, so a large quantity of heat is generated within the fuel cell. - Durability, service life, and special requirements for some type of cells. Stationary applications typically require more than 40,000 hours of reliable operation at a temperature of -35 °C to 40 °C, while automotive fuel cells require a 5,000 hour lifespan (the equivalent of 150,000 miles) under extreme temperatures. Automotive engines must also be able to start reliably at -30 °C and have a high power to volume ratio (typically 2.5 kW per liter). - Limited carbon monoxide tolerance of the anode. # History The principle of the fuel cell was discovered by German scientist Christian Friedrich Schönbein in 1838 and published in the January 1839 edition of the "Philosophical Magazine".[8] Based on this work, the first fuel cell was developed by Welsh scientist Sir William Robert Grove in 1843. The fuel cell he made used similar materials to today's phosphoric-acid fuel cell. In 1955, W. Thomas Grubb, a chemist working for the General Electric Company (GE), further modified the original fuel cell design by using a sulphonated polystyrene ion-exchange membrane as the electrolyte. Three years later another GE chemist, Leonard Niedrach, devised a way of depositing platinum onto the membrane, which served as catalyst for the necessary hydrogen oxidation and oxygen reduction reactions. This became known as the 'Grubb-Niedrach fuel cell'. GE went on to develop this technology with NASA and McDonnell Aircraft, leading to its use during Project Gemini. This was the first commercial use of a fuel cell. It wasn't until 1959 that British engineer Francis Thomas Bacon successfully developed a 5 kW stationary fuel cell. In 1959, a team led by Harry Ihrig built a 15 kW fuel cell tractor for Allis-Chalmers which was demonstrated across the US at state fairs. This system used potassium hydroxide as the electrolyte and compressed hydrogen and oxygen as the reactants. Later in 1959, Bacon and his colleagues demonstrated a practical five-kilowatt unit capable of powering a welding machine. In the 1960s, Pratt and Whitney licensed Bacon's U.S. patents for use in the U.S. space program to supply electricity and drinking water (hydrogen and oxygen being readily available from the spacecraft tanks). United Technology Corp.'s UTC Power subsidiary was the first company to manufacture and commercialize a large, stationary fuel cell system for use as a co-generation power plant in hospitals, universities and large office buildings. UTC Power continues to market this fuel cell as the PureCell 200, a 200 kW system.[9] UTC Power continues to be the sole supplier of fuel cells to NASA for use in space vehicles, having supplied the Apollo missions, [10] and currently the Space Shuttle program, and is developing fuel cells for automobiles, buses, and cell phone towers; the company has demonstrated the first fuel cell capable of starting under freezing conditions with its proton exchange membrane automotive fuel cell. # Types of fuel cells # Efficiency ## Fuel cell efficiency The efficiency of a fuel cell is dependent on the amount of power drawn from it. Drawing more power means drawing more current, which increases the losses in the fuel cell. As a general rule, the more power (current) drawn, the lower the efficiency. Most losses manifest themselves as a voltage drop in the cell, so the efficiency of a cell is almost proportional to its voltage. For this reason, it is common to show graphs of voltage versus current (so-called polarization curves) for fuel cells. A typical cell running at 0.7 V has an efficiency of about 50%, meaning that 50% of the energy content of the hydrogen is converted into electrical energy; the remaining 50% will be converted into heat. (Depending on the fuel cell system design, some fuel might leave the system unreacted, constituting an additional loss.) For a hydrogen cell operating at standard conditions with no reactant leaks, the efficiency is equal to the cell voltage divided by 1.48 V, based on the enthalpy, or heating value, of the reaction. For the same cell, the second law efficiency is equal to cell voltage divided by 1.23 V. (This voltage varies with fuel used, and quality and temperature of the cell.) The difference between these number represents the difference between the reaction's enthalpy and Gibbs free energy. This difference always appears as heat, along with any losses in electrical conversion efficiency. Fuel cells are not constrained by the maximum Carnot cycle efficiency as combustion engines are, because they do not operate with a thermal cycle. At times this is misrepresented by saying that fuel cells are exempt from the laws of thermodynamics, because most people think of thermodynamics in terms of combustion processes (enthalpy of formation). The laws of thermodynamics also hold for chemical processes (Gibb's free energy) like fuel cells, but the maximum theoretical efficiency is higher (83% efficient at 298K [11]) than the Otto cycle thermal efficiency (60% for compression ratio of 10 and specific heat ratio of 1.4). Of course, comparing limits imposed by thermodynamics is not a good predictor of practically achievable efficiencies. Also, if propulsion is the goal, electrical output of the fuel cell has to still be converted into mechanical power with the corresponding inefficiency. In reference to the exemption claim, the correct claim is that the "limitations imposed by the second law of thermodynamics on the operation of fuel cells are much less severe than the limitations imposed on conventional energy conversion systems".[12] Consequently, they can have very high efficiencies in converting chemical energy to electrical energy, especially when they are operated at low power density, and using pure hydrogen and oxygen as reactants. ## In practice For a fuel cell operated on air (rather than bottled oxygen), losses due to the air supply system must also be taken into account. This refers to the pressurization of the air and adding moisture to it. This reduces the efficiency significantly and brings it near to the efficiency of a compression ignition engine. Furthermore fuel cells have lower efficiencies at higher loads. The tank-to-wheel efficiency of a fuel cell vehicle is about 45% at low loads and shows average values of about 36% when a driving cycle like the NEDC (New European Driving Cycle) is used as test procedure.[13] The comparable NEDC value for a Diesel vehicle is 22%. It is also important to take losses due to production, transportation, and storage into account. Fuel cell vehicles running on compressed hydrogen may have a power-plant-to-wheel efficiency of 22% if the hydrogen is stored as high-pressure gas, and 17% if it is stored as liquid hydrogen.[14] Fuel cells cannot store energy like a battery, but in some applications, such as stand-alone power plants based on discontinuous sources such as solar or wind power, they are combined with electrolyzers and storage systems to form an energy storage system. The overall efficiency (electricity to hydrogen and back to electricity) of such plants (known as round-trip efficiency) is between 30 and 50%, depending on conditions.[15] While a much cheaper lead-acid battery might return about 90%, the electrolyzer/fuel cell system can store indefinite quantities of hydrogen, and is therefore better suited for long-term storage. Solid-oxide fuel cells produce exothermic heat from the recombination of the oxygen and hydrogen. The ceramic can run as hot as 800 degrees Celsius. This heat can be captured and used to heat water in a micro combined heat and power (m-CHP) application. When the heat is captured, total efficiency can reach 80-90%. CHP units are being developed today for the European home market. # Fuel cell applications Fuel cells are very useful as power sources in remote locations, such as spacecraft, remote weather stations, large parks, rural locations, and in certain military applications. A fuel cell system running on hydrogen can be compact, lightweight and has no major moving parts. Because fuel cells have no moving parts and do not involve combustion, in ideal conditions they can achieve up to 99.9999% reliability.[16] This equates to less than one minute of down time in a six year period. A new application is micro combined heat and power, which is cogeneration for family homes, office buildings and factories. This type of system generates constant electric power (selling excess power back to the grid when it is not consumed), and at the same time produces hot air and water from the waste heat. A lower fuel-to-electricity conversion efficiency is tolerated (typically 15-20%), because most of the energy not converted into electricity is utilized as heat. Some heat is lost with the exhaust gas just as in a normal furnace, so the combined heat and power efficiency is still lower than 100%, typically around 80%. In terms of exergy however, the process is inefficient, and one could do better by maximizing the electricity generated and then using the electricity to drive a heat pump. Phosphoric-acid fuel cells (PAFC) comprise the largest segment of existing CHP products worldwide and can provide combined efficiencies close to 90%[17] (35-50% electric + remainder as thermal) Molten-carbonate fuel cells have also been installed in these applications, and solid-oxide fuel cell prototypes exist. . However, since electrolyzer systems do not store fuel in themselves, but rather rely on external storage units, they can be successfully applied in large-scale energy storage, rural areas being one example. In this application, batteries would have to be largely oversized to meet the storage demand, but fuel cells only need a larger storage unit (typically cheaper than an electrochemical device). One such pilot program is operating on Stuart Island in Washington State. There the Stuart Island Energy Initiative [18]has built a complete, closed-loop system: Solar panels power an electrolyzer which makes hydrogen. The hydrogen is stored in a 500 gallon tank at 200 PSI, and runs a ReliOn fuel cell to provide full electric back-up to the off-the-grid residence. The SIEI website gives extensive technical details. The world's first Fuel Cell operated and certified passenger ship was the "HYDRA" (see picture). Mr. Christian Machens was the founder of the company "etaing GmbH" and realised this project with a small team of young engineers in Leipzig. It was christened in June 2000 in Bonn. The Fuel Cell System (AFC type, 6,5 kWel net output) was built in Wurzen near Leipzig, the hull was built in Hamburg and it was certified by the Germanischer Lloyd (Hamburg). The boat has transported around 2.000 persons without any major technical problems. The main advantages of the AFC technology are that the system can start at freezing temperatures (-10°C) and is not sensitive to a salty environment. ## Suggested applications - Base load power plants - Electric and hybrid vehicles. - Auxiliary power - Off-grid power supply - Notebook computers for applications where AC charging may not be available for weeks at a time. - Portable charging docks for small electronics (e.g. a belt clip that charges your cell phone or PDA). ## Hydrogen transportation and refueling Template:Seedetails Template:Seedetails The first public hydrogen refueling station was opened in Reykjavík, Iceland in April 2003. This station serves three buses built by DaimlerChrysler that are in service in the public transport net of Reykjavík. The station produces the hydrogen it needs by itself, with an electrolyzing unit (produced by Norsk Hydro), and does not need refilling: all that enters is electricity and water. Royal Dutch Shell is also a partner in the project. The station has no roof, in order to allow any leaked hydrogen to escape to the atmosphere. Template:Seedetails The GM 1966 Electrovan was the automotive industry's first attempt at an automobile powered by a hydrogen fuel cell. The Electrovan, which weighed more than twice as much as a normal van, could travel up to 70mph for 30 seconds.[19][20] The 2001 Chrysler Natrium used its own on-board hydrogen processor. It produces hydrogen for the fuel cell by reacting sodium borohydride fuel with Borax, both of which Chrysler claimed was naturally occurring in great quantity in the United States.[21] The hydrogen produces electric power in the fuel cell for near-silent operation and a range of 300 miles without impinging on passenger space. Chrysler also developed vehicles which separated hydrogen from gasoline in the vehicle, the purpose being to reduce emissions without relying on a nonexistent hydrogen infrastructure and to avoid large storage tanks.[22] In 2005 the British firm Intelligent Energy produced the first ever working hydrogen run motorcycle called the ENV (Emission Neutral Vehicle). The motorcycle holds enough fuel to run for four hours, and to travel 100 miles in an urban area. Its top speed is 50 miles per hour.[23] Honda is also going to offer fuel-cell motorcycles.[24][25] There are numerous prototype or production cars and buses based on fuel cell technology being researched or manufactured. Research is ongoing at a variety of motor car manufacturers. Honda has announced the release of a hydrogen vehicle in 2008.[26] Type 212 submarines use fuel cells to remain submerged for weeks without the need to surface. Boeing researchers and industry partners throughout Europe are planning to conduct experimental flight tests in 2007 of a manned airplane powered only by a fuel cell and lightweight batteries. The Fuel Cell Demonstrator Airplane research project was completed recently and thorough systems integration testing is now under way in preparation for upcoming ground and flight testing. The Boeing demonstrator uses a Proton Exchange Membrane (PEM) fuel cell/lithium-ion battery hybrid system to power an electric motor, which is coupled to a conventional propeller. ## Market structure Not all geographic markets are ready for SOFC powered m-CHP appliances. Currently, the regions that lead the race in Distributed Generation and deployment of fuel cell m-CHP units are the EU and Japan.[27] # Hydrogen economy Electrochemical extraction of energy from hydrogen via fuel cells is an especially clean method of meeting our power needs, but not an efficient one, due to the necessity of adding large amounts of energy to either water or hydrocarbon fuels in order to produce the hydrogen. Additionally, during the extraction of hydrogen from hydrocarbons, carbon monoxide is released. Although this gas is artificially converted into carbon dioxide, such a method of extracting hydrogen remains environmentally injurious. It must however be noted that regarding the concept of the hydrogen vehicle, burning/combustion of hydrogen in an internal combustion engine (IC/ICE) is often confused with the electrochemical process of generating electricity via fuel cells (FC) in which there is no combustion (though there is a small byproduct of heat in the reaction). Both processes require the establishment of a hydrogen economy before they may be considered commercially viable, and even then, the aforementioned energy costs make a hydrogen economy of questionable environmental value. Hydrogen combustion is similar to petroleum combustion, and like petroleum combustion, still results in nitrogen oxides as a by-product of the combustion, which lead to smog. Hydrogen combustion, like that of petroleum, is limited by the Carnot efficiency, but is completely different from the hydrogen fuel cell's chemical conversion process of hydrogen to electricity and water without combustion. Hydrogen fuel cells emit only water during use, while producing carbon dioxide emissions during the majority of hydrogen production, which comes from natural gas. Direct methane or natural gas conversion (whether IC or FC) also generate carbon dioxide emissions, but direct hydrocarbon conversion in high-temperature fuel cells produces lower carbon dioxide emissions than either combustion of the same fuel (due to the higher efficiency of the fuel cell process compared to combustion), and also lower carbon dioxide emissions than hydrogen fuel cells, which use methane less efficiently than high-temperature fuel cells by first converting it to high-purity hydrogen by steam reforming. Although hydrogen can also be produced by electrolysis of water using renewable energy, at present less than 3% of hydrogen is produced in this way. Hydrogen is an energy carrier, and not an energy source, because it is usually produced from other energy sources via petroleum combustion, wind power, or solar photovoltaic cells. Hydrogen may be produced from subsurface reservoirs of methane and natural gas by a combination of steam reforming with the water gas shift reaction, from coal by coal gasification, or from oil shale by oil shale gasification.[citation needed] Electrolysis, which requires electricity, and high-temperature electrolysis/thermochemical production, which requires high temperatures (ideal for nuclear reactors), are two primary methods for the extraction of hydrogen from water. As of 2005, 49.7% of the electricity produced in the United States comes from coal, 19.3% comes from nuclear, 18.7% comes from natural gas, 6.5% from hydroelectricity, 3% from petroleum and the remaining 2.8% mostly coming from geothermal, solar and biomass. [28] When hydrogen is produced through electrolysis, the energy comes from these sources. Though the fuel cell itself will only emit heat and water as waste, pollution is often caused when generating the electricity required to produce the hydrogen that the fuel cell uses as its power source (for example, when coal, oil, or natural gas-generated electricity is used). This will be the case unless the hydrogen is produced using electricity generated by hydroelectric, geothermal, solar, wind or other clean power sources (which may or may not include nuclear power, depending on one's attitude to the nuclear waste byproducts); hydrogen is only as clean as the energy sources used to produce it. If fusion power were to become a viable energy source, then this would provide a clean method of producing abundant electricity. A holistic approach has to take into consideration the impacts of an extended hydrogen scenario, including the production, the use and the disposal of infrastructure and energy converters. Nowadays low temperature fuel cell stacks proton exchange membrane fuel cell (PEMFC), direct methanol fuel cell (DMFC) and phosphoric acid fuel cell (PAFC) make extensive use of catalysts. Impurities poison or foul the catalysts (reducing activity and efficiency), thus higher catalyst densities are required.[29] Limited reserves of platinum quicken the synthesis of an inorganic complex very similar to the catalytic iron-sulfur core of bacterial hydrogenase to step in.[30] Although platinum is seen by some as one of the major "showstoppers" to mass market fuel cell commercialization companies, most predictions of platinum running out and/or platinum prices soaring do not take into account effects of thrifting (reduction in catalyst loading) and recycling. Recent research at Brookhaven National Laboratory could lead to the replacement of platinum by a gold-palladium coating which may be less susceptible to poisoning and thereby improve fuel cell lifetime considerably.[31] Current targets for a transport PEM fuel cells are 0.2 g/kW Pt – which is a factor of 5 decrease over current loadings – and recent comments from major original equipment manufacturers (OEMs) indicate that this is possible. Also it is fully anticipated that recycling of fuel cells components, including platinum, will kick-in. High-temperature fuel cells, including molten carbonate fuel cells (MCFC's) and solid oxide fuel cells (SOFC's), do not use platinum as catalysts, but instead use cheaper materials such as nickel and nickel oxide, which are considerably more abundant (for example, nickel is used in fairly large quantities in common stainless steel). # Research and development - August 2005: Georgia Institute of Technology researchers use triazole to raise the operating temperature of PEM fuel cells from below 100 °C to over 120 °C, claiming this will require less carbon-monoxide purification of the hydrogen fuel.[32] - 2006:Staxon introduced an inexpensive OEM fuel cell module for system integration. In 2006 Angstrom Power, a British Columbia based company, began commercial sales of portable devices using proprietary hydrogen fuel cell technology, trademarked as "micro hydrogen."[33][34]	https://www.wikidoc.org/index.php/Fuel_cell
87d9f01839b942dcf6e1cb8775e9135f9643564e	wikidoc	Fume hood	Fume hood A fume hood or fume cupboard is a large piece of scientific equipment common to chemistry laboratories designed to limit a person's exposure to hazardous and/or unpleasant fumes. Fume hoods were originally manufactured from timber, but now epoxy coated mild steel is the main construction material. Two main types of unit exist, ducted and recirculating. With the ducted type, old asbestos vent pipe has been superseded on health grounds, typically with PVC or polypropylene. The principle is the same for all units; air is drawn in from the front of the cabinet by a fan, and either expelled outside the building or made safe through filtration and fed back into the room. # Construction and location Fume hoods (fume cupboards) are generally available in 5 different widths; 1000 mm, 1200 mm, 1500 mm, 1800 mm and 2000 mm. The depth varies between 700 mm and 900 mm, and the height between 1900 mm and 2400 mm. These can accommodate from one to three operators. They are generally set back against the walls and are often fitted with infills above, to cover up the extract ductwork. Because of their shape they are generally dim inside, so many have internal lights with gas-proof covers. The front is a movable sash, usually in glass, able to move up and down on a counterbalance mechanism. On educational versions, the sides of the unit are often also glass, so that several pupils can gather around a fume hood at once. Alarm control panels are common, see below. # Recirculating fume hoods Mainly for educational use, or where the design of a building does not permit the fitting of external ductwork, these units generally have a fan mounted on the top (soffit) of the hood, or beneath the worktop. Air is sucked through the front opening of the hood and through a filter, before passing through the fan and being fed back into the workplace. ## Pre-filtration The first stage of filtration consists of a physical barrier, typically of open cell foam, which prevents large particles from passing through. A filter of this type is generally inexpensive, and would last for approximately six months, dependent on usage. ## Main filtration After pre-filtration, the fumes are sucked through a layer of activated charcoal which absorbs the majority of chemicals that pass through it. Ammonia and carbon monoxide will, however, pass through most carbon filters. Additional specific filtration techniques can be added to combat chemicals that would otherwise be pumped back into the room. A main filter will generally last for approximately two years, dependent on usage. ### Pros - Ductwork not required. - Heated air is not removed from the workplace. - Contaminated air is not pumped into the atmosphere. ### Cons - Filters must be regularly maintained and replaced. - Greater risk of chemical exposure than with ducted equivalents. - The extract fan is near the operator, so noise may be an issue. # Ducted fume hoods Most fume hoods for industrial purposes are ducted. A large variety of ducted fume hoods exist. Air is removed from the workspace and dispersed into the atmosphere. The fume hood is only one piece of the lab ventilation system. As the recirculation of lab air to the rest of the facility is not permitted, air handling units serving the non-laboratory areas are kept segregated from the laboratory units. As a means of improving indoor air quality, some laboratories also utilise single-pass air handling systems, where air that is heated or cooled is used only once prior to discharge. Many laboratories continue to utilise return air systems to the laboratory areas to minimise energy and running costs, while still providing adequate ventilation rates for acceptable working conditions. The fume cupboards serve to evacuate hazardous levels of contaminant. To reduce lab ventilation costs, variable air volume systems are employed, which reduce the volume of the air exhausted as the fume hood sash is closed. This product is often enhanced by an automatic sash closing device, which will close the fume hood sash when the user leaves the fume hood face. The result is that the hoods are operating at the minimum exhaust volume all of the time that no one is actually working in front of them. Since a six foot constant volume hood uses as much energy as three average homes in America, the reduction of minimization of exhaust volume is particularly beneficial in reducing facility energy costs as well as minimizing the impact on the facility infrastructure. Particular attention must be paid to the discharge location, so as not to risk public safety, or to pull the exhaust air back into the building supply air system. ### Pros - Fumes are completely eradicated from the workplace. - Low maintenance. - Quiet operation, due to the extract fan being some distance from the operator. ### Cons - Unsightly ductwork. - Heated air is removed from the workplace. - Fumes are dispersed into the atmosphere, rather than being treated. ## Specific types ### Low flow / high performance In recent years, laboratory fume hood manufacturers have developed and introduced energy-efficient low-flow / high-performance fume hoods, designed to maintain or improve operator protection while reducing expensive HVAC operating costs. ### Perchloric acid These units feature a waterwash system in the ductwork. Because perchloric acid fumes settle, and form explosive crystals, it is vital that the ductwork is cleaned internally with a series of sprays. ### Waterwash These fume hoods have an internal wash system that cleans the interior of the unit, to prevent a build-up of dangerous chemicals. ### Scrubber This type of fume hood absorbs the fumes through a chamber filled with plastic shapes, which are doused with water. The chemicals are washed into a sump, which is often filled with a neutralising liquid. The fumes are then dispersed, or disposed of, in the conventional manner. # Use To determine whether a chemical is likely to require a fume hood for safe usage, its MSDS should be consulted. If there is any doubt, a hood should be used. An operating and maintenance manual should be provided with a new fume hood, which will detail full usage instructions for a new user. If you already know about the hood you are going to use, begin by making sure no one else is using it or has left things in it. If it's free collect what you need to be in the hood (reagents and/or the experimental apparatus if the products will give off noxious fumes). If the light in the hood is too dim to see (It probably will be; even if there's enough light in the room, you will be working in your own shadow) then turn on the internal light. Stand (or sit if there is a stool) where you will be likely to be when you are working, then lower the glass front as far as you can without making it impossible to get your arms under it and work around. # Control panels Most fume hoods are fitted with a mains-powered control panel. Typically, they perform one or more of the following functions: - Warn of low air flow. - Warn of too large an opening at the front of the unit. Known as a "high sash" alarm, this is caused by the sliding glass at the front of the unit being raised higher than is considered safe, due to the resulting air velocity drop. - Provide a method of switching the extract fan on or off. - Provide a method of turning the internal light on or off. Specific extra functions can be added, for example, a switch to turn a waterwash system on or off. ## A warning Even though a properly functioning fume hood provides adequate ventilation, users should not directly smell any chemicals even when using one. Doing this could cause severe damage to the trachea and lungs. A safer method is to wave the palm above the test tube or beaker to waft reduced amounts of the substance towards the user's nose although there is still a danger if toxic fumes are present.	Fume hood Template:Infobox Laboratory equipment A fume hood or fume cupboard is a large piece of scientific equipment common to chemistry laboratories designed to limit a person's exposure to hazardous and/or unpleasant fumes. Fume hoods were originally manufactured from timber, but now epoxy coated mild steel is the main construction material. Two main types of unit exist, ducted and recirculating. With the ducted type, old asbestos vent pipe has been superseded on health grounds, typically with PVC or polypropylene. The principle is the same for all units; air is drawn in from the front of the cabinet by a fan, and either expelled outside the building or made safe through filtration and fed back into the room. # Construction and location Fume hoods (fume cupboards) are generally available in 5 different widths; 1000 mm, 1200 mm, 1500 mm, 1800 mm and 2000 mm. The depth varies between 700 mm and 900 mm, and the height between 1900 mm and 2400 mm. These can accommodate from one to three operators. They are generally set back against the walls and are often fitted with infills above, to cover up the extract ductwork. Because of their shape they are generally dim inside, so many have internal lights with gas-proof covers. The front is a movable sash, usually in glass, able to move up and down on a counterbalance mechanism. On educational versions, the sides of the unit are often also glass, so that several pupils can gather around a fume hood at once. Alarm control panels are common, see below. # Recirculating fume hoods Mainly for educational use, or where the design of a building does not permit the fitting of external ductwork, these units generally have a fan mounted on the top (soffit) of the hood, or beneath the worktop. Air is sucked through the front opening of the hood and through a filter, before passing through the fan and being fed back into the workplace. ## Pre-filtration The first stage of filtration consists of a physical barrier, typically of open cell foam, which prevents large particles from passing through. A filter of this type is generally inexpensive, and would last for approximately six months, dependent on usage. ## Main filtration After pre-filtration, the fumes are sucked through a layer of activated charcoal which absorbs the majority of chemicals that pass through it. Ammonia and carbon monoxide will, however, pass through most carbon filters. Additional specific filtration techniques can be added to combat chemicals that would otherwise be pumped back into the room. A main filter will generally last for approximately two years, dependent on usage. ### Pros - Ductwork not required. - Heated air is not removed from the workplace. - Contaminated air is not pumped into the atmosphere. ### Cons - Filters must be regularly maintained and replaced. - Greater risk of chemical exposure than with ducted equivalents. - The extract fan is near the operator, so noise may be an issue. # Ducted fume hoods Most fume hoods for industrial purposes are ducted. A large variety of ducted fume hoods exist. Air is removed from the workspace and dispersed into the atmosphere. The fume hood is only one piece of the lab ventilation system. As the recirculation of lab air to the rest of the facility is not permitted, air handling units serving the non-laboratory areas are kept segregated from the laboratory units. As a means of improving indoor air quality, some laboratories also utilise single-pass air handling systems, where air that is heated or cooled is used only once prior to discharge. Many laboratories continue to utilise return air systems to the laboratory areas to minimise energy and running costs, while still providing adequate ventilation rates for acceptable working conditions. The fume cupboards serve to evacuate hazardous levels of contaminant. To reduce lab ventilation costs, variable air volume systems are employed, which reduce the volume of the air exhausted as the fume hood sash is closed. This product is often enhanced by an automatic sash closing device, which will close the fume hood sash when the user leaves the fume hood face. The result is that the hoods are operating at the minimum exhaust volume all of the time that no one is actually working in front of them. Since a six foot constant volume hood uses as much energy as three average homes in America, the reduction of minimization of exhaust volume is particularly beneficial in reducing facility energy costs as well as minimizing the impact on the facility infrastructure. Particular attention must be paid to the discharge location, so as not to risk public safety, or to pull the exhaust air back into the building supply air system. ### Pros - Fumes are completely eradicated from the workplace. - Low maintenance. - Quiet operation, due to the extract fan being some distance from the operator. ### Cons - Unsightly ductwork. - Heated air is removed from the workplace. - Fumes are dispersed into the atmosphere, rather than being treated. ## Specific types ### Low flow / high performance In recent years, laboratory fume hood manufacturers have developed and introduced energy-efficient low-flow / high-performance fume hoods, designed to maintain or improve operator protection while reducing expensive HVAC operating costs. ### Perchloric acid These units feature a waterwash system in the ductwork. Because perchloric acid fumes settle, and form explosive crystals, it is vital that the ductwork is cleaned internally with a series of sprays. ### Waterwash These fume hoods have an internal wash system that cleans the interior of the unit, to prevent a build-up of dangerous chemicals. ### Scrubber This type of fume hood absorbs the fumes through a chamber filled with plastic shapes, which are doused with water. The chemicals are washed into a sump, which is often filled with a neutralising liquid. The fumes are then dispersed, or disposed of, in the conventional manner. # Use To determine whether a chemical is likely to require a fume hood for safe usage, its MSDS should be consulted. If there is any doubt, a hood should be used. An operating and maintenance manual should be provided with a new fume hood, which will detail full usage instructions for a new user. If you already know about the hood you are going to use, begin by making sure no one else is using it or has left things in it. If it's free collect what you need to be in the hood (reagents and/or the experimental apparatus if the products will give off noxious fumes). If the light in the hood is too dim to see (It probably will be; even if there's enough light in the room, you will be working in your own shadow) then turn on the internal light. Stand (or sit if there is a stool) where you will be likely to be when you are working, then lower the glass front as far as you can without making it impossible to get your arms under it and work around. # Control panels Most fume hoods are fitted with a mains-powered control panel. Typically, they perform one or more of the following functions: - Warn of low air flow. - Warn of too large an opening at the front of the unit. Known as a "high sash" alarm, this is caused by the sliding glass at the front of the unit being raised higher than is considered safe, due to the resulting air velocity drop. - Provide a method of switching the extract fan on or off. - Provide a method of turning the internal light on or off. Specific extra functions can be added, for example, a switch to turn a waterwash system on or off. ## A warning Even though a properly functioning fume hood provides adequate ventilation, users should not directly smell any chemicals even when using one. Doing this could cause severe damage to the trachea and lungs. A safer method is to wave the palm above the test tube or beaker to waft reduced amounts of the substance towards the user's nose although there is still a danger if toxic fumes are present.	https://www.wikidoc.org/index.php/Fume_hood
e16c7cf1654c3880ff90e6cdfcb2fc4dd95a5a5a	wikidoc	Nephritis	Nephritis # Overview Nephritis is inflammation of the kidney. The word comes from the Greek nephro- meaning "of the kidney" and -itis meaning "inflammation". Nephritis is often caused by infections, toxins, and auto-immune diseases. # Subtypes - Glomerulonephritis is inflammation of the glomeruli. (Often when the term "nephritis" is used without qualification, this is the condition meant.) - Interstitial nephritis or tubulo-interstitial nephritis is inflammation is of the spaces between renal tubules. - Pyelonephritis is when a urinary tract infection has reached the pyelum (pelvis) of the kidney. - Lupus nephritis is an inflammation of the kidney caused by systemic lupus erythematosus (SLE), a disease of the immune system. # Causes Drug Side Effect: - Nivolumab - Sulfasalazine - Oxacillin # Related Chapters - Bright's Disease - Wegener's granulomatosis bg:Нефрит de:Nephritis it:Nefrite nl:Nefritis fi:Munuaistulehdus	Nephritis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Nephritis is inflammation of the kidney. The word comes from the Greek nephro- meaning "of the kidney" and -itis meaning "inflammation". Nephritis is often caused by infections, toxins, and auto-immune diseases. # Subtypes - Glomerulonephritis is inflammation of the glomeruli. (Often when the term "nephritis" is used without qualification, this is the condition meant.) - Interstitial nephritis or tubulo-interstitial nephritis is inflammation is of the spaces between renal tubules. - Pyelonephritis is when a urinary tract infection has reached the pyelum (pelvis) of the kidney. - Lupus nephritis is an inflammation of the kidney caused by systemic lupus erythematosus (SLE), a disease of the immune system. # Causes Drug Side Effect: - Nivolumab - Sulfasalazine - Oxacillin # Related Chapters - Bright's Disease - Wegener's granulomatosis bg:Нефрит de:Nephritis it:Nefrite nl:Nefritis fi:Munuaistulehdus Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Fungal_Nephritis
48c3841d050c2f7c75d920e1c1903ecad6043b29	wikidoc	Furazabol	Furazabol Furazabol (Miotolan) is a derivative of the anabolic steroid stanozolol. It differs from stanozolol by having a furazan ring system in place of the pyrazole. It has a c-17alpha methyl group, which allows it to be taken orally and causes heptatoxicity in some individuals. The more intriguing characteristic of this steroid is that (unlike other anabolic steroids) furazabol has the ability to lower cholesterol levels. According to William Llewellyn, author of Anabolics 2007, the cholesterol-lowering effects of Furazabol are a myth. In the 1970s, research studies showed that Furazabol along with many other orally-active AAS like Anavar (oxandrolone) lowered total serum cholesterol. It was subsequently established that the cholesterol reduction from oral AAS was the result of suppressed HDL levels. As such, it would be expected that Furazabol, like other oral anabolic steroids, while reducing total cholesterol levels would still adversely affect the HDL/LDL ratio and increase the risk of cardiovascular disease. Diversion of this obscure pharmaceutical steroid to the black market rarely occurred while it was being manufactured by Daiichi Seiyaku Company in Japan. However, a number of underground labs (UGL) have produced limited quantities of Furazabol in recent years. Additionally, a non-methylated derivative of Furazabol called Furaguno is currently being sold over-the-counter on the sport nutrition market in the United States in 2006 and 2007. de:Furazabol nl:Furazabol	Furazabol Furazabol (Miotolan) is a derivative of the anabolic steroid stanozolol. It differs from stanozolol by having a furazan ring system in place of the pyrazole. It has a c-17alpha methyl group, which allows it to be taken orally and causes heptatoxicity in some individuals. The more intriguing characteristic of this steroid is that (unlike other anabolic steroids) furazabol has the ability to lower cholesterol levels.[citation needed] According to William Llewellyn, author of Anabolics 2007, the cholesterol-lowering effects of Furazabol are a myth. In the 1970s, research studies showed that Furazabol along with many other orally-active AAS like Anavar (oxandrolone) lowered total serum cholesterol. It was subsequently established that the cholesterol reduction from oral AAS was the result of suppressed HDL levels. As such, it would be expected that Furazabol, like other oral anabolic steroids, while reducing total cholesterol levels would still adversely affect the HDL/LDL ratio and increase the risk of cardiovascular disease. Diversion of this obscure pharmaceutical steroid to the black market rarely occurred while it was being manufactured by Daiichi Seiyaku Company in Japan. However, a number of underground labs (UGL) have produced limited quantities of Furazabol in recent years. Additionally, a non-methylated derivative of Furazabol called Furaguno is currently being sold over-the-counter on the sport nutrition market in the United States in 2006 and 2007. Template:Anabolic steroids de:Furazabol nl:Furazabol Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Furazabol
70e3709cd74e6fde4efb5b65b15528168da94e00	wikidoc	G protein	G protein # Overview G proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. Their nomenclature originates from their ability to function as "molecular switches", alternating between an inactive guanosine diphosphate (GDP) and activated guanosine triphosphate (GTP) bound state, ultimately going on to regulate downstream cell processes. G proteins belong to the larger group of enzymes called GTPases. # History Alfred Gilman and Martin Rodbell were awarded the Nobel Prize in Physiology or Medicine in 1994 for their discovery of and research on G proteins. # Function G proteins are important signal transducing molecules in cells. In fact, diseases such as diabetes and certain forms of cancer, among other pathologies, are thought to arise due to derangement of G protein signaling. # Types of G protein signaling G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins that are activated by G protein-coupled receptors and made up of alpha (α), beta (β) and gamma (γ) subunits. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha (α) subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction. ## Heterotrimeric G proteins Heterotrimeric G proteins share a common mode of action, i.e. activation in response to a conformation change in the G-protein coupled receptor, exchange of GTP for GDP and dissociation in order to activate further proteins in the signal transduction pathway. However, the specific mechanism differs between different types of G proteins. ### Common mechanism Receptor activated G proteins are bound to the inside surface of the cell membrane. They consist of the Gα and the tightly associated Gβγ subunits. Presently, four main families exist for Gα subunits: Gαs, Gαi, Gαq/11, and Gα12/13. These groups differ primarily in effector recognition, but share a similar mechanism of activation. When a ligand activates the G protein-coupled receptor, it induces a conformation change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GTP for GDP on the Gα subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the Gα subunit from the Gβγ dimer and the receptor. However, models that suggest molecular rearrangement, reorganization and pre-complexing of effector molecules are beginning to be accepted. Regardless, both, Gα-GTP and Gβγ, can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein. The Gα subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to re-associate with Gβγ and starting a new cycle. Although, there do exist groups of proteins called RBMs that act as GTPase activating proteins (GAPs) which are specific for Gα subunits, which act to accelerate hydrolysis and terminate the transduced signal. In some cases the effector itself may possess intrinsic GAP activity, which helps deactivate the pathway. This is true in the case of phospholipase C beta which possesses GAP activity within its C-terminal region. This is an alternate form of regulation for the Gα subunit. ### Specific mechanisms - Gαs stimulates the production of cAMP from ATP. This is accomplished by direct stimulation of the membrane associated enzyme adenylate cyclase. cAMP acts as a second messenger which goes on to interact with and activate protein kinase A (PKA). PKA can then phosphorylate a myriad of downstream targets. - Gαi inhibits the production of cAMP from ATP. - Gαq/11 stimulates membrane bound phospholipase C beta which then cleaves PIP2 (a minor membrane phosphoinositol) into two second messengers, IP3 and diacylglycerol (DAG). - Gα12/13 are involved in Rho family GTPase signaling (through RhoGEF superfamily) and control cell cytoskeleton remodeling, thus regulating cell migration. - Gβγ sometimes also have active functions, e.g. coupling to L-type calcium channels. ## Small GTPases Small GTPases also bind GTP and GDP and are involved in signal transduction. These proteins are homologous to the alpha (α) subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction. They are small (20-25 kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to Ras GTPases and is also called the Ras superfamily GTPases. # Lipidation In order to associate with the inner leaflet of the plasma membrane, many G proteins are covalently modified with lipid extensions, i.e. they are lipidated. - Heterotrimeric G protein subunits may be myristolated, palmitoylated, or prenylated. - Small G proteins may be prenylated.	G protein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview G proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. Their nomenclature originates from their ability to function as "molecular switches", alternating between an inactive guanosine diphosphate (GDP) and activated guanosine triphosphate (GTP) bound state, ultimately going on to regulate downstream cell processes. G proteins belong to the larger group of enzymes called GTPases. # History Alfred Gilman and Martin Rodbell were awarded the Nobel Prize in Physiology or Medicine in 1994 for their discovery of and research on G proteins. # Function G proteins are important signal transducing molecules in cells. In fact, diseases such as diabetes and certain forms of cancer, among other pathologies, are thought to arise due to derangement of G protein signaling. # Types of G protein signaling G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins that are activated by G protein-coupled receptors and made up of alpha (α), beta (β) and gamma (γ) subunits. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha (α) subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction. ## Heterotrimeric G proteins Heterotrimeric G proteins share a common mode of action, i.e. activation in response to a conformation change in the G-protein coupled receptor, exchange of GTP for GDP and dissociation in order to activate further proteins in the signal transduction pathway. However, the specific mechanism differs between different types of G proteins. ### Common mechanism Receptor activated G proteins are bound to the inside surface of the cell membrane. They consist of the Gα and the tightly associated Gβγ subunits. Presently, four main families exist for Gα subunits: Gαs, Gαi, Gαq/11, and Gα12/13. These groups differ primarily in effector recognition, but share a similar mechanism of activation. When a ligand activates the G protein-coupled receptor, it induces a conformation change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GTP for GDP on the Gα subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the Gα subunit from the Gβγ dimer and the receptor. However, models that suggest molecular rearrangement, reorganization and pre-complexing of effector molecules are beginning to be accepted. Regardless, both, Gα-GTP and Gβγ, can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein. The Gα subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to re-associate with Gβγ and starting a new cycle. Although, there do exist groups of proteins called RBMs that act as GTPase activating proteins (GAPs) which are specific for Gα subunits, which act to accelerate hydrolysis and terminate the transduced signal. In some cases the effector itself may possess intrinsic GAP activity, which helps deactivate the pathway. This is true in the case of phospholipase C beta which possesses GAP activity within its C-terminal region. This is an alternate form of regulation for the Gα subunit. ### Specific mechanisms - Gαs stimulates the production of cAMP from ATP. This is accomplished by direct stimulation of the membrane associated enzyme adenylate cyclase. cAMP acts as a second messenger which goes on to interact with and activate protein kinase A (PKA). PKA can then phosphorylate a myriad of downstream targets. - Gαi inhibits the production of cAMP from ATP. - Gαq/11 stimulates membrane bound phospholipase C beta which then cleaves PIP2 (a minor membrane phosphoinositol) into two second messengers, IP3 and diacylglycerol (DAG). - Gα12/13 are involved in Rho family GTPase signaling (through RhoGEF superfamily) and control cell cytoskeleton remodeling, thus regulating cell migration. - Gβγ sometimes also have active functions, e.g. coupling to L-type calcium channels. ## Small GTPases Small GTPases also bind GTP and GDP and are involved in signal transduction. These proteins are homologous to the alpha (α) subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction. They are small (20-25 kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to Ras GTPases and is also called the Ras superfamily GTPases. # Lipidation In order to associate with the inner leaflet of the plasma membrane, many G proteins are covalently modified with lipid extensions, i.e. they are lipidated. - Heterotrimeric G protein subunits may be myristolated, palmitoylated, or prenylated. - Small G proteins may be prenylated.	https://www.wikidoc.org/index.php/G-protein
f5426ac85ae666f2695ec9458c084208f9a62d3c	wikidoc	Tiagabine	Tiagabine # 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 Tiagabine is an anticonvulsant, gamma aminobutyric acid Uptake Inhibitor that is FDA approved for the treatment of partial seizures in adults and children > 12 years. Common adverse reactions include pruritus, abdominal pain, nausea, asthenia, ataxia, confusion, disturbance in speech, dizziness, feeling nervous, insomnia, somnolence, tremor, unable to concentrate and pharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## General - The blood level of tiagabine obtained after a given dose depends on whether the patient also is receiving a drug that induces the metabolism of tiagabine. The presence of an inducer means that the attained blood level will be substantially reduced. Dosing should take the presence of concomitant medications into account. - Tiagabine is recommended as adjunctive therapy for the treatment of partial seizures in patients 12 years and older. The following dosing recommendations apply to all patients taking Tiagabine: - Tiagabine is given orally and should be taken with food. - Do not use a loading dose of Tiagabine. - Dose titration: Rapid escalation and/or large dose increments of Tiagabine should not be used. - Missed dose(s): If the patient forgets to take the prescribed dose of Tiagabine at the scheduled time, the patient should not attempt to make up for the missed dose by increasing the next dose. If a patient has missed multiple doses, patient should refer back to his or her physician for possible re-titration as clinically indicated. - Dosage adjustment of Tiagabine should be considered whenever a change in patient’s enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent. ## Induced Adults and Adolescents 12 Years or Older - The following dosing recommendations apply to patients who are already taking enzyme-inducing antiepilepsy drugs (AEDs) (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). Such patients are considered induced patients when administering Tiagabine. - In adolescents 12 to 18 years old, Tiagabine should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of Tiagabine may be increased by 4 mg at the beginning of Week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 32 mg/day have been tolerated in a small number of adolescent patients for a relatively short duration. - In adults, Tiagabine should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of Tiagabine may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 56 mg/day have not been systematically evaluated in adequate and well-controlled clinical trials. Experience is limited in patients taking total daily doses above 32 mg/day using twice daily dosing. A typical dosing titration regimen for patients taking enzyme-inducing AEDs (induced patients) is provided in Table 7 ## Non-Induced Adults and Adolescents 12 Years or Older - The following dosing recommendations apply to patients who are taking only non-enzyme-inducing AEDs. Such patients are considered non-induced patients: Following a given dose of Tiagabine, the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in non-induced patients requires lower doses of Tiagabine. These patients may also require a slower titration of Tiagabine compared to that of induced patients - Following a given dose of Tiagabine, the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in non-induced patients requires lower doses of Tiagabine. These patients may also require a slower titration of Tiagabine compared to that of induced patients ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tiagabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiagabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Tiagabine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tiagabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiagabine in pediatric patients. # Contraindications - Tiagabine is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. # Warnings - Seizures in Patients Without Epilepsy: Post-marketing reports have shown that Tiagabine use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of Tiagabine as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing. - The Tiagabine dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of Tiagabine by inducing its metabolism. Use of Tiagabine without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based. - Safety and effectiveness of Tiagabine have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older. - In nonepileptic patients who develop seizures while on Tiagabine treatment, Tiagabine should be discontinued and patients should be evaluated for an underlying seizure disorder. - Seizures and status epilepticus are known to occur with Tiagabine overdosage. ### Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including Tiagabine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs use for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. - Anyone considering prescribing Tiagabine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Withdrawal Seizures - As a rule, antiepilepsy drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In a placebo-controlled, double-blind, dose-response study (Study 1 described in CLINICAL STUDIES) designed, in part, to investigate the capacity of Tiagabine to induce withdrawal seizures, study drug was tapered over a 4-week period after 16 weeks of treatment. Patients’ seizure frequency during this 4-week withdrawal period was compared to their baseline seizure frequency (before study drug). For each partial seizure type, for all partial seizure types combined, and for secondarily generalized tonic-clonic seizures, more patients experienced increases in their seizure frequencies during the withdrawal period in the three Tiagabine groups than in the placebo group. The increase in seizure frequency was not affected by dose. Tiagabine should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. ### Cognitive/Neuropsychiatric Adverse Events - Adverse events most often associated with the use of Tiagabine were related to the central nervous system. The most significant of these can be classified into 2 general categories: 1) impaired concentration, speech or language problems, and confusion (effects on thought processes); and 2) somnolence and fatigue (effects on level of consciousness). The majority of these events were mild to moderate. In controlled clinical trials, these events led to discontinuation of treatment with Tiagabine in 6% (31 of 494) of patients compared to 2% (5 of 275) of the placebo-treated patients. A total of 1.6% (8 of 494) of the Tiagabine treated patients in the controlled trials were hospitalized secondary to the occurrence of these events compared to 0% of the placebo treated patients. Some of these events were dose related and usually began during initial titration. - Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with these cognitive/neuropsychiatric events. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity. In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment. - Additionally, there have been postmarketing reports of patients who have experienced cognitive/neuropsychiatric symptoms, some accompanied by EEG abnormalities such as generalized spike and wave activity, that have been reported as nonconvulsant status epilepticus. Some reports describe recovery following reduction of dose or discontinuation of Tiagabine. ### Status Epilepticus - In the three double-blind, placebo-controlled, parallel-group studies (Studies 1, 2, and 3), the incidence of any type of status epilepticus (simple, complex, or generalized tonic-clonic) in patients receiving Tiagabine was 0.8% (4 of 494 patients) versus 0.7% (2 of 275 patients) receiving placebo. Among the patients treated with Tiagabine across all epilepsy studies (controlled and uncontrolled), 5% had some form of status epilepticus. Of the 5%, 57% of patients experienced complex partial status epilepticus. A critical risk factor for status epilepticus was the presence of a previous history; 33% of patients with a history of status epilepticus had recurrence during Tiagabine treatment. Because adequate information about the incidence of status epilepticus in a similar population of patients with epilepsy who have not received treatment with Tiagabine is not available, it is impossible to state whether or not treatment with Tiagabine is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with Tiagabine. ### Sudden Unexpected Death In Epilepsy (SUDEP) - There have been as many as 10 cases of sudden unexpected deaths during the clinical development of tiagabine among 2531 patients with epilepsy (3831 patient-years of exposure). - This represents an estimated incidence of 0.0026 deaths per patient-year. This rate is within the range of estimates for the incidence of sudden and unexpected deaths in patients with epilepsy not receiving Tiagabine (ranging from 0.0005 for the general population with epilepsy, 0.003 to 0.004 for clinical trial populations similar to that in the clinical development program for Tiagabine to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving Tiagabine are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to Tiagabine that underwent clinical testing in similar populations at about the same time. This evidence suggests that the SUDEP rates reflect population rates, not a drug effect. # Adverse Reactions ## Clinical Trials Experience - The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of Tiagabine in combination with other antiepilepsy drugs not seen at an equivalent frequency among placebo-treated patients were dizziness/light-headedness, asthenia/lack of energy, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, and thinking abnormal/difficulty with concentration or attention. - Approximately 21% of the 2531 patients who received Tiagabine in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were dizziness (1.7%), somnolence (1.6%), depression (1.3%), confusion (1.1%), and asthenia (1.1%). - In Studies 1 and 2 (U.S. studies), the double-blind, placebo-controlled, parallel-group, add-on studies, the proportion of patients who discontinued treatment because of adverse events was 11% for the group treated with Tiagabine and 6% for the placebo group. The most common adverse events considered the primary reason for discontinuation were confusion (1.2%), somnolence (1.0%), and ataxia (1.0%). ## Adverse Event Incidence in Controlled Clinical Trials - Table 5 lists treatment-emergent signs and symptoms that occurred in at least 1% of patients treated with Tiagabine for epilepsy participating in parallel-group, placebo-controlled trials and were numerically more common in the Tiagabine group. In these studies, either Tiagabine or placebo was added to the patient’s current antiepilepsy drug therapy. Adverse events were usually mild or moderate in intensity. - The prescriber should be aware that these figures, obtained when Tiagabine was added to concurrent antiepilepsy drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. Table 5: Treatment-Emergent Adverse Event1 Incidence in Parallel-Group, Placebo-Controlled, Add-On Trials (events in at least 1% of patients treated with Tiagabine and numerically more frequent than in the placebo group) - Patients in these add-on studies were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to Tiagabine or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category. - Other events reported by 1% or more of patients treated with Tiagabine but equally or more frequent in the placebo group were: accidental injury, chest pain, constipation, flu syndrome, rhinitis, anorexia, back pain, dry mouth, flatulence, ecchymosis, twitching, fever, amblyopia, conjunctivitis, urinary tract infection, urinary frequency, infection, dyspepsia, gastroenteritis, nausea and vomiting, myalgia, diplopia, headache, anxiety, acne, sinusitis, and incoordination. - Study 1 was a dose-response study including doses of 32 mg and 56 mg. Table 6 shows adverse events reported at a rate of ≥ 5% in at least one Tiagabine group and more frequent than in the placebo group. Among these events, depression, tremor, nervousness, difficulty with concentration/attention, and perhaps asthenia exhibited a positive relationship to dose. Table 6: Treatment-Emergent Adverse Event Incidence in Study 1† (events in at least 5% of patients treated with Tiagabine 32 or 56 mg and numerically more frequent than in the placebo group) - Patients in this study were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to Tiagabine or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category. - The effects of Tiagabine in relation to those of placebo on the incidence of adverse events and the types of adverse events reported were independent of age, weight, and gender. Because only 10% of patients were non-Caucasian in parallel-group, placebo-controlled trials, there is insufficient data to support a statement regarding the distribution of adverse experience reports by race. ## Other Adverse Events Observed During All Clinical Trials - Tiagabine has been administered to 2531 patients during all phase 2/3 clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 2531 patients exposed to Tiagabine who experienced events of the type cited on at least one occasion while receiving Tiagabine All reported events are included except those already listed above, events seen only three times or fewer (unless potentially important), events very unlikely to be drug-related, and those too general to be informative. Events are included without regard to determination of a causal relationship to tiagabine. - Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. ### Body as a Whole - Frequent: Allergic reaction, chest pain, chills, cyst, neck pain, and malaise. - Infrequent: Abscess, cellulitis, facial edema, halitosis, hernia, neck rigidity, neoplasm, pelvic pain, photosensitivity reaction, sepsis, sudden death, and suicide attempt. ### Cardiovascular System - Frequent: Hypertension, palpitation, syncope, and tachycardia. - Infrequent: Angina pectoris, cerebral ischemia, electrocardiogram abnormal, hemorrhage, hypotension, myocardial infarct, pallor, peripheral vascular disorder, phlebitis, postural hypotension, and thrombophlebitis. ### Digestive System - Frequent: Gingivitis and stomatitis. - Infrequent: Abnormal stools, cholecystitis, cholelithiasis, dysphagia, eructation, esophagitis, fecal incontinence, gastritis, gastrointestinal hemorrhage, glossitis, gum hyperplasia, hepatomegaly, increased salivation, liver function tests abnormal, melena, periodontal abscess, rectal hemorrhage, thirst, tooth caries, and ulcerative stomatitis. ### Endocrine System - Infrequent: Goiter and hypothyroidism. ### Hemic and Lymphatic System - Frequent: Lymphadenopathy. - Infrequent: Anemia, erythrocytes abnormal, leukopenia, petechia, and thrombocytopenia. ### Metabolic and Nutritional - Frequent: Edema, peripheral edema, weight gain, and weight loss. - Infrequent: Dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia, and hyponatremia. ### Musculoskeletal System - Frequent: Arthralgia. - Infrequent: Arthritis, arthrosis, bursitis, generalized spasm, and tendinous contracture. ### Nervous System - Frequent: Depersonalization, dysarthria, euphoria, hallucination, hyperkinesia, hypertonia, hypesthesia, hypokinesia, hypotonia, migraine, myoclonus, paranoid reaction, personality disorder, reflexes decreased, stupor, twitching, and vertigo. - Infrequent: Abnormal dreams, apathy, choreoathetosis, circumoral paresthesia, CNS neoplasm, coma, delusions, dry mouth, dystonia, encephalopathy, hemiplegia, leg cramps, libido increased, libido decreased, movement disorder, neuritis, neurosis, paralysis, peripheral neuritis, psychosis, reflexes increased, and urinary retention. ### Respiratory System - Frequent: Bronchitis, dyspnea, epistaxis, and pneumonia. - lnfrequent: Apnea, asthma, hemoptysis, hiccups, hyperventilation, laryngitis, respiratory disorder, and voice alteration. ### Skin and Appendages - Frequent: Alopecia, dry skin, and sweating. - Infrequent: Contact dermatitis, eczema, exfoliative dermatitis, furunculosis, herpes simplex, herpes zoster, hirsutism, maculopapular rash, psoriasis, skin benign neoplasm, skin carcinoma, skin discolorations, skin nodules, skin ulcer, subcutaneous nodule, urticaria, and vesiculobullous rash. ### Special Senses - Frequent: Abnormal vision, ear pain, otitis media, and tinnitus. - Infrequent: Blepharitis, blindness, deafness, eye pain, hyperacusis, keratoconjunctivitis, otitis externa, parosmia, photophobia, taste loss, taste perversion, and visual field defect. ### Urogenital System - Frequent: Dysmenorrhea, dysuria, metrorrhagia, urinary incontinence, and vaginitis. - Infrequent: Abortion, amenorrhea, breast enlargement, breast pain, cystitis, fibrocystic breast, hematuria, impotence, kidney failure, menorrhagia, nocturia, papanicolaou smear suspicious, polyuria, pyelonephritis, salpingitis, urethritis, urinary urgency, and vaginal hemorrhage. ## Postmarketing Experience There is limited information regarding Tiagabine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Tiagabine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Tiagabine has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, when administered to pregnant rats and rabbits at doses greater than the human therapeutic dose. - An increased incidence of malformed fetuses (various craniofacial, appendicular, and visceral defects) and decreased fetal weights were observed following oral administration of 100 mg/kg/day to pregnant rats during the period of organogenesis. This dose is approximately 16 times the maximum recommended human dose (MRHD) of 56 mg/day, based on body surface area (mg/m2). Maternal toxicity (transient weight loss/reduced maternal weight gain during gestation) was associated with this dose, but there is no evidence to suggest that the teratogenic effects were secondary to the maternal effects. No adverse maternal or embryo-fetal effects were seen at a dose of 20 mg/kg/day (3 times the MRHD on a mg/m2 basis). - Decreased maternal weight gain, increased resorption of embryos and increased incidences of fetal variations, but not malformations, were observed when pregnant rabbits were given 25 mg/kg/day (8 times the MRHD on a mg/m2 basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). - When female rats were given tiagabine 100 mg/kg/day during late gestation and throughout parturition and lactation, decreased maternal weight gain during gestation, an increase in stillbirths, and decreased postnatal offspring viability and growth were found. There are no adequate and well-controlled studies in pregnant women. Tiagabine should be used during pregnancy only if clearly needed. - To provide additional information regarding the effects of in utero exposure to Tiagabine physicians are advised to recommend that pregnant patients taking Tiagabine enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website. Decreased maternal weight gain, increased resorption of embryos and increased incidences of fetal variations, but not malformations, were observed when pregnant rabbits were given 25 mg/kg/day (8 times the MRHD on a mg/m2 basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiagabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tiagabine during labor and delivery. ### Nursing Mothers - Studies in rats have shown that tiagabine HCl and/or its metabolites are excreted in the milk of that species. Levels of excretion of tiagabine and/or its metabolites in human milk have not been determined and effects on the nursing infant are unknown. Tiagabine should be used in women who are nursing only if the benefits clearly outweigh the risks. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 12 have not been established. The pharmacokinetics of tiagabine were evaluated in pediatric patients age 3 to 10 years ( ### Geriatic Use - Because few patients over the age of 65 (approximately 20) were exposed to Tiagabine during its clinical evaluation, no specific statements about the safety or effectiveness of Tiagabine in this age group could be made. ### Gender There is no FDA guidance on the use of Tiagabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tiagabine with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of total and unbound tiagabine were similar in subjects with normal renal function (creatinine clearance >80 mL/min) and in subjects with mild (creatinine clearance 40 to 80 mL/min), moderate (creatinine clearance 20 to 39 mL/min), or severe (creatinine clearance 5 to 19 mL/min) renal impairment. The pharmacokinetics of total and unbound tiagabine were also unaffected in subjects with renal failure requiring hemodialysis. ### Hepatic Impairment - In patients with moderate hepatic impairment (Child-Pugh Class B), clearance of unbound tiagabine was reduced by about 60%. Patients with impaired liver function may require reduced initial and maintenance doses of tiagabine and/or longer dosing intervals compared to patients with normal hepatic function ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tiagabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tiagabine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Tiagabine Administration in the drug label. ### Monitoring There is limited information regarding Tiagabine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Tiagabine and IV administrations. # Overdosage ### Human Overdose Experience - Human experience of acute overdose with Tiagabine is limited. Eleven patients in clinical trials took single doses of Tiagabine up to 800 mg. All patients fully recovered, usually within one day. The most common symptoms reported after overdose included somnolence, impaired consciousness, agitation, confusion, speech difficulty, hostility, depression, weakness, and myoclonus. One patient who ingested a single dose of 400 mg experienced generalized tonic-clonic status epilepticus, which responded to intravenous phenobarbital. - From post-marketing experience, there have been no reports of fatal overdoses involving Tiagabine alone (doses up to 720 mg), although a number of patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including Tiagabine have resulted in fatal outcomes. Symptoms most often accompanying Tiagabine overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures. ### Management of Overdose - There is no specific antidote for overdose with Tiagabine If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of clinical status of the patient. Since tiagabine is mostly metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial. A Certified Poison Control Center should be consulted for up to date information on the management of overdose with Tiagabine. # Pharmacology ## Mechanism of Action - The precise mechanism by which tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability, documented in in vitro experiments, to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. These experiments have shown that tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures. In rat-derived hippocampal slices, tiagabine has been shown to prolong GABA-mediated inhibitory post-synaptic potentials. Tiagabine increases the amount of GABA available in the extracellular space of the globus pallidus, ventral palladum, and substantia nigra in rats at the ED50 and ED85 doses for inhibition of pentylenetetrazol (PTZ)-induced tonic seizures. This suggests that tiagabine prevents the propagation of neural impulses that contribute to seizures by a GABA-ergic action. - Tiagabine has shown efficacy in several animal models of seizures. It is effective against the tonic phase of subcutaneous PTZ-induced seizures in mice and rats, seizures induced by the proconvulsant DMCM in mice, audiogenic seizures in genetically epilepsy-prone rats (GEPR), and amygdala-kindled seizures in rats. Tiagabine has little efficacy against maximal electroshock seizures in rats and is only partially effective against subcutaneous PTZ-induced clonic seizures in mice, picrotoxin-induced tonic seizures in the mouse, bicuculline-induced seizures in the rat, and photic seizures in photosensitive baboons. Tiagabine produces a biphasic dose-response curve against PTZ- and DMCM-induced convulsions, with attenuated effectiveness at higher doses. - Based on in vitro binding studies, tiagabine does not significantly inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline and shows little or no binding to dopamine D1 and D2, muscarinic, serotonin 5HT1A, 5HT2, and 5HT3, beta-1 and beta-2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine A1 and adenosine A2, opiate µ and opiate K1, NMDA glutamate, and GABAA receptors at 100 µM. It also lacks significant affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonin 5HT1B, benzodiazepine, and chloride channel receptors at concentrations 20 to 400 times those inhibiting the uptake of GABA. ## Structure - Its chemical name is (-)-(R)-1-4,4-Bis(3-methyl-2-thienyl)-3-buteny)nipecotic acid hydrochloride, its molecular formula is C20H25NO2S2 HCl, and its molecular weight is 412.0. Tiagabine HCl is a white to off-white, odorless, crystalline powder. It is insoluble in heptane, sparingly soluble in water, and soluble in aqueous base. The structural formula is: ## Pharmacodynamics There is limited information regarding Tiagabine Pharmacodynamics in the drug label. ## Pharmacokinetics - Tiagabine is well absorbed, with food slowing absorption rate but not altering the extent of absorption. The elimination half-life of tiagabine is 7 to 9 hours in normal volunteers. In epilepsy clinical trials, most patients were receiving hepatic enzyme-inducing agents (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). The pharmacokinetic profile in induced patients is significantly different from the non-induced population. The systemic clearance of tiagabine in induced patients is approximately 60% greater resulting in considerably lower plasma concentrations and an elimination half-life of 2 to 5 hours. Given this difference in clearance, the systemic exposure after a dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a non-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a non-induced population. ### Absorption and Distribution - Absorption of tiagabine is rapid, with peak plasma concentrations occurring at approximately 45 minutes following an oral dose in the fasting state. Tiagabine is nearly completely absorbed (>95%), with an absolute oral bioavailability of about 90%. A high fat meal decreases the rate (mean Tmax was prolonged to 2.5 hours, and mean Cmax was reduced by about 40%) but not the extent (AUC) of tiagabine absorption. In all clinical trials, tiagabine was given with meals. The pharmacokinetics of tiagabine are linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days. - Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin and α1-acid glycoprotein over the concentration range of 10 ng/mL to 10,000 ng/mL. While the relationship between tiagabine plasma concentrations and clinical response is not currently understood, trough plasma concentrations observed in controlled clinical trials at doses from 30 to 56 mg/day ranged from <1 ng/mL to 234 ng/mL. ### Metabolism and Elimination - Although the metabolism of tiagabine has not been fully elucidated, in vivo and in vitro studies suggest that at least two metabolic pathways for tiagabine have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and 2) glucuronidation. The 5-oxo-tiagabine metabolite does not contribute to the pharmacologic activity of tiagabine. - Based on in vitro data, tiagabine is likely to be metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A), although contributions to the metabolism of tiagabine from CYP1A2, CYP2D6 or CYP2C19 have not been excluded. - Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites, at least 2 of which have not been identified. The mean systemic plasma clearance is 109 mL/min (CV = 23%) and the average elimination half-life for tiagabine in healthy subjects ranged from 7 to 9 hours. The elimination half-life decreased by 50 to 65% in hepatic enzyme-induced patients with epilepsy compared to uninduced patients with epilepsy. - A diurnal effect on the pharmacokinetics of tiagabine was observed. Mean steady-state Cminvalues were 40% lower in the evening than in the morning. Tiagabine steady-state AUC values were also found to be 15% lower following the evening tiagabine dose compared to the AUC following the morning dose. ## Nonclinical Toxicology There is limited information regarding Tiagabine Nonclinical Toxicology in the drug label. # Clinical Studies - The effectiveness of Tiagabine as adjunctive therapy (added to other antiepilepsy drugs) was examined in three multi-center, double-blind, placebo-controlled, parallel-group, clinical trials in 769 patients with refractory partial seizures who were taking at least one hepatic enzyme-inducing antiepilepsy drug (AED), and two placebo-controlled cross-over studies in 90 patients. In the parallel-group trials, patients had a history of at least six complex partial seizures (Study 1 and Study 2, U.S. studies), or six partial seizures of any type (Study 3, European study), occurring alone or in combination with any other seizure type within the 8-week period preceding the first study visit in spite of receiving one or more AEDs at therapeutic concentrations. - In the first two studies, the primary protocol-specified outcome measure was the median reduction from baseline in the 4-week complex partial seizure (CPS) rates during treatment. In the third study, the protocol-specified primary outcome measure was the proportion of patients achieving a 50% or greater reduction from baseline in the 4-week seizure rate of all partial seizures during treatment. The results given below include data for complex partial seizures and all partial seizures for the intent-to-treat population (all patients who received at least one dose of treatment and at least one seizure evaluation) in each study. - Study 1 was a double-blind, placebo-controlled, parallel-group trial comparing Tiagabine 16 mg/day, Tiagabine 32 mg/day, Tiagabine 56 mg/day, and placebo. Study drug was given as a four times a day regimen. After a prospective Baseline Phase of 12 weeks, patients were randomized to one of the four treatment groups described above. The 16-week Treatment Phase consisted of a 4-week Titration Period, followed by a 12-week Fixed-Dose Period, during which concomitant AED doses were held constant. The primary outcome was assessed for the combined 32 and 56 mg/day groups compared to placebo. - Study 2 was a double-blind, placebo-controlled, parallel-group trial consisting of an 8-week Baseline Phase and a 12-week Treatment Phase, the first 4 weeks of which constituted a Titration Period and the last 8 weeks a Fixed-Dose Period. This study compared Tiagabine 16 mg BID and 8 mg QID to placebo. The protocol-specified primary outcome measure was assessed separately for each group treated with Tiagabine. The following tables display the results of the analyses of these two trials. - Figures 1 to 4 present the proportion of patients (X-axis) whose percent reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y axis in the three placebo-controlled adjunctive studies (Studies 1, 2, and 3). A positive value on the Y axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. - Figure 1 indicates that the proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the combined Tiagabine 32 mg and 56 mg groups compared to the placebo group in Study 1. For example, Figure 1 indicates that approximately 24% of patients treated with Tiagabine experienced a 50% or greater reduction, compared to 4% in the placebo group. - Figure 2 also displays the results for Study 1, which was a dose-response study, by treatment group, without combining Tiagabine dosage groups. Figure 2 indicates a dose-response relationship across the three Tiagabine groups. The proportion of patients achieving any particular level of reduction in all partial seizure rates was consistently higher as the dose of Tiagabine was increased. For example, Figure 2 indicates that approximately 4% of patients in the placebo group experienced a 50% or greater reduction in all partial seizure rate, compared to approximately 10% of the Tiagabine 16 mg/day group, 21% of the Tiagabine 32 mg/day group, and 30% of the Tiagabine 56 mg/day group. - Figure 3 indicates that the proportion of patients achieving any particular level of reduction in partial seizure rate was consistently greater in patients taking Tiagabine than in those taking placebo in Study 2. (Study 2 compared placebo to Tiagabine 32 mg/day; one of the Tiagabine groups received 8 mg QID, while the other Tiagabine group received 16 mg BID). For example, Figure 3 indicates that approximately 7% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate, compared to approximately 23% of patients in the Tiagabine 8 mg QID group and 28% of patients in the Tiagabine 16 mg BID group. - Study 3 was a double-blind, placebo-controlled, parallel-group trial that compared Tiagabine 10 mg TID (N=77) with placebo (N=77). In this trial, patients were followed prospectively during a 12-week Baseline Phase and then randomized to receive study drug during an 18-week Treatment Phase. During the first 6 weeks of treatment (Titration Period), patients were titrated to 30 mg/day, after which they were maintained on this dose during the 12-week Fixed-Dose Period. The protocol-specified primary outcome measure (proportion of patients who achieved at least a 50% reduction from baseline in partial seizure rate) did not reach statistical significance. However, analyses of the median reduction from baseline in 4-week partial seizure rate (the analyses presented above for Study 1 and Study 2) were performed and showed a statistically significant improvement compared to placebo in all partial and complex partial seizure rates (Table 3): - Figure 4 indicates that the proportion of patients achieving any particular level of reduction in seizure activity was consistently higher in those taking Tiagabine than those taking placebo in Study 3. For example, Figure 4 indicates that approximately 5% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate compared to approximately 10% of patients in the Tiagabine group. - The two other placebo-controlled trials that examined the effectiveness of Tiagabine were small cross-over trials (N=46 and 44). Both trials included an open Screening Phase during which patients were titrated to an optimal dose and then treated with this dose for an additional 4 weeks. After this Open Phase, patients were randomized to one of two blinded treatment sequences (Tiagabine followed by placebo or placebo followed by Tiagabine). The Double-Blind Phase consisted of two Treatment Periods, each lasting 7 weeks (with a 3 week washout between periods). The outcome measures were median with-in patient differences between placebo and Tiagabine Treatment Periods in 4-week complex partial and all partial seizure rates. The reductions in seizure rates were statistically significant in both studies. # How Supplied Tiagabine tablets are available in four dosage strengths. - 2 mg orange-peach, round tablets, debossed with Cephalon Imprint on one side and 402 on the opposite side, are available in bottles of 30 (NDC 63459-402-30). - 4 mg yellow, round tablets, debossed with Cephalon Imprint on one side and 404 on the opposite side, are available in bottles of 30 (NDC 63459-404-30). - 12 mg green, ovaloid tablets, debossed with Cephalon Imprint on one side and 412 on the opposite side, are available in bottles of 30 (NDC 63459-412-30). - 16 mg blue, ovaloid tablets, debossed with Cephalon Imprint on one side and 416 on the opposite side, are available in bottles of 30 (NDC 63459-416-30). ## Storage - Store tablets at controlled room temperature, between 20-25°C (68-77°F). # Images ## Drug Images ## Package and Label Display Panel Tiagabine P2mg.png # Patient Counseling Information There is limited information regarding Tiagabine Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Tiagabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Gabitril # Look-Alike Drug Names There is limited information regarding Tiagabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tiagabine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Tiagabine is an anticonvulsant, gamma aminobutyric acid Uptake Inhibitor that is FDA approved for the treatment of partial seizures in adults and children > 12 years. Common adverse reactions include pruritus, abdominal pain, nausea, asthenia, ataxia, confusion, disturbance in speech, dizziness, feeling nervous, insomnia, somnolence, tremor, unable to concentrate and pharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## General - The blood level of tiagabine obtained after a given dose depends on whether the patient also is receiving a drug that induces the metabolism of tiagabine. The presence of an inducer means that the attained blood level will be substantially reduced. Dosing should take the presence of concomitant medications into account. - Tiagabine is recommended as adjunctive therapy for the treatment of partial seizures in patients 12 years and older. The following dosing recommendations apply to all patients taking Tiagabine: - Tiagabine is given orally and should be taken with food. - Do not use a loading dose of Tiagabine. - Dose titration: Rapid escalation and/or large dose increments of Tiagabine should not be used. - Missed dose(s): If the patient forgets to take the prescribed dose of Tiagabine at the scheduled time, the patient should not attempt to make up for the missed dose by increasing the next dose. If a patient has missed multiple doses, patient should refer back to his or her physician for possible re-titration as clinically indicated. - Dosage adjustment of Tiagabine should be considered whenever a change in patient’s enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent. ## Induced Adults and Adolescents 12 Years or Older - The following dosing recommendations apply to patients who are already taking enzyme-inducing antiepilepsy drugs (AEDs) (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). Such patients are considered induced patients when administering Tiagabine. - In adolescents 12 to 18 years old, Tiagabine should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of Tiagabine may be increased by 4 mg at the beginning of Week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 32 mg/day have been tolerated in a small number of adolescent patients for a relatively short duration. - In adults, Tiagabine should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of Tiagabine may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 56 mg/day have not been systematically evaluated in adequate and well-controlled clinical trials. Experience is limited in patients taking total daily doses above 32 mg/day using twice daily dosing. A typical dosing titration regimen for patients taking enzyme-inducing AEDs (induced patients) is provided in Table 7 ## Non-Induced Adults and Adolescents 12 Years or Older - The following dosing recommendations apply to patients who are taking only non-enzyme-inducing AEDs. Such patients are considered non-induced patients: Following a given dose of Tiagabine, the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in non-induced patients requires lower doses of Tiagabine. These patients may also require a slower titration of Tiagabine compared to that of induced patients - Following a given dose of Tiagabine, the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in non-induced patients requires lower doses of Tiagabine. These patients may also require a slower titration of Tiagabine compared to that of induced patients ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tiagabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiagabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Tiagabine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tiagabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiagabine in pediatric patients. # Contraindications - Tiagabine is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. # Warnings - Seizures in Patients Without Epilepsy: Post-marketing reports have shown that Tiagabine use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of Tiagabine as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing. - The Tiagabine dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of Tiagabine by inducing its metabolism. Use of Tiagabine without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based. - Safety and effectiveness of Tiagabine have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older. - In nonepileptic patients who develop seizures while on Tiagabine treatment, Tiagabine should be discontinued and patients should be evaluated for an underlying seizure disorder. - Seizures and status epilepticus are known to occur with Tiagabine overdosage. ### Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including Tiagabine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs use for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. - Anyone considering prescribing Tiagabine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Withdrawal Seizures - As a rule, antiepilepsy drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In a placebo-controlled, double-blind, dose-response study (Study 1 described in CLINICAL STUDIES) designed, in part, to investigate the capacity of Tiagabine to induce withdrawal seizures, study drug was tapered over a 4-week period after 16 weeks of treatment. Patients’ seizure frequency during this 4-week withdrawal period was compared to their baseline seizure frequency (before study drug). For each partial seizure type, for all partial seizure types combined, and for secondarily generalized tonic-clonic seizures, more patients experienced increases in their seizure frequencies during the withdrawal period in the three Tiagabine groups than in the placebo group. The increase in seizure frequency was not affected by dose. Tiagabine should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. ### Cognitive/Neuropsychiatric Adverse Events - Adverse events most often associated with the use of Tiagabine were related to the central nervous system. The most significant of these can be classified into 2 general categories: 1) impaired concentration, speech or language problems, and confusion (effects on thought processes); and 2) somnolence and fatigue (effects on level of consciousness). The majority of these events were mild to moderate. In controlled clinical trials, these events led to discontinuation of treatment with Tiagabine in 6% (31 of 494) of patients compared to 2% (5 of 275) of the placebo-treated patients. A total of 1.6% (8 of 494) of the Tiagabine treated patients in the controlled trials were hospitalized secondary to the occurrence of these events compared to 0% of the placebo treated patients. Some of these events were dose related and usually began during initial titration. - Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with these cognitive/neuropsychiatric events. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity. In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment. - Additionally, there have been postmarketing reports of patients who have experienced cognitive/neuropsychiatric symptoms, some accompanied by EEG abnormalities such as generalized spike and wave activity, that have been reported as nonconvulsant status epilepticus. Some reports describe recovery following reduction of dose or discontinuation of Tiagabine. ### Status Epilepticus - In the three double-blind, placebo-controlled, parallel-group studies (Studies 1, 2, and 3), the incidence of any type of status epilepticus (simple, complex, or generalized tonic-clonic) in patients receiving Tiagabine was 0.8% (4 of 494 patients) versus 0.7% (2 of 275 patients) receiving placebo. Among the patients treated with Tiagabine across all epilepsy studies (controlled and uncontrolled), 5% had some form of status epilepticus. Of the 5%, 57% of patients experienced complex partial status epilepticus. A critical risk factor for status epilepticus was the presence of a previous history; 33% of patients with a history of status epilepticus had recurrence during Tiagabine treatment. Because adequate information about the incidence of status epilepticus in a similar population of patients with epilepsy who have not received treatment with Tiagabine is not available, it is impossible to state whether or not treatment with Tiagabine is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with Tiagabine. ### Sudden Unexpected Death In Epilepsy (SUDEP) - There have been as many as 10 cases of sudden unexpected deaths during the clinical development of tiagabine among 2531 patients with epilepsy (3831 patient-years of exposure). - This represents an estimated incidence of 0.0026 deaths per patient-year. This rate is within the range of estimates for the incidence of sudden and unexpected deaths in patients with epilepsy not receiving Tiagabine (ranging from 0.0005 for the general population with epilepsy, 0.003 to 0.004 for clinical trial populations similar to that in the clinical development program for Tiagabine to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving Tiagabine are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to Tiagabine that underwent clinical testing in similar populations at about the same time. This evidence suggests that the SUDEP rates reflect population rates, not a drug effect. # Adverse Reactions ## Clinical Trials Experience - The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of Tiagabine in combination with other antiepilepsy drugs not seen at an equivalent frequency among placebo-treated patients were dizziness/light-headedness, asthenia/lack of energy, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, and thinking abnormal/difficulty with concentration or attention. - Approximately 21% of the 2531 patients who received Tiagabine in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were dizziness (1.7%), somnolence (1.6%), depression (1.3%), confusion (1.1%), and asthenia (1.1%). - In Studies 1 and 2 (U.S. studies), the double-blind, placebo-controlled, parallel-group, add-on studies, the proportion of patients who discontinued treatment because of adverse events was 11% for the group treated with Tiagabine and 6% for the placebo group. The most common adverse events considered the primary reason for discontinuation were confusion (1.2%), somnolence (1.0%), and ataxia (1.0%). ## Adverse Event Incidence in Controlled Clinical Trials - Table 5 lists treatment-emergent signs and symptoms that occurred in at least 1% of patients treated with Tiagabine for epilepsy participating in parallel-group, placebo-controlled trials and were numerically more common in the Tiagabine group. In these studies, either Tiagabine or placebo was added to the patient’s current antiepilepsy drug therapy. Adverse events were usually mild or moderate in intensity. - The prescriber should be aware that these figures, obtained when Tiagabine was added to concurrent antiepilepsy drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. Table 5: Treatment-Emergent Adverse Event1 Incidence in Parallel-Group, Placebo-Controlled, Add-On Trials (events in at least 1% of patients treated with Tiagabine and numerically more frequent than in the placebo group) - Patients in these add-on studies were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to Tiagabine or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category. - Other events reported by 1% or more of patients treated with Tiagabine but equally or more frequent in the placebo group were: accidental injury, chest pain, constipation, flu syndrome, rhinitis, anorexia, back pain, dry mouth, flatulence, ecchymosis, twitching, fever, amblyopia, conjunctivitis, urinary tract infection, urinary frequency, infection, dyspepsia, gastroenteritis, nausea and vomiting, myalgia, diplopia, headache, anxiety, acne, sinusitis, and incoordination. - Study 1 was a dose-response study including doses of 32 mg and 56 mg. Table 6 shows adverse events reported at a rate of ≥ 5% in at least one Tiagabine group and more frequent than in the placebo group. Among these events, depression, tremor, nervousness, difficulty with concentration/attention, and perhaps asthenia exhibited a positive relationship to dose. Table 6: Treatment-Emergent Adverse Event Incidence in Study 1† (events in at least 5% of patients treated with Tiagabine 32 or 56 mg and numerically more frequent than in the placebo group) - Patients in this study were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to Tiagabine or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category. - The effects of Tiagabine in relation to those of placebo on the incidence of adverse events and the types of adverse events reported were independent of age, weight, and gender. Because only 10% of patients were non-Caucasian in parallel-group, placebo-controlled trials, there is insufficient data to support a statement regarding the distribution of adverse experience reports by race. ## Other Adverse Events Observed During All Clinical Trials - Tiagabine has been administered to 2531 patients during all phase 2/3 clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 2531 patients exposed to Tiagabine who experienced events of the type cited on at least one occasion while receiving Tiagabine All reported events are included except those already listed above, events seen only three times or fewer (unless potentially important), events very unlikely to be drug-related, and those too general to be informative. Events are included without regard to determination of a causal relationship to tiagabine. - Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. ### Body as a Whole - Frequent: Allergic reaction, chest pain, chills, cyst, neck pain, and malaise. - Infrequent: Abscess, cellulitis, facial edema, halitosis, hernia, neck rigidity, neoplasm, pelvic pain, photosensitivity reaction, sepsis, sudden death, and suicide attempt. ### Cardiovascular System - Frequent: Hypertension, palpitation, syncope, and tachycardia. - Infrequent: Angina pectoris, cerebral ischemia, electrocardiogram abnormal, hemorrhage, hypotension, myocardial infarct, pallor, peripheral vascular disorder, phlebitis, postural hypotension, and thrombophlebitis. ### Digestive System - Frequent: Gingivitis and stomatitis. - Infrequent: Abnormal stools, cholecystitis, cholelithiasis, dysphagia, eructation, esophagitis, fecal incontinence, gastritis, gastrointestinal hemorrhage, glossitis, gum hyperplasia, hepatomegaly, increased salivation, liver function tests abnormal, melena, periodontal abscess, rectal hemorrhage, thirst, tooth caries, and ulcerative stomatitis. ### Endocrine System - Infrequent: Goiter and hypothyroidism. ### Hemic and Lymphatic System - Frequent: Lymphadenopathy. - Infrequent: Anemia, erythrocytes abnormal, leukopenia, petechia, and thrombocytopenia. ### Metabolic and Nutritional - Frequent: Edema, peripheral edema, weight gain, and weight loss. - Infrequent: Dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia, and hyponatremia. ### Musculoskeletal System - Frequent: Arthralgia. - Infrequent: Arthritis, arthrosis, bursitis, generalized spasm, and tendinous contracture. ### Nervous System - Frequent: Depersonalization, dysarthria, euphoria, hallucination, hyperkinesia, hypertonia, hypesthesia, hypokinesia, hypotonia, migraine, myoclonus, paranoid reaction, personality disorder, reflexes decreased, stupor, twitching, and vertigo. - Infrequent: Abnormal dreams, apathy, choreoathetosis, circumoral paresthesia, CNS neoplasm, coma, delusions, dry mouth, dystonia, encephalopathy, hemiplegia, leg cramps, libido increased, libido decreased, movement disorder, neuritis, neurosis, paralysis, peripheral neuritis, psychosis, reflexes increased, and urinary retention. ### Respiratory System - Frequent: Bronchitis, dyspnea, epistaxis, and pneumonia. - lnfrequent: Apnea, asthma, hemoptysis, hiccups, hyperventilation, laryngitis, respiratory disorder, and voice alteration. ### Skin and Appendages - Frequent: Alopecia, dry skin, and sweating. - Infrequent: Contact dermatitis, eczema, exfoliative dermatitis, furunculosis, herpes simplex, herpes zoster, hirsutism, maculopapular rash, psoriasis, skin benign neoplasm, skin carcinoma, skin discolorations, skin nodules, skin ulcer, subcutaneous nodule, urticaria, and vesiculobullous rash. ### Special Senses - Frequent: Abnormal vision, ear pain, otitis media, and tinnitus. - Infrequent: Blepharitis, blindness, deafness, eye pain, hyperacusis, keratoconjunctivitis, otitis externa, parosmia, photophobia, taste loss, taste perversion, and visual field defect. ### Urogenital System - Frequent: Dysmenorrhea, dysuria, metrorrhagia, urinary incontinence, and vaginitis. - Infrequent: Abortion, amenorrhea, breast enlargement, breast pain, cystitis, fibrocystic breast, hematuria, impotence, kidney failure, menorrhagia, nocturia, papanicolaou smear suspicious, polyuria, pyelonephritis, salpingitis, urethritis, urinary urgency, and vaginal hemorrhage. ## Postmarketing Experience There is limited information regarding Tiagabine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Tiagabine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Tiagabine has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, when administered to pregnant rats and rabbits at doses greater than the human therapeutic dose. - An increased incidence of malformed fetuses (various craniofacial, appendicular, and visceral defects) and decreased fetal weights were observed following oral administration of 100 mg/kg/day to pregnant rats during the period of organogenesis. This dose is approximately 16 times the maximum recommended human dose (MRHD) of 56 mg/day, based on body surface area (mg/m2). Maternal toxicity (transient weight loss/reduced maternal weight gain during gestation) was associated with this dose, but there is no evidence to suggest that the teratogenic effects were secondary to the maternal effects. No adverse maternal or embryo-fetal effects were seen at a dose of 20 mg/kg/day (3 times the MRHD on a mg/m2 basis). - Decreased maternal weight gain, increased resorption of embryos and increased incidences of fetal variations, but not malformations, were observed when pregnant rabbits were given 25 mg/kg/day (8 times the MRHD on a mg/m2 basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). - When female rats were given tiagabine 100 mg/kg/day during late gestation and throughout parturition and lactation, decreased maternal weight gain during gestation, an increase in stillbirths, and decreased postnatal offspring viability and growth were found. There are no adequate and well-controlled studies in pregnant women. Tiagabine should be used during pregnancy only if clearly needed. - To provide additional information regarding the effects of in utero exposure to Tiagabine physicians are advised to recommend that pregnant patients taking Tiagabine enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website. Decreased maternal weight gain, increased resorption of embryos and increased incidences of fetal variations, but not malformations, were observed when pregnant rabbits were given 25 mg/kg/day (8 times the MRHD on a mg/m2 basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiagabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tiagabine during labor and delivery. ### Nursing Mothers - Studies in rats have shown that tiagabine HCl and/or its metabolites are excreted in the milk of that species. Levels of excretion of tiagabine and/or its metabolites in human milk have not been determined and effects on the nursing infant are unknown. Tiagabine should be used in women who are nursing only if the benefits clearly outweigh the risks. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 12 have not been established. The pharmacokinetics of tiagabine were evaluated in pediatric patients age 3 to 10 years ( ### Geriatic Use - Because few patients over the age of 65 (approximately 20) were exposed to Tiagabine during its clinical evaluation, no specific statements about the safety or effectiveness of Tiagabine in this age group could be made. ### Gender There is no FDA guidance on the use of Tiagabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tiagabine with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of total and unbound tiagabine were similar in subjects with normal renal function (creatinine clearance >80 mL/min) and in subjects with mild (creatinine clearance 40 to 80 mL/min), moderate (creatinine clearance 20 to 39 mL/min), or severe (creatinine clearance 5 to 19 mL/min) renal impairment. The pharmacokinetics of total and unbound tiagabine were also unaffected in subjects with renal failure requiring hemodialysis. ### Hepatic Impairment - In patients with moderate hepatic impairment (Child-Pugh Class B), clearance of unbound tiagabine was reduced by about 60%. Patients with impaired liver function may require reduced initial and maintenance doses of tiagabine and/or longer dosing intervals compared to patients with normal hepatic function ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tiagabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tiagabine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Tiagabine Administration in the drug label. ### Monitoring There is limited information regarding Tiagabine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Tiagabine and IV administrations. # Overdosage ### Human Overdose Experience - Human experience of acute overdose with Tiagabine is limited. Eleven patients in clinical trials took single doses of Tiagabine up to 800 mg. All patients fully recovered, usually within one day. The most common symptoms reported after overdose included somnolence, impaired consciousness, agitation, confusion, speech difficulty, hostility, depression, weakness, and myoclonus. One patient who ingested a single dose of 400 mg experienced generalized tonic-clonic status epilepticus, which responded to intravenous phenobarbital. - From post-marketing experience, there have been no reports of fatal overdoses involving Tiagabine alone (doses up to 720 mg), although a number of patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including Tiagabine have resulted in fatal outcomes. Symptoms most often accompanying Tiagabine overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures. ### Management of Overdose - There is no specific antidote for overdose with Tiagabine If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of clinical status of the patient. Since tiagabine is mostly metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial. A Certified Poison Control Center should be consulted for up to date information on the management of overdose with Tiagabine. # Pharmacology ## Mechanism of Action - The precise mechanism by which tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability, documented in in vitro experiments, to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. These experiments have shown that tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures. In rat-derived hippocampal slices, tiagabine has been shown to prolong GABA-mediated inhibitory post-synaptic potentials. Tiagabine increases the amount of GABA available in the extracellular space of the globus pallidus, ventral palladum, and substantia nigra in rats at the ED50 and ED85 doses for inhibition of pentylenetetrazol (PTZ)-induced tonic seizures. This suggests that tiagabine prevents the propagation of neural impulses that contribute to seizures by a GABA-ergic action. - Tiagabine has shown efficacy in several animal models of seizures. It is effective against the tonic phase of subcutaneous PTZ-induced seizures in mice and rats, seizures induced by the proconvulsant DMCM in mice, audiogenic seizures in genetically epilepsy-prone rats (GEPR), and amygdala-kindled seizures in rats. Tiagabine has little efficacy against maximal electroshock seizures in rats and is only partially effective against subcutaneous PTZ-induced clonic seizures in mice, picrotoxin-induced tonic seizures in the mouse, bicuculline-induced seizures in the rat, and photic seizures in photosensitive baboons. Tiagabine produces a biphasic dose-response curve against PTZ- and DMCM-induced convulsions, with attenuated effectiveness at higher doses. - Based on in vitro binding studies, tiagabine does not significantly inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline and shows little or no binding to dopamine D1 and D2, muscarinic, serotonin 5HT1A, 5HT2, and 5HT3, beta-1 and beta-2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine A1 and adenosine A2, opiate µ and opiate K1, NMDA glutamate, and GABAA receptors at 100 µM. It also lacks significant affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonin 5HT1B, benzodiazepine, and chloride channel receptors at concentrations 20 to 400 times those inhibiting the uptake of GABA. ## Structure - Its chemical name is (-)-(R)-1-4,4-Bis(3-methyl-2-thienyl)-3-buteny)nipecotic acid hydrochloride, its molecular formula is C20H25NO2S2 HCl, and its molecular weight is 412.0. Tiagabine HCl is a white to off-white, odorless, crystalline powder. It is insoluble in heptane, sparingly soluble in water, and soluble in aqueous base. The structural formula is: ## Pharmacodynamics There is limited information regarding Tiagabine Pharmacodynamics in the drug label. ## Pharmacokinetics - Tiagabine is well absorbed, with food slowing absorption rate but not altering the extent of absorption. The elimination half-life of tiagabine is 7 to 9 hours in normal volunteers. In epilepsy clinical trials, most patients were receiving hepatic enzyme-inducing agents (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). The pharmacokinetic profile in induced patients is significantly different from the non-induced population. The systemic clearance of tiagabine in induced patients is approximately 60% greater resulting in considerably lower plasma concentrations and an elimination half-life of 2 to 5 hours. Given this difference in clearance, the systemic exposure after a dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a non-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a non-induced population. ### Absorption and Distribution - Absorption of tiagabine is rapid, with peak plasma concentrations occurring at approximately 45 minutes following an oral dose in the fasting state. Tiagabine is nearly completely absorbed (>95%), with an absolute oral bioavailability of about 90%. A high fat meal decreases the rate (mean Tmax was prolonged to 2.5 hours, and mean Cmax was reduced by about 40%) but not the extent (AUC) of tiagabine absorption. In all clinical trials, tiagabine was given with meals. The pharmacokinetics of tiagabine are linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days. - Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin and α1-acid glycoprotein over the concentration range of 10 ng/mL to 10,000 ng/mL. While the relationship between tiagabine plasma concentrations and clinical response is not currently understood, trough plasma concentrations observed in controlled clinical trials at doses from 30 to 56 mg/day ranged from <1 ng/mL to 234 ng/mL. ### Metabolism and Elimination - Although the metabolism of tiagabine has not been fully elucidated, in vivo and in vitro studies suggest that at least two metabolic pathways for tiagabine have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and 2) glucuronidation. The 5-oxo-tiagabine metabolite does not contribute to the pharmacologic activity of tiagabine. - Based on in vitro data, tiagabine is likely to be metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A), although contributions to the metabolism of tiagabine from CYP1A2, CYP2D6 or CYP2C19 have not been excluded. - Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites, at least 2 of which have not been identified. The mean systemic plasma clearance is 109 mL/min (CV = 23%) and the average elimination half-life for tiagabine in healthy subjects ranged from 7 to 9 hours. The elimination half-life decreased by 50 to 65% in hepatic enzyme-induced patients with epilepsy compared to uninduced patients with epilepsy. - A diurnal effect on the pharmacokinetics of tiagabine was observed. Mean steady-state Cminvalues were 40% lower in the evening than in the morning. Tiagabine steady-state AUC values were also found to be 15% lower following the evening tiagabine dose compared to the AUC following the morning dose. ## Nonclinical Toxicology There is limited information regarding Tiagabine Nonclinical Toxicology in the drug label. # Clinical Studies - The effectiveness of Tiagabine as adjunctive therapy (added to other antiepilepsy drugs) was examined in three multi-center, double-blind, placebo-controlled, parallel-group, clinical trials in 769 patients with refractory partial seizures who were taking at least one hepatic enzyme-inducing antiepilepsy drug (AED), and two placebo-controlled cross-over studies in 90 patients. In the parallel-group trials, patients had a history of at least six complex partial seizures (Study 1 and Study 2, U.S. studies), or six partial seizures of any type (Study 3, European study), occurring alone or in combination with any other seizure type within the 8-week period preceding the first study visit in spite of receiving one or more AEDs at therapeutic concentrations. - In the first two studies, the primary protocol-specified outcome measure was the median reduction from baseline in the 4-week complex partial seizure (CPS) rates during treatment. In the third study, the protocol-specified primary outcome measure was the proportion of patients achieving a 50% or greater reduction from baseline in the 4-week seizure rate of all partial seizures during treatment. The results given below include data for complex partial seizures and all partial seizures for the intent-to-treat population (all patients who received at least one dose of treatment and at least one seizure evaluation) in each study. - Study 1 was a double-blind, placebo-controlled, parallel-group trial comparing Tiagabine 16 mg/day, Tiagabine 32 mg/day, Tiagabine 56 mg/day, and placebo. Study drug was given as a four times a day regimen. After a prospective Baseline Phase of 12 weeks, patients were randomized to one of the four treatment groups described above. The 16-week Treatment Phase consisted of a 4-week Titration Period, followed by a 12-week Fixed-Dose Period, during which concomitant AED doses were held constant. The primary outcome was assessed for the combined 32 and 56 mg/day groups compared to placebo. - Study 2 was a double-blind, placebo-controlled, parallel-group trial consisting of an 8-week Baseline Phase and a 12-week Treatment Phase, the first 4 weeks of which constituted a Titration Period and the last 8 weeks a Fixed-Dose Period. This study compared Tiagabine 16 mg BID and 8 mg QID to placebo. The protocol-specified primary outcome measure was assessed separately for each group treated with Tiagabine. The following tables display the results of the analyses of these two trials. - Figures 1 to 4 present the proportion of patients (X-axis) whose percent reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y axis in the three placebo-controlled adjunctive studies (Studies 1, 2, and 3). A positive value on the Y axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. - Figure 1 indicates that the proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the combined Tiagabine 32 mg and 56 mg groups compared to the placebo group in Study 1. For example, Figure 1 indicates that approximately 24% of patients treated with Tiagabine experienced a 50% or greater reduction, compared to 4% in the placebo group. - Figure 2 also displays the results for Study 1, which was a dose-response study, by treatment group, without combining Tiagabine dosage groups. Figure 2 indicates a dose-response relationship across the three Tiagabine groups. The proportion of patients achieving any particular level of reduction in all partial seizure rates was consistently higher as the dose of Tiagabine was increased. For example, Figure 2 indicates that approximately 4% of patients in the placebo group experienced a 50% or greater reduction in all partial seizure rate, compared to approximately 10% of the Tiagabine 16 mg/day group, 21% of the Tiagabine 32 mg/day group, and 30% of the Tiagabine 56 mg/day group. - Figure 3 indicates that the proportion of patients achieving any particular level of reduction in partial seizure rate was consistently greater in patients taking Tiagabine than in those taking placebo in Study 2. (Study 2 compared placebo to Tiagabine 32 mg/day; one of the Tiagabine groups received 8 mg QID, while the other Tiagabine group received 16 mg BID). For example, Figure 3 indicates that approximately 7% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate, compared to approximately 23% of patients in the Tiagabine 8 mg QID group and 28% of patients in the Tiagabine 16 mg BID group. - Study 3 was a double-blind, placebo-controlled, parallel-group trial that compared Tiagabine 10 mg TID (N=77) with placebo (N=77). In this trial, patients were followed prospectively during a 12-week Baseline Phase and then randomized to receive study drug during an 18-week Treatment Phase. During the first 6 weeks of treatment (Titration Period), patients were titrated to 30 mg/day, after which they were maintained on this dose during the 12-week Fixed-Dose Period. The protocol-specified primary outcome measure (proportion of patients who achieved at least a 50% reduction from baseline in partial seizure rate) did not reach statistical significance. However, analyses of the median reduction from baseline in 4-week partial seizure rate (the analyses presented above for Study 1 and Study 2) were performed and showed a statistically significant improvement compared to placebo in all partial and complex partial seizure rates (Table 3): - Figure 4 indicates that the proportion of patients achieving any particular level of reduction in seizure activity was consistently higher in those taking Tiagabine than those taking placebo in Study 3. For example, Figure 4 indicates that approximately 5% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate compared to approximately 10% of patients in the Tiagabine group. - The two other placebo-controlled trials that examined the effectiveness of Tiagabine were small cross-over trials (N=46 and 44). Both trials included an open Screening Phase during which patients were titrated to an optimal dose and then treated with this dose for an additional 4 weeks. After this Open Phase, patients were randomized to one of two blinded treatment sequences (Tiagabine followed by placebo or placebo followed by Tiagabine). The Double-Blind Phase consisted of two Treatment Periods, each lasting 7 weeks (with a 3 week washout between periods). The outcome measures were median with-in patient differences between placebo and Tiagabine Treatment Periods in 4-week complex partial and all partial seizure rates. The reductions in seizure rates were statistically significant in both studies. # How Supplied Tiagabine tablets are available in four dosage strengths. - 2 mg orange-peach, round tablets, debossed with Cephalon Imprint on one side and 402 on the opposite side, are available in bottles of 30 (NDC 63459-402-30). - 4 mg yellow, round tablets, debossed with Cephalon Imprint on one side and 404 on the opposite side, are available in bottles of 30 (NDC 63459-404-30). - 12 mg green, ovaloid tablets, debossed with Cephalon Imprint on one side and 412 on the opposite side, are available in bottles of 30 (NDC 63459-412-30). - 16 mg blue, ovaloid tablets, debossed with Cephalon Imprint on one side and 416 on the opposite side, are available in bottles of 30 (NDC 63459-416-30). ## Storage - Store tablets at controlled room temperature, between 20-25°C (68-77°F). # Images ## Drug Images ## Package and Label Display Panel Tiagabine P2mg.png # Patient Counseling Information There is limited information regarding Tiagabine Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Tiagabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Gabitril # Look-Alike Drug Names There is limited information regarding Tiagabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gabitril
e338e8058fcd467c94573bfde9bedfc95d1c4cea	wikidoc	Galanthus	Galanthus # Overview Galanthus (snowdrop; Greek gála "milk", ánthos "flower") is a small genus of about 20 species of bulbous herbaceous perennials in the Amaryllis family. Most flower in winter, before the vernal equinox (20 or 21 March in the Northern Hemisphere), but certain species flower in early spring and late autumn. Snowdrops are sometimes confused with the two related genera within Galantheae, snowflakes Leucojum and Acis. # Description All species of Galanthus are perennial, herbaceous plants which grow from bulbs. Each bulb generally produces just two or three linear leaves and an erect, leafless scape (flowering stalk), which bears at the top a pair of bract-like spathe valves joined by a papery membrane. From between them emerges a solitary, pendulous, bell-shaped white flower, held on a slender pedicel. The flower has no petals: it consists of six tepals, the outer three being larger and more convex than the inner series. The six anthers open by pores or short slits. The ovary is three-celled, ripening into a three-celled capsule. Each whitish seed has a small, fleshy tail (elaiosome) containing substances attractive to ants which distribute the seeds. The leaves die back a few weeks after the flowers have faded. The inner flower segments are usually marked with a green, or greenish-yellow, bridge-shaped mark over the small "sinus" (notch) at the tip of each tepal. An important feature which helps to distinguish between species (and to help to determine the parentage of hybrids) is their "vernation" (the arrangement of the emerging leaves relative to each other). This can be "applanate", "supervolute" or "explicative". In applanate vernation the two leaf blades are pressed flat to each other within the bud and as they emerge; explicative leaves are also pressed flat against each other, but the edges of the leaves are folded back or sometimes rolled; in supervolute plants one leaf is tightly clasped around the other within the bud and generally remains at the point where the leaves emerge from the soil. Notable species include: - Common snowdrop, Galanthus nivalis, grows to around 7–15 cm tall, flowering between January and April in the northern temperate zone (January–May in the wild). Applanate vernation - Crimean snowdrop, Galanthus plicatus, 30 cm tall, flowering January/March, white flowers, with broad leaves folded back at the edges (explicative vernation) - Giant snowdrop, Galanthus elwesii, a native of the Levant, 23 cm tall, flowering January/February, with large flowers, the three inner segments of which often have a much larger and more conspicuous green blotch (or blotches) than the more common kinds; supervolute vernation - Galanthus reginae-olgae, from Greece and Sicily, is quite similar in appearance to G. nivalis, but flowers in autumn before the leaves appear. The leaves, which appear in the spring, have a characteristic white stripe on their upper side; applanate vernation G. reginae-olgae subsp. vernalis, from Sicily, northern Greece and the southern part of former Yugoslavia, blooms at the end of the winter with developed young leaves and is thus easily confused with G. nivalis. - G. reginae-olgae subsp. vernalis, from Sicily, northern Greece and the southern part of former Yugoslavia, blooms at the end of the winter with developed young leaves and is thus easily confused with G. nivalis. # Taxonomy The genus was created by Carl Linnaeus in 1753, based on the type species Galanthus nivalis. Galanthus is from the Greek gala, meaning "milk", and anthos, meaning "flower", alluding to the colour of the flowers. The epithet nivalis means "of the snow". ## Similar genera Snowdrops are sometimes confused with the two related genera that constitute the Galantheae, snowflakes or Leucojum and Acis . Leucojum are much larger and flower in spring (or early summer, depending on the species), with all six tepals in the flower being the same size, though some "poculiform" (goblet- or cup-shaped) Galanthus can have inner segments similar in shape and length to the outer ones. ## Species As of February 2012, the World Checklist of Selected Plant Families recognises 19 species. A 20th species, Galanthus panjutinii (Panjutin's snowdrop), was recognised during 2012. Discovered in five locations in a small area (estimated at 20 km2) of the northern Colchis area (western Transcaucasus) of Georgia and Russia, it is classed as Endangered. One of its five known sites, at Sochi, was destroyed by preparations for the 2014 Winter Olympics. - Galanthus alpinus Sosn. - Turkey, Caucasus - Galanthus angustifolius Koss - Caucasus - Galanthus cilicicus Baker - Turkey - Galanthus elwesii Hook.f. - Greece, Balkans, Ukraine, Turkey - Galanthus fosteri Baker - Turkey, Syria, Jordan - Galanthus gracilis Celak. - Greece, Balkans, Ukraine, Turkey - Galanthus ikariae Baker - Aegean Islands (Andros, Ikaria, Naxos, Skyros) - Galanthus koenenianus Lobin - Turkey - Galanthus krasnovii Khokhr. - Turkey, Caucasus - Galanthus lagodechianus Kem.-Nath. - Caucasus - Galanthus nivalis L. - southern + central Europe from Pyrenees to Ukraine - Galanthus panjutinii Zubov & A.P.Davis - Caucasus - Galanthus peshmenii A.P.Davis & C.D.Brickell - southwestern Turkey, Greek Island of Kastellorizo (Megisti) - Galanthus platyphyllus Traub & Moldenke - Caucasus - Galanthus plicatus M.Bieb. - Caucasus, Turkey, Ukraine, Crimea, Romania - Galanthus reginae-olgae Orph. - Greece, Sicily, Balkans - Galanthus rizehensis Stern - Turkey, Caucasus - Galanthus transcaucasicus Fomin - Iran, Caucasus - Galanthus trojanus A.P.Davis & Özhatay - Turkey - Galanthus woronowii Losinsk. - Turkey, Caucasus # Distribution and habitat The genus Galanthus is native to Europe and the Middle East, from Spain, France and Germany in the west through to Iran in the east. It has become naturalized in other parts of Europe – Norway, Sweden, Great Britain, Belgium and the Netherlands – as well as in eastern Canada and the United States. Galanthus nivalis is the best-known and most widespread representative of the genus Galanthus. It is native to a large area of Europe, stretching from the Pyrenees in the west, through France and Germany to Poland in the north, Italy, Northern Greece, Bulgaria, Romania, Ukraine and European Turkey. It has been introduced and is widely naturalised elsewhere. Although it is often thought of as a British native wild flower, or to have been brought to the British Isles by the Romans, it was probably introduced around the early sixteenth century and is currently not a protected species in the UK. Most other Galanthus species are from the eastern Mediterranean, though several are found in southern Russia, Georgia, Armenia and Azerbaijan. Galanthus fosteri comes from Jordan, Lebanon, Syria, Turkey and maybe Israel. # Conservation Some snowdrop species are threatened in their wild habitats, and in most countries it is now illegal to collect bulbs from the wild. Under CITES regulations, international trade in any quantity of Galanthus, whether bulbs, live plants or even dead ones, is illegal without a CITES permit. This applies to hybrids and named cultivars as well as species. CITES does, however, allow a limited trade in wild-collected bulbs of just three species (G. nivalis, G, elwesii and G. woronowii) from Turkey and Georgia. # Cultivation ## Snowdrop gardens Celebrated as a sign of spring, snowdrops can form impressive carpets of white in areas where they are native or have been naturalised. These displays may attract large numbers of sightseers. There are a number of snowdrop gardens in England, Wales, Scotland and Ireland. Several gardens open specially in February for visitors to admire the flowers. Sixty gardens took part in Scotland's first Snowdrop Festival (1 Feb–11 March 2007). Several gardens in England open during snowdrop season for the National Gardens Scheme (NGS) and in Scotland for Scotland's Gardens. ## Cultivars There are numerous single- and double-flowered cultivars of Galanthus nivalis, and also of several other Galanthus species, particularly G. plicatus and G. elwesii. There are also many hybrids between these and other species (there are more than 500 cultivars described in Bishop, Davis & Grimshaw's book, plus lists of many cultivars that have now been lost, and others not seen by the authors). They differ particularly in the size, shape and markings of the flower, the period of flowering, and other characteristics, mainly of interest to the keen (even fanatical) snowdrop collectors, known as "galanthophiles", who hold meetings where the scarcer cultivars change hands. Double-flowered cultivars and forms, such as the extremely common Galanthus nivalis f. pleniflorus 'Flore Pleno', may be less attractive to some people but they can have greater visual impact in a garden setting. The following species and cultivars have gained the Royal Horticultural Society's Award of Garden Merit:- A list of Irish cultivars can be found here ## Propagation Propagation is by offset bulbs, either by careful division of clumps in full growth ("in the green"), or removed when the plants are dormant, immediately after the leaves have withered; or by seeds sown either when ripe, or in spring. Professional growers and keen amateurs also use such methods as "twin-scaling" to increase the stock of choice cultivars quickly. # Active substances It was suggested by Andreas Plaitakis and Roger Duvoisin in 1983 that the mysterious magical herb moly that appears in Homer's Odyssey is actually snowdrop. An active substance in snowdrop is called galantamine, which, as anticholinesterase, could have acted as an antidote to Circe's poisons. Galantamine (or galanthamine) can be helpful in the treatment of Alzheimer's disease, though it is not a cure; the substance also occurs naturally in daffodils and other narcissi. Snowdrops contain also an active lectin or agglutinin named GNA for Galanthus nivalis agglutinin. In 1995 Árpád Pusztai genetically modified potatoes with the GNA gene, which work he discussed on a radio interview in 1998 and published in the Lancet in 1999. In 1998 said in an interview on a World in Action programme that his group had observed damage to the intestines and immune systems of rats fed the genetically modified potatoes. He also said "If I had the choice I would certainly not eat it", and that "I find it's very unfair to use our fellow citizens as guinea pigs". These remarks started the so-called Pusztai affair. # In popular culture - In the fairy-tale play The Twelve Months by Russian writer Samuil Marshak, a greedy queen decrees that a basket of gold coins shall be rewarded to anyone who can bring her galanthus flowers in the dead of winter. A young orphan Girl is sent out during a snow storm by her cruel stepmother and find the spirits of the 12 months of the year, who take pity on her and not only save her from freezing to death, but make it possible for her to gather the flowers even in winter. The Soviet traditionally animated film The Twelve Months (1956), Lenfilm film The Twelve Months (1972) and the anime film Twelve Months (1980) (Sekai meisaku dowa mori wa ikiteiru in Japan) are based on this fairy-tale play. - "Snowdrops" was the nickname that the British people gave during the Second World War to the military police of the United States Army (who were stationed in the UK preparatory to the invasion of the continent) because they wore a white helmet, gloves, gaiters, and Sam Browne belt against their olive drab uniform - The short story The Snowdrop by Hans Christian Andersen follows the fate of a snowdrop from a bulb striving towards the light to a picked flower placed in a book of poetry. - In Stardust, a glass snowdrop is given to Dunstan for a kiss by Una. It's later used to protect Tristan from the magic of Lamia. - In the musical Kiss Me, Kate by Cole Porter (1948) the character Lilli/Katherine is deeply pleased at receiving a pre-opening night performance bouquet of "pansies, snowdrops, and rosemary. Our wedding bouquet," from her ex, Fred/Patruchio. But--the bouquet was meant for the younger, ingenue lead, Lois/Bianca.	Galanthus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Galanthus (snowdrop; Greek gála "milk", ánthos "flower") is a small genus of about 20 species of bulbous herbaceous perennials in the Amaryllis family.[1] Most flower in winter, before the vernal equinox (20 or 21 March in the Northern Hemisphere), but certain species flower in early spring and late autumn. Snowdrops are sometimes confused with the two related genera within Galantheae, snowflakes Leucojum and Acis. # Description All species of Galanthus are perennial, herbaceous plants which grow from bulbs. Each bulb generally produces just two or three linear leaves and an erect, leafless scape (flowering stalk), which bears at the top a pair of bract-like spathe valves joined by a papery membrane. From between them emerges a solitary, pendulous, bell-shaped white flower, held on a slender pedicel. The flower has no petals: it consists of six tepals, the outer three being larger and more convex than the inner series. The six anthers open by pores or short slits. The ovary is three-celled, ripening into a three-celled capsule. Each whitish seed has a small, fleshy tail (elaiosome) containing substances attractive to ants which distribute the seeds.[2] The leaves die back a few weeks after the flowers have faded. The inner flower segments are usually marked with a green, or greenish-yellow, bridge-shaped mark over the small "sinus" (notch) at the tip of each tepal. An important feature which helps to distinguish between species (and to help to determine the parentage of hybrids) is their "vernation" (the arrangement of the emerging leaves relative to each other). This can be "applanate", "supervolute" or "explicative". In applanate vernation the two leaf blades are pressed flat to each other within the bud and as they emerge; explicative leaves are also pressed flat against each other, but the edges of the leaves are folded back or sometimes rolled; in supervolute plants one leaf is tightly clasped around the other within the bud and generally remains at the point where the leaves emerge from the soil.[3] Notable species include: - Common snowdrop, Galanthus nivalis, grows to around 7–15 cm tall, flowering between January and April in the northern temperate zone (January–May in the wild). Applanate vernation[4] - Crimean snowdrop, Galanthus plicatus, 30 cm tall, flowering January/March, white flowers, with broad leaves folded back at the edges (explicative vernation) - Giant snowdrop, Galanthus elwesii, a native of the Levant, 23 cm tall, flowering January/February, with large flowers, the three inner segments of which often have a much larger and more conspicuous green blotch (or blotches) than the more common kinds; supervolute vernation - Galanthus reginae-olgae, from Greece and Sicily, is quite similar in appearance to G. nivalis, but flowers in autumn before the leaves appear. The leaves, which appear in the spring, have a characteristic white stripe on their upper side; applanate vernation G. reginae-olgae subsp. vernalis, from Sicily, northern Greece and the southern part of former Yugoslavia, blooms at the end of the winter with developed young leaves and is thus easily confused with G. nivalis. - G. reginae-olgae subsp. vernalis, from Sicily, northern Greece and the southern part of former Yugoslavia, blooms at the end of the winter with developed young leaves and is thus easily confused with G. nivalis. # Taxonomy The genus was created by Carl Linnaeus in 1753, based on the type species Galanthus nivalis.[5] Galanthus is from the Greek gala, meaning "milk", and anthos, meaning "flower", alluding to the colour of the flowers. The epithet nivalis means "of the snow".[6] ## Similar genera Snowdrops are sometimes confused with the two related genera that constitute the Galantheae, snowflakes or Leucojum and Acis . Leucojum are much larger and flower in spring (or early summer, depending on the species), with all six tepals in the flower being the same size, though some "poculiform" (goblet- or cup-shaped) Galanthus can have inner segments similar in shape and length to the outer ones. ## Species As of February 2012[update], the World Checklist of Selected Plant Families recognises 19 species.[5] A 20th species, Galanthus panjutinii (Panjutin's snowdrop), was recognised during 2012. Discovered in five locations in a small area (estimated at 20 km2) of the northern Colchis area (western Transcaucasus) of Georgia and Russia, it is classed as Endangered. One of its five known sites, at Sochi, was destroyed by preparations for the 2014 Winter Olympics.[7] - Galanthus alpinus Sosn. - Turkey, Caucasus - Galanthus angustifolius Koss - Caucasus - Galanthus cilicicus Baker - Turkey - Galanthus elwesii Hook.f. - Greece, Balkans, Ukraine, Turkey - Galanthus fosteri Baker - Turkey, Syria, Jordan - Galanthus gracilis Celak. - Greece, Balkans, Ukraine, Turkey - Galanthus ikariae Baker - Aegean Islands (Andros, Ikaria, Naxos, Skyros) - Galanthus koenenianus Lobin - Turkey - Galanthus krasnovii Khokhr. - Turkey, Caucasus - Galanthus lagodechianus Kem.-Nath. - Caucasus - Galanthus nivalis L. - southern + central Europe from Pyrenees to Ukraine - Galanthus panjutinii Zubov & A.P.Davis - Caucasus - Galanthus peshmenii A.P.Davis & C.D.Brickell - southwestern Turkey, Greek Island of Kastellorizo (Megisti) - Galanthus platyphyllus Traub & Moldenke - Caucasus - Galanthus plicatus M.Bieb. - Caucasus, Turkey, Ukraine, Crimea, Romania - Galanthus reginae-olgae Orph. - Greece, Sicily, Balkans - Galanthus rizehensis Stern - Turkey, Caucasus - Galanthus transcaucasicus Fomin - Iran, Caucasus - Galanthus trojanus A.P.Davis & Özhatay - Turkey - Galanthus woronowii Losinsk. - Turkey, Caucasus # Distribution and habitat The genus Galanthus is native to Europe and the Middle East, from Spain, France and Germany in the west through to Iran in the east. It has become naturalized in other parts of Europe – Norway, Sweden, Great Britain, Belgium and the Netherlands – as well as in eastern Canada and the United States.[8] Galanthus nivalis is the best-known and most widespread representative of the genus Galanthus. It is native to a large area of Europe, stretching from the Pyrenees in the west, through France and Germany to Poland in the north, Italy, Northern Greece, Bulgaria, Romania, Ukraine and European Turkey. It has been introduced and is widely naturalised elsewhere.[9] Although it is often thought of as a British native wild flower, or to have been brought to the British Isles by the Romans, it was probably introduced around the early sixteenth century and is currently not a protected species in the UK.[4] Most other Galanthus species are from the eastern Mediterranean, though several are found in southern Russia, Georgia, Armenia and Azerbaijan.[10] Galanthus fosteri comes from Jordan, Lebanon, Syria, Turkey and maybe Israel.[11] # Conservation Some snowdrop species are threatened in their wild habitats, and in most countries it is now illegal to collect bulbs from the wild. Under CITES regulations, international trade in any quantity of Galanthus, whether bulbs, live plants or even dead ones, is illegal without a CITES permit. This applies to hybrids and named cultivars as well as species. CITES does, however, allow a limited trade in wild-collected bulbs of just three species (G. nivalis, G, elwesii and G. woronowii) from Turkey and Georgia.[12] # Cultivation ## Snowdrop gardens Celebrated as a sign of spring, snowdrops can form impressive carpets of white in areas where they are native or have been naturalised. These displays may attract large numbers of sightseers. There are a number of snowdrop gardens in England, Wales, Scotland and Ireland.[13] Several gardens open specially in February for visitors to admire the flowers. Sixty gardens took part in Scotland's first Snowdrop Festival (1 Feb–11 March 2007).[14] Several gardens in England open during snowdrop season for the National Gardens Scheme (NGS) and in Scotland for Scotland's Gardens. ## Cultivars There are numerous single- and double-flowered cultivars of Galanthus nivalis, and also of several other Galanthus species, particularly G. plicatus and G. elwesii. There are also many hybrids between these and other species (there are more than 500 cultivars described in Bishop, Davis & Grimshaw's book, plus lists of many cultivars that have now been lost, and others not seen by the authors). They differ particularly in the size, shape and markings of the flower, the period of flowering, and other characteristics, mainly of interest to the keen (even fanatical) snowdrop collectors, known as "galanthophiles", who hold meetings where the scarcer cultivars change hands.[15] Double-flowered cultivars and forms, such as the extremely common Galanthus nivalis f. pleniflorus 'Flore Pleno', may be less attractive to some people but they can have greater visual impact in a garden setting. The following species and cultivars have gained the Royal Horticultural Society's Award of Garden Merit:- A list of Irish cultivars can be found here [2] ## Propagation Propagation is by offset bulbs, either by careful division of clumps in full growth ("in the green"), or removed when the plants are dormant, immediately after the leaves have withered; or by seeds sown either when ripe, or in spring. Professional growers and keen amateurs also use such methods as "twin-scaling" to increase the stock of choice cultivars quickly. # Active substances It was suggested by Andreas Plaitakis and Roger Duvoisin in 1983 that the mysterious magical herb moly that appears in Homer's Odyssey is actually snowdrop. An active substance in snowdrop is called galantamine, which, as anticholinesterase, could have acted as an antidote to Circe's poisons.[25] Galantamine (or galanthamine) can be helpful in the treatment of Alzheimer's disease, though it is not a cure;[citation needed] the substance also occurs naturally in daffodils and other narcissi.[citation needed] Snowdrops contain also an active lectin or agglutinin named GNA for Galanthus nivalis agglutinin.[26] In 1995 Árpád Pusztai genetically modified potatoes with the GNA gene, which work he discussed on a radio interview in 1998[27] and published in the Lancet in 1999.[28] In 1998 said in an interview on a World in Action programme that his group had observed damage to the intestines and immune systems of rats fed the genetically modified potatoes. He also said "If I had the choice I would certainly not eat it", and that "I find it's very unfair to use our fellow citizens as guinea pigs".[27] These remarks started the so-called Pusztai affair. # In popular culture - In the fairy-tale play The Twelve Months by Russian writer Samuil Marshak, a greedy queen decrees that a basket of gold coins shall be rewarded to anyone who can bring her galanthus flowers in the dead of winter. A young orphan Girl is sent out during a snow storm by her cruel stepmother and find the spirits of the 12 months of the year, who take pity on her and not only save her from freezing to death, but make it possible for her to gather the flowers even in winter. The Soviet traditionally animated film The Twelve Months (1956), Lenfilm film The Twelve Months (1972) and the anime film Twelve Months (1980) (Sekai meisaku dowa mori wa ikiteiru in Japan) are based on this fairy-tale play. - "Snowdrops" was the nickname that the British people gave during the Second World War to the military police of the United States Army (who were stationed in the UK preparatory to the invasion of the continent) because they wore a white helmet, gloves, gaiters, and Sam Browne belt against their olive drab uniform - The short story The Snowdrop by Hans Christian Andersen follows the fate of a snowdrop from a bulb striving towards the light to a picked flower placed in a book of poetry. - In Stardust, a glass snowdrop is given to Dunstan for a kiss by Una. It's later used to protect Tristan from the magic of Lamia. - In the musical Kiss Me, Kate by Cole Porter (1948) the character Lilli/Katherine is deeply pleased at receiving a pre-opening night performance bouquet of "pansies, snowdrops, and rosemary. Our wedding bouquet," from her ex, Fred/Patruchio. But--the bouquet was meant for the younger, ingenue lead, Lois/Bianca.	https://www.wikidoc.org/index.php/Galanthus
4cfadbc57d223053cbd60e90436f4990e8624128	wikidoc	Gallamine	Gallamine # Overview Gallamine triethiodide (Flaxedil) is a non-depolarising muscle relaxant. It acts by combining with the cholinergic receptor sites in muscle and competitively blocking the transmitter action of acetylcholine. Gallamine triethiodide has a parasympatholytic effect on the cardiac vagus nerve which causes tachycardia and occasionally hypertension. Very high doses cause histamine release. Gallamine triethiodide is commonly used to stabilize muscle contractions during surgical procedures. It was developed by Daniel Bovet in 1947. The pharmaceutical is no longer marketed in the United States, according to the FDA Orange Book.	Gallamine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gallamine triethiodide (Flaxedil) is a non-depolarising muscle relaxant.[1] It acts by combining with the cholinergic receptor sites in muscle and competitively blocking the transmitter action of acetylcholine.[2] Gallamine triethiodide has a parasympatholytic effect on the cardiac vagus nerve which causes tachycardia[3][4] and occasionally hypertension. Very high doses cause histamine release. Gallamine triethiodide is commonly used to stabilize muscle contractions during surgical procedures. It was developed by Daniel Bovet in 1947.[5] The pharmaceutical is no longer marketed in the United States, according to the FDA Orange Book.	https://www.wikidoc.org/index.php/Gallamine
671b7f7ca3e27efb2fd21fbe715da691a5e00080	wikidoc	Galvanism	Galvanism In biology, galvanism is the contraction of a muscle that is stimulated by an electric current. In physics and chemistry, it is the induction of electrical current from a chemical reaction, typically between two chemicals with differing electronegativites. # History The effect was named by Alessandro Volta after his contemporary, the scientist Luigi Galvani, who investigated the effect of electricity on dissected animals in the 1780s and 1790s. Galvani himself referred to the phenomenon as animal electricity, believing that he had discovered a distinct form of electricity. Volta, on the other hand, claimed that the reputed animal electricity was due to an interaction between the metals used to mount and dissect the frog's leg, and in 1800, before the Royal Society in London, announced the Voltaic Cell or pile, essentially the battery. The modern study of galvanic effects in biology is called electrophysiology, the term galvanism being used only in historical contexts. The term is also used to describe the bringing to life of organisms using electricity, as shown in Mary Shelley's work Frankenstein (which was influenced by galvanism) and people still speak of being 'galvanized into action'. Many Victorian scientists believed that if the right amount of electricity was charged into the brain, the corpse would come back to life. ## Experiments in Galvanism The concept of galvanism was recently explored in contemporary art by Canadian artist Garnet Hertz, with his piece Experiments in Galvanism. A miniature web server was implanted in the body of a frog specimen, which was suspended in a clear glass container. Through an ethernet cable connected to the embedded web server, remote viewers could trigger movement in either the right or left leg of the frog, thereby updating Luigi Galvani's original 1786 experiment causing the legs of a dead frog to twitch simply by touching muscles and nerves with metal. Although true galvanic action is not taking place -- two small motors/actuators physically move the frog's legs -- the project attempts to draw a parallel between the excitement that galvanism caused in contemporary culture in the era of Mary Shelly and the excitement that internet technologies generated at the turn of the 21st century.	Galvanism In biology, galvanism is the contraction of a muscle that is stimulated by an electric current. In physics and chemistry, it is the induction of electrical current from a chemical reaction, typically between two chemicals with differing electronegativites. # History The effect was named by Alessandro Volta after his contemporary, the scientist Luigi Galvani, who investigated the effect of electricity on dissected animals in the 1780s and 1790s. Galvani himself referred to the phenomenon as animal electricity, believing that he had discovered a distinct form of electricity. Volta, on the other hand, claimed that the reputed animal electricity was due to an interaction between the metals used to mount and dissect the frog's leg, and in 1800, before the Royal Society in London, announced the Voltaic Cell or pile, essentially the battery. The modern study of galvanic effects in biology is called electrophysiology, the term galvanism being used only in historical contexts. The term is also used to describe the bringing to life of organisms using electricity, as shown in Mary Shelley's work Frankenstein (which was influenced by galvanism) and people still speak of being 'galvanized into action'. Many Victorian scientists believed that if the right amount of electricity was charged into the brain, the corpse would come back to life. ## Experiments in Galvanism The concept of galvanism was recently explored in contemporary art by Canadian artist Garnet Hertz, with his piece Experiments in Galvanism. A miniature web server was implanted in the body of a frog specimen, which was suspended in a clear glass container. Through an ethernet cable connected to the embedded web server, remote viewers could trigger movement in either the right or left leg of the frog, thereby updating Luigi Galvani's original 1786 experiment causing the legs of a dead frog to twitch simply by touching muscles and nerves with metal. Although true galvanic action is not taking place -- two small motors/actuators physically move the frog's legs -- the project attempts to draw a parallel between the excitement that galvanism caused in contemporary culture in the era of Mary Shelly and the excitement that internet technologies generated at the turn of the 21st century.	https://www.wikidoc.org/index.php/Galvanism
a6ef6927c145a7261ea7addb46ac6d85813d128f	wikidoc	Gamma ray	Gamma ray # Overview Gamma rays (denoted as γ) are a form of electromagnetic radiation or light emission of frequencies produced by sub-atomic particle interactions, such as electron-positron annihilation or radioactive decay. Gamma rays are generally characterized as electromagnetic radiation having the highest frequency and energy, and also the shortest wavelength (below about 10 picometer), within the electromagnetic spectrum. Gamma rays consist of high energy photons with energies above about 100 keV. Gamma rays were discovered by Paul Villard, a French chemist and physicist, in 1900, while studying uranium. Hard X-rays overlap the range of "long"-wavelength (lower energy) gamma rays. The distinction between the two terms, however, depends on the source of the radiation, not its wavelength; X-ray photons are generated by energetic electron processes, gamma rays by transitions within atomic nuclei. Due to their high energy content, gamma rays can cause serious damage when absorbed by living cells. # Properties ## Shielding Shielding gamma rays requires large amounts of mass. They are better absorbed by materials with high atomic numbers and high density. The higher the energy of the gamma rays, the thicker the shielding required. Materials for shielding gamma rays are typically measured by the thickness required to reduce the intensity of the gamma rays by one half (the half value layer or HVL). For example, gamma rays that require 1 cm (0.4 inches) of lead to reduce their intensity by 50% will also have their intensity reduced in half by 6 cm (2½ inches) of concrete or 9 cm (3½ inches) of packed dirt. ## Matter interaction File:Gamma Abs Al.png File:Gamma Abs Pb.png When a gamma ray passes through matter, the probability for absorption in a thin layer is proportional to the thickness of that layer. This leads to an exponential decrease of intensity with thickness. The exponential absorption holds only for a narrow beam of gamma rays. If a wide beam of gamma rays passes through a thick slab of concrete, the scattering from the sides reduces the absorption. I(d) = I_0 \cdot e ^{-\mu d}. Here, μ = nσ is the absorption coefficient, measured in cm−1, n the number of atoms per cm3 in the material, σ the absorption cross section in cm2 and d the thickness of material in cm. In passing through matter, gamma radiation ionizes via three main processes: the photoelectric effect, Compton scattering, and pair production. - Photoelectric Effect: This describes the case in which a gamma photon interacts with and transfers its energy to an atomic electron, ejecting that electron from the atom. The kinetic energy of the resulting photoelectron is equal to the energy of the incident gamma photon minus the binding energy of the electron. The photoelectric effect is the dominant energy transfer mechanism for x-ray and gamma ray photons with energies below 50 keV (thousand electron volts), but it is much less important at higher energies. - Compton Scattering: This is an interaction in which an incident gamma photon loses enough energy to an atomic electron to cause its ejection, with the remainder of the original photon's energy being emitted as a new, lower energy gamma photon with an emission direction different from that of the incident gamma photon. The probability of Compton scatter decreases with increasing photon energy. Compton scattering is thought to be the principal absorption mechanism for gamma rays in the intermediate energy range 100 keV to 10 MeV. Compton scattering is relatively independent of the atomic number of the absorbing material. - Pair Production: By interaction with the electric field of a nucleus, the energy of the incident photon is converted into the mass of an electron-positron pair. Energy in excess of the equivalent rest mass of the two particles (1.02 MeV) appears as the kinetic energy of the pair and the recoil nucleus. At the end of the positron's range, it combines with a free electron. The entire mass of these two particles is then converted into two gamma photons of at least 0.51 MeV energy each (or higher according to the kinetic energy of the annihilated particles) The secondary electrons (and/or positrons) produced in any of these three processes frequently have enough energy to produce much ionization themselves. ## Gamma production Gamma rays are often produced alongside other forms of radiation such as alpha or beta. When a nucleus emits an α or β particle, the daughter nucleus is sometimes left in an excited state. It can then jump down to a lower level by emitting a gamma ray in much the same way that an atomic electron can jump to a lower level by emitting visible light or ultraviolet radiation. Gamma rays, x-rays, visible light, and radio waves are all forms of electromagnetic radiation. The only difference is the frequency and hence the energy of the photons. Gamma rays are the most energetic. An example of gamma ray production follows. First 60Co decays to excited 60Ni by beta decay: {}^{60}\hbox{Co}\;\to\;^{60}\hbox{Ni}\;+\;e^-\;+\;\overline{\nu}_e. Then the 60Ni drops down to the ground state (see nuclear shell model) by emitting two gamma rays in succession: {}^{60}\hbox{Ni}\;\to\;^{60}\hbox{Ni}\;+\;\gamma. Gamma rays of 1.17 MeV and 1.33 MeV are produced. Another example is the alpha decay of 241Am to form 237Np; this alpha decay is accompanied by gamma emission. In some cases, the gamma emission spectrum for a nucleus (daughter nucleus) is quite simple, (eg 60Co/60Ni) while in other cases, such as with (241Am/237Np and 192Ir/192Pt), the gamma emission spectrum is complex, revealing that a series of nuclear energy levels can exist. The fact that an alpha spectrum can have a series of different peaks with different energies reinforces the idea that several nuclear energy levels are possible. Because a beta decay is accompanied by the emission of a neutrino which also carries energy away, the beta spectrum does not have sharp lines, but instead is a broad peak. Hence from beta decay alone it is not possible to probe the different energy levels found in the nucleus. In optical spectroscopy, it is well known that an entity which emits light can also absorb light at the same wavelength (photon energy). For instance, a sodium flame can emit yellow light as well as absorb the yellow light from a sodium vapor lamp. In the case of gamma rays, this can be seen in Mössbauer spectroscopy. Here, a correction for the energy lost by the recoil of the nucleus is made and the exact conditions for gamma ray absorption through resonance can be attained. This is similar to the Franck Condon effects seen in optical spectroscopy. # Uses Because the wavelength of gamma radiation is so short, a single incident photon can impart significant damage to a living cell. This property means that gamma radiation is often used to kill living organisms, in a process called irradiation. Applications of this include sterilizing medical equipment (as an alternative to autoclaves or chemical means), removing decay-causing bacteria from many foodstuffs or preventing fruit and vegetables from sprouting to maintain freshness and flavor. Due to their tissue penetrating property, gamma rays/X-rays have a wide variety of medical uses such as in CT Scans and radiation therapy (see X-ray). However, as a form of ionizing radiation they have the ability to effect molecular changes, giving them the potential to cause cancer when DNA is affected. The molecular changes can also be used to alter the properties of semi-precious stones, and is often used to change white topaz into blue topaz. Despite their cancer-causing properties, gamma rays are also used to treat some types of cancer. In the procedure called gamma-knife surgery, multiple concentrated beams of gamma rays are directed on the growth in order to kill the cancerous cells. The beams are aimed from different angles to focus the radiation on the growth while minimizing damage to the surrounding tissues. Gamma rays are also used for diagnostic purposes in nuclear medicine. Several gamma-emitting radioisotopes are used, one of which is technetium-99m. When administered to a patient, a gamma camera can be used to form an image of the radioisotope's distribution by detecting the gamma radiation emitted. Such a technique can be employed to diagnose a wide range of conditions (e.g. spread of cancer to the bones). Gamma ray detectors are also starting to be used in Pakistan as part of the Container Security Initiative (CSI). These US$5 million machines are advertised to scan 30 containers per hour. The objective of this technique is to pre-screen merchant ship containers before they enter US ports. # Health effects Gamma rays are the most dangerous form of radiation emitted by a nuclear explosion because of the difficulty in shielding them. This is because gamma rays have the shortest wavelength of all waves in the electromagnetic spectrum, and therefore the most ability to penetrate through any gap, even a subatomic one, in a what might otherwise be a shield. Gamma-rays are not stopped by the skin. They can induce DNA alteration by interfering with the genetic material of the cell. DNA double-strand breaks are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer and hereditary disease.. A study done on Russian nuclear workers exposed to external whole-body gamma radiation at high cumulative doses shows the link between radiation exposure and death from leukemia, lung, liver, skeletal and other solid cancers.. Alongside radiation, gamma-rays also produce thermal burn injuries and induce an immunosuppressive effect. ## Body response After gamma-irradiation, and the breaking of DNA double-strands, a cell can repair the damaged genetic material to the limit of its capability. However, a study of Rothkamm and Lobrich has shown that the repairing process works well after high-dose exposure but is much slower in the case of a low-dose exposure. This could mean that a chronic low-dose exposure cannot be fought by the body. The probability of detecting small alterations or of a detectable defect occurring is most likely small enough that the cell would replicate before initiating a full repair. Some cells can not detect their own genetic defects. ## Risk assessment The natural outdoor exposure in Great Britain is in the range 20-40 nSv/h. Natural exposure to gamma rays is about 1 to 2 millisieverts per year, and the average total amount of radiation received in one year per inhabitant in the USA is 3.6 mSv. By comparison, the radiation dose from chest radiography is a fraction of the annual naturally occurring background radiation dose, and the dose from fluoroscopy of the stomach is, at most, 0.05 Sv on the skin of the back. For acute full-body equivalent dose, 1 Sv causes slight blood changes, 2-5 Sv causes nausea, hair loss, hemorrhaging and will cause death in many cases. More than 3 Sv will lead to death in less than two months in more than 80 percent of cases, and much over 4 Sv usually causes death (see Sievert). For low dose exposure, for example among nuclear workers, who receive an average radiation dose of 19 mSv, the risk of dying from cancer (excluding leukemia) increases by 2 percent. For a dose of 100 mSv, that risk increase is at 10 percent. By comparison, it was 32 percent for the Atom Bomb survivors..	Gamma ray Template:Nuclear physics Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gamma rays (denoted as γ) are a form of electromagnetic radiation or light emission of frequencies produced by sub-atomic particle interactions, such as electron-positron annihilation or radioactive decay. Gamma rays are generally characterized as electromagnetic radiation having the highest frequency and energy, and also the shortest wavelength (below about 10 picometer), within the electromagnetic spectrum. Gamma rays consist of high energy photons with energies above about 100 keV. Gamma rays were discovered by Paul Villard, a French chemist and physicist, in 1900, while studying uranium. Hard X-rays overlap the range of "long"-wavelength (lower energy) gamma rays. The distinction between the two terms, however, depends on the source of the radiation, not its wavelength; X-ray photons are generated by energetic electron processes, gamma rays by transitions within atomic nuclei. Due to their high energy content, gamma rays can cause serious damage when absorbed by living cells. # Properties ## Shielding Shielding gamma rays requires large amounts of mass. They are better absorbed by materials with high atomic numbers and high density. The higher the energy of the gamma rays, the thicker the shielding required. Materials for shielding gamma rays are typically measured by the thickness required to reduce the intensity of the gamma rays by one half (the half value layer or HVL). For example, gamma rays that require 1 cm (0.4 inches) of lead to reduce their intensity by 50% will also have their intensity reduced in half by 6 cm (2½ inches) of concrete or 9 cm (3½ inches) of packed dirt. ## Matter interaction File:Gamma Abs Al.png File:Gamma Abs Pb.png When a gamma ray passes through matter, the probability for absorption in a thin layer is proportional to the thickness of that layer. This leads to an exponential decrease of intensity with thickness. The exponential absorption holds only for a narrow beam of gamma rays. If a wide beam of gamma rays passes through a thick slab of concrete, the scattering from the sides reduces the absorption. I(d) = I_0 \cdot e ^{-\mu d}. </math> Here, μ = nσ is the absorption coefficient, measured in cm−1, n the number of atoms per cm3 in the material, σ the absorption cross section in cm2 and d the thickness of material in cm. In passing through matter, gamma radiation ionizes via three main processes: the photoelectric effect, Compton scattering, and pair production. - Photoelectric Effect: This describes the case in which a gamma photon interacts with and transfers its energy to an atomic electron, ejecting that electron from the atom. The kinetic energy of the resulting photoelectron is equal to the energy of the incident gamma photon minus the binding energy of the electron. The photoelectric effect is the dominant energy transfer mechanism for x-ray and gamma ray photons with energies below 50 keV (thousand electron volts), but it is much less important at higher energies. - Compton Scattering: This is an interaction in which an incident gamma photon loses enough energy to an atomic electron to cause its ejection, with the remainder of the original photon's energy being emitted as a new, lower energy gamma photon with an emission direction different from that of the incident gamma photon. The probability of Compton scatter decreases with increasing photon energy. Compton scattering is thought to be the principal absorption mechanism for gamma rays in the intermediate energy range 100 keV to 10 MeV. Compton scattering is relatively independent of the atomic number of the absorbing material. - Pair Production: By interaction with the electric field of a nucleus, the energy of the incident photon is converted into the mass of an electron-positron pair. Energy in excess of the equivalent rest mass of the two particles (1.02 MeV) appears as the kinetic energy of the pair and the recoil nucleus. At the end of the positron's range, it combines with a free electron. The entire mass of these two particles is then converted into two gamma photons of at least 0.51 MeV energy each (or higher according to the kinetic energy of the annihilated particles) The secondary electrons (and/or positrons) produced in any of these three processes frequently have enough energy to produce much ionization themselves. ## Gamma production Gamma rays are often produced alongside other forms of radiation such as alpha or beta. When a nucleus emits an α or β particle, the daughter nucleus is sometimes left in an excited state. It can then jump down to a lower level by emitting a gamma ray in much the same way that an atomic electron can jump to a lower level by emitting visible light or ultraviolet radiation. Gamma rays, x-rays, visible light, and radio waves are all forms of electromagnetic radiation. The only difference is the frequency and hence the energy of the photons. Gamma rays are the most energetic. An example of gamma ray production follows. First 60Co decays to excited 60Ni by beta decay: {}^{60}\hbox{Co}\;\to\;^{60}\hbox{Ni}\;+\;e^-\;+\;\overline{\nu}_e. </math> Then the 60Ni drops down to the ground state (see nuclear shell model) by emitting two gamma rays in succession: {}^{60}\hbox{Ni}\;\to\;^{60}\hbox{Ni}\;+\;\gamma. </math> Gamma rays of 1.17 MeV and 1.33 MeV are produced. Another example is the alpha decay of 241Am to form 237Np; this alpha decay is accompanied by gamma emission. In some cases, the gamma emission spectrum for a nucleus (daughter nucleus) is quite simple, (eg 60Co/60Ni) while in other cases, such as with (241Am/237Np and 192Ir/192Pt), the gamma emission spectrum is complex, revealing that a series of nuclear energy levels can exist. The fact that an alpha spectrum can have a series of different peaks with different energies reinforces the idea that several nuclear energy levels are possible. Because a beta decay is accompanied by the emission of a neutrino which also carries energy away, the beta spectrum does not have sharp lines, but instead is a broad peak. Hence from beta decay alone it is not possible to probe the different energy levels found in the nucleus. In optical spectroscopy, it is well known that an entity which emits light can also absorb light at the same wavelength (photon energy). For instance, a sodium flame can emit yellow light as well as absorb the yellow light from a sodium vapor lamp. In the case of gamma rays, this can be seen in Mössbauer spectroscopy. Here, a correction for the energy lost by the recoil of the nucleus is made and the exact conditions for gamma ray absorption through resonance can be attained. This is similar to the Franck Condon effects seen in optical spectroscopy. # Uses Because the wavelength of gamma radiation is so short, a single incident photon can impart significant damage to a living cell. This property means that gamma radiation is often used to kill living organisms, in a process called irradiation. Applications of this include sterilizing medical equipment (as an alternative to autoclaves or chemical means), removing decay-causing bacteria from many foodstuffs or preventing fruit and vegetables from sprouting to maintain freshness and flavor. Due to their tissue penetrating property, gamma rays/X-rays have a wide variety of medical uses such as in CT Scans and radiation therapy (see X-ray). However, as a form of ionizing radiation they have the ability to effect molecular changes, giving them the potential to cause cancer when DNA is affected. The molecular changes can also be used to alter the properties of semi-precious stones, and is often used to change white topaz into blue topaz. Despite their cancer-causing properties, gamma rays are also used to treat some types of cancer. In the procedure called gamma-knife surgery, multiple concentrated beams of gamma rays are directed on the growth in order to kill the cancerous cells. The beams are aimed from different angles to focus the radiation on the growth while minimizing damage to the surrounding tissues. Gamma rays are also used for diagnostic purposes in nuclear medicine. Several gamma-emitting radioisotopes are used, one of which is technetium-99m. When administered to a patient, a gamma camera can be used to form an image of the radioisotope's distribution by detecting the gamma radiation emitted. Such a technique can be employed to diagnose a wide range of conditions (e.g. spread of cancer to the bones). Gamma ray detectors are also starting to be used in Pakistan as part of the Container Security Initiative (CSI). These US$5 million machines are advertised to scan 30 containers per hour. The objective of this technique is to pre-screen merchant ship containers before they enter US ports. # Health effects Gamma rays are the most dangerous form of radiation emitted by a nuclear explosion because of the difficulty in shielding them. This is because gamma rays have the shortest wavelength of all waves in the electromagnetic spectrum, and therefore the most ability to penetrate through any gap, even a subatomic one, in a what might otherwise be a shield. Gamma-rays are not stopped by the skin. They can induce DNA alteration by interfering with the genetic material of the cell. DNA double-strand breaks are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer and hereditary disease.[1]. A study done on Russian nuclear workers exposed to external whole-body gamma radiation at high cumulative doses shows the link between radiation exposure and death from leukemia, lung, liver, skeletal and other solid cancers.[2]. Alongside radiation, gamma-rays also produce thermal burn injuries and induce an immunosuppressive effect.[3][4] ## Body response After gamma-irradiation, and the breaking of DNA double-strands, a cell can repair the damaged genetic material to the limit of its capability. However, a study of Rothkamm and Lobrich has shown that the repairing process works well after high-dose exposure but is much slower in the case of a low-dose exposure. [1] This could mean that a chronic low-dose exposure cannot be fought by the body. The probability of detecting small alterations or of a detectable defect occurring is most likely small enough that the cell would replicate before initiating a full repair. Some cells can not detect their own genetic defects. ## Risk assessment The natural outdoor exposure in Great Britain is in the range 20-40 nSv/h.[5] Natural exposure to gamma rays is about 1 to 2 millisieverts per year, and the average total amount of radiation received in one year per inhabitant in the USA is 3.6 mSv.[6] By comparison, the radiation dose from chest radiography is a fraction of the annual naturally occurring background radiation dose,[7] and the dose from fluoroscopy of the stomach is, at most, 0.05 Sv on the skin of the back. For acute full-body equivalent dose, 1 Sv causes slight blood changes, 2-5 Sv causes nausea, hair loss, hemorrhaging and will cause death in many cases. More than 3 Sv will lead to death in less than two months in more than 80 percent of cases, and much over 4 Sv usually causes death (see Sievert). For low dose exposure, for example among nuclear workers, who receive an average radiation dose of 19 mSv, the risk of dying from cancer (excluding leukemia) increases by 2 percent. For a dose of 100 mSv, that risk increase is at 10 percent. By comparison, it was 32 percent for the Atom Bomb survivors.[8].	https://www.wikidoc.org/index.php/Gamma-ray
cb8d4100bfe90f4ee5b80a975a170e9005b3b584	wikidoc	Ganirelix	Ganirelix # 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 Ganirelix is a Endocrine-Metabolic Agent that is FDA approved for the treatment of inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation. Common adverse reactions include Abdominal Pain (gynecological), Headache, Ovarian Hyperstimulation Syndrome, Vaginal Bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Ganirelix Acetate Injection is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation. ### Dosage - After initiating FSH therapy on Day 2 or 3 of the cycle, Ganirelix Acetate Injection 250 mcg may be administered subcutaneously once daily during the mid to late portion of the follicular phase. By taking advantage of endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced. Treatment with Ganirelix Acetate should be continued daily until the day of hCG administration. When a sufficient number of follicles of adequate size are present, as assessed by ultrasound, final maturation of follicles is induced by administering hCG. The administration of hCG should be withheld in cases where the ovaries are abnormally enlarged on the last day of FSH therapy to reduce the chance of developing OHSS (Ovarian Hyperstimulation Syndrome). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ganirelix in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ganirelix in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Ganirelix in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ganirelix in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ganirelix in pediatric patients. # Contraindications - Ganirelix Acetate Injection is contraindicated under the following conditions: - Known hypersensitivity to Ganirelix Acetate or to any of its components. - Known hypersensitivity to GnRH or any other GnRH analog. - Known or suspected pregnancy # Warnings - Ganirelix Acetate Injection should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Ganirelix Acetate, pregnancy must be excluded. Safe use of Ganirelix Acetate during pregnancy has not been established ### Precautions - Special care should be taken in women with signs and symptoms of active allergic conditions. Cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported, as early as with the first dose, during post-marketing surveillance . In the absence of clinical experience, Ganirelix Acetate treatment is not advised in women with severe allergic conditions. - The packaging of this product contains natural rubber latex which may cause allergic reactions. - Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed. - Ganirelix Acetate should not be prescribed if the patient is pregnant. - A neutrophil count ≥ 8.3 ( x 109/L) was noted in 11.9% (up to 16.8 x 109/L) of all subjects treated within the adequate and well-controlled clinical trials. In addition, downward shifts within the Ganirelix Acetate Injection group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined. # Adverse Reactions ## Clinical Trials Experience - The safety of Ganirelix Acetate Injection was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Ganirelix Acetate ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Ganirelix Acetate administration until confirmation of pregnancy by ultrasound at an incidence of ≥ 1% in Ganirelix Acetate-treated subjects without regard to causality. - Ongoing clinical follow-up studies of 283 newborns of women administered Ganirelix Acetate Injection were reviewed. There were three neonates with major congenital anomalies and 18 neonates with minor congenital anomalies. The major congenital anomalies were: hydrocephalus/meningocele, omphalocele, and Beckwith-Wiedemann Syndrome. The minor congenital anomalies were: nevus, skin tags, sacral sinus, hemangioma, torticollis/asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis. The causal relationship between these congenital anomalies and Ganirelix Acetate is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may confound ART (Assisted Reproductive Technology) procedures. ## Postmarketing Experience - During post-marketing surveillance, rare cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported, as early as with the first dose # Drug Interactions - No formal drug-drug interaction studies have been performed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Ganirelix Acetate Injection is contraindicated in pregnant women. When administered from Day 7 to near term to pregnant rats and rabbits at doses up to 10 and 30 mcg/day (approximately 0.4 to 3.2 times the human dose based on body surface area), Ganirelix Acetate increased the incidence of litter resorption. There was no increase in fetal abnormalities. No treatment-related changes in fertility, physical, or behavioral characteristics were observed in the offspring of female rats treated with Ganirelix Acetate during pregnancy and lactation. - The effects on fetal resorption are logical consequences of the alteration in hormonal levels brought about by the antigonadotropic properties of this drug and could result in fetal loss in humans. Therefore, this drug should not be used in pregnant women Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ganirelix in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ganirelix during labor and delivery. ### Nursing Mothers - Ganirelix Acetate Injection should not be used by lactating women. It is not known whether this drug is excreted in human milk. ### Pediatric Use There is no FDA guidance on the use of Ganirelix with respect to pediatric patients. ### Geriatic Use - Clinical studies with Ganirelix Acetate Injection did not include a sufficient number of subjects aged 65 and over. ### Gender There is no FDA guidance on the use of Ganirelix with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ganirelix with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ganirelix in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ganirelix in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ganirelix in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ganirelix in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ganirelix Acetate Injection is supplied in a sterile, prefilled syringe and is intended for SUBCUTANEOUS administration only. - Wash hands thoroughly with soap and water. - The most convenient sites for SUBCUTANEOUS injection are in the abdomen around the navel or upper thigh. - The injection site should be swabbed with a disinfectant to remove any surface bacteria. Clean about two inches around the point where the needle will be inserted and let the disinfectant dry for at least one minute before proceeding. - With syringe held upward, remove needle cover. - Pinch up a large area of skin between the finger and thumb. Vary the injection site a little with each injection. - The needle should be inserted at the base of the pinched-up skin at an angle of 45–90° to the skin surface. - When the needle is correctly positioned, it will be difficult to draw back on the plunger. If any blood is drawn into the syringe, the needle tip has penetrated a vein or artery. If this happens, withdraw the needle slightly and reposition the needle without removing it from the skin. Alternatively, remove the needle and use a new, sterile, prefilled syringe. Cover the injection site with a swab containing disinfectant and apply pressure; the site should stop bleeding within one or two minutes. - Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin is not damaged. - Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. - Use the sterile, prefilled syringe only once and dispose of it properly. ### Monitoring There is limited information regarding Monitoring of Ganirelix in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Ganirelix in the drug label. # Overdosage - There have been no reports of overdosage with Ganirelix Acetate Injection in humans. # Pharmacology ## Mechanism of Action - The pulsatile release of GnRH stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The frequency of LH pulses in the mid and late follicular phase is approximately 1 pulse per hour. These pulses can be detected as transient rises in serum LH. At midcycle, a large increase in GnRH release results in an LH surge. The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. Luteinization results in a rise in serum progesterone with an accompanying decrease in estradiol levels. - Ganirelix Acetate acts by competitively blocking the GnRH receptors on the pituitary gonadotroph and subsequent transduction pathway. It induces a rapid, reversible suppression of gonadotropin secretion. The suppression of pituitary LH secretion by Ganirelix Acetate is more pronounced than that of FSH. An initial release of endogenous gonadotropins has not been detected with Ganirelix Acetate, which is consistent with an antagonist effect. Upon discontinuation of Ganirelix Acetate, pituitary LH and FSH levels are fully recovered within 48 hours. ## Structure - Ganirelix Acetate Injection is a synthetic decapeptide with high antagonistic activity against naturally occurring gonadotropin-releasing hormone (GnRH). Ganirelix Acetate is derived from native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, 8, and 10 to form the following molecular formula of the peptide: N-acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-N9,N10-diethyl-D-homoarginyl-L-leucyl-N9,N10-diethyl-L-homoarginyl-L-prolyl-D-alanylamide acetate. The molecular weight for Ganirelix Acetate is 1570.4 as an anhydrous free base. The structural formula is as follows: Ganirelix Acetate - Ganirelix Acetate Injection is supplied as a colorless, sterile, ready-to-use, aqueous solution intended for SUBCUTANEOUS administration only. Each sterile, prefilled syringe contains 250 mcg/0.5 mL of Ganirelix Acetate, 0.1 mg glacial acetic acid, 23.5 mg mannitol, and water for injection adjusted to pH 5.0 with acetic acid, NF and/or sodium hydroxide, NF. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ganirelix in the drug label. ## Pharmacokinetics - The pharmacokinetic parameters of single and multiple injections of Ganirelix Acetate Injection in healthy adult females are summarized in Table I. Steady-state serum concentrations are reached after 3 days of treatment. The pharmacokinetics of Ganirelix Acetate are dose-proportional in the dose range of 125 to 500 mcg. - Ganirelix Acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Ganirelix Acetate following a single 250 mcg subcutaneous injection to healthy female volunteers is 91.1%. - The mean (SD) volume of distribution of Ganirelix Acetate in healthy females following intravenous administration of a single 250-mcg dose is 43.7 (11.4) liters (L). In vitro protein binding to human plasma is 81.9%. - Following single-dose intravenous administration of radiolabeled Ganirelix Acetate to healthy female volunteers, Ganirelix Acetate is the major compound present in the plasma (50–70% of total radioactivity in the plasma) up to 4 hours and urine (17.1–18.4% of administered dose) up to 24 hours. Ganirelix Acetate is not found in the feces. The 1–4 peptide and 1–6 peptide of Ganirelix Acetate are the primary metabolites observed in the feces. - On average, 97.2% of the total radiolabeled Ganirelix Acetate dose is recovered in the feces and urine (75.1% and 22.1%, respectively) over 288 h following intravenous single dose administration of 1 mg -Ganirelix Acetate. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing. - The pharmacokinetics of Ganirelix Acetate Injection have not been determined in special populations such as geriatric, pediatric, renally impaired and hepatically impaired patients. - Formal in vivo or in vitro drug-drug interaction studies have not been conducted (see PRECAUTIONS). Since Ganirelix Acetate can suppress the secretion of pituitary gonadotropins, dose adjustments of exogenous gonadotropins may be necessary when used during controlled ovarian hyperstimulation (COH). ## Nonclinical Toxicology - Long-term toxicity studies in animals have not been performed with Ganirelix Acetate Injection to evaluate the carcinogenic potential of the drug. Ganirelix Acetate did not induce a mutagenic response in the Ames test (S. typhimurium and E. coli) or produce chromosomal aberrations in in vitro assay using Chinese Hamster Ovary cells. # Clinical Studies - The efficacy of Ganirelix Acetate Injection was established in two adequate and well-controlled clinical studies which included women with normal endocrine and pelvic ultrasound parameters. The studies intended to exclude subjects with polycystic ovary syndrome (PCOS) and subjects with low or no ovarian reserve. One cycle of study medication was administered to each randomized subject. For both studies, the administration of exogenous recombinant FSH 150 IU daily was initiated on the morning of Day 2 or 3 of a natural menstrual cycle. Ganirelix Acetate Injection was administered on the morning of Day 7 or 8 (Day 6 of recombinant FSH administration). The dose of recombinant FSH administered was adjusted according to individual responses starting on the day of initiation of Ganirelix Acetate. Both recombinant FSH and Ganirelix Acetate were continued daily until at least three follicles were 17 mm or greater in diameter at which time hCG was administered. Following hCG administration, Ganirelix Acetate and recombinant FSH administration were discontinued. Oocyte retrieval, followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), was subsequently performed. - In a multicenter, double-blind, randomized, dose-finding study, the safety and efficacy of Ganirelix Acetate Injection were evaluated for the prevention of LH surges in women undergoing COH with recombinant FSH. Ganirelix Acetate Injection doses ranging from 62.5 mcg to 2000 mcg and recombinant FSH were administered to 332 patients undergoing COH for IVF (see TABLE II). Median serum LH on the day of hCG administration decreased with increasing doses of Ganirelix Acetate. Median serum E2 (17β-estradiol) on the day of hCG administration was 1475, 1110, and 1160 pg/mL for the 62.5-, 125-, and 250-mcg doses, respectively. Lower peak serum E2 levels of 823, 703, and 441 pg/mL were seen at higher doses of Ganirelix Acetate 500, 1000, and 2000 mcg, respectively. The highest pregnancy and implantation rates were achieved with the 250-mcg dose of Ganirelix Acetate Injection as summarized in Table II. - Transient LH rises alone were not deleterious to achieving pregnancy with Ganirelix Acetate at doses of 125 mcg (3/6 subjects) and 250 mcg (1/1 subjects). In addition, none of the subjects with LH rises ≥ 10 mIU/mL had premature luteinization indicated by a serum progesterone above 2 ng/mL. - A multicenter, open-label, randomized study was conducted to assess the efficacy and safety of Ganirelix Acetate Injection in women undergoing COH. Follicular phase treatment with Ganirelix Acetate 250 mcg was studied using a luteal phase GnRH agonist as a reference treatment. A total of 463 subjects were treated with Ganirelix Acetate by subcutaneous injection once daily starting on Day 6 of recombinant FSH treatment. Recombinant FSH was maintained at 150 IU for the first 5 days of ovarian stimulation and was then adjusted by the investigator on the sixth day of gonadotropin use according to individual responses. The results for the Ganirelix Acetate arm are summarized in Table III. - The mean number of days of Ganirelix Acetate treatment was 5.4 (2–14). - The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. In 463 subjects administered Ganirelix Acetate Injection 250 mcg, a premature LH surge prior to hCG administration, (LH rise ≥ 10 mIU/mL with a significant rise in serum progesterone > 2 ng/mL, or a significant decline in serum estradiol) occurred in less than 1% of subjects. # How Supplied - Ganirelix Acetate Injection is supplied in: - Disposable, sterile, ready for use, prefilled 1 mL glass syringes containing 250 mcg/0.5 mL aqueous solution of Ganirelix Acetate closed with a rubber piston that does not contain latex. Each Ganirelix Acetate sterile, prefilled syringe is affixed with a 27 gauge × ½-inch needle closed by a needle shield of natural rubber latex and is blister-packed. ## Storage - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) . Protect from light. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 250 MCG/0.5 ML PREFILLED SYRINGE CARTON NDC 0052-0301-51 250 mcg Sterile Prefilled Syringe 27 gauge by 1/2" needle Ganirelix Acetate Injection 250 mcg/0.5 mL For Subcutaneous Use Rx only ### Ingredients and Appearance # Patient Counseling Information - Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see ADVERSE REACTIONS). - Ganirelix Acetate should not be prescribed if the patient is pregnant. # Precautions with Alcohol - Alcohol-Ganirelix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Antagon® # Look-Alike Drug Names There is limited information regarding Ganirelix Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ganirelix Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Ganirelix is a Endocrine-Metabolic Agent that is FDA approved for the treatment of inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation. Common adverse reactions include Abdominal Pain (gynecological), Headache, Ovarian Hyperstimulation Syndrome, Vaginal Bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Ganirelix Acetate Injection is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation. ### Dosage - After initiating FSH therapy on Day 2 or 3 of the cycle, Ganirelix Acetate Injection 250 mcg may be administered subcutaneously once daily during the mid to late portion of the follicular phase. By taking advantage of endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced. Treatment with Ganirelix Acetate should be continued daily until the day of hCG administration. When a sufficient number of follicles of adequate size are present, as assessed by ultrasound, final maturation of follicles is induced by administering hCG. The administration of hCG should be withheld in cases where the ovaries are abnormally enlarged on the last day of FSH therapy to reduce the chance of developing OHSS (Ovarian Hyperstimulation Syndrome). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ganirelix in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ganirelix in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Ganirelix in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ganirelix in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ganirelix in pediatric patients. # Contraindications - Ganirelix Acetate Injection is contraindicated under the following conditions: - Known hypersensitivity to Ganirelix Acetate or to any of its components. - Known hypersensitivity to GnRH or any other GnRH analog. - Known or suspected pregnancy # Warnings - Ganirelix Acetate Injection should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Ganirelix Acetate, pregnancy must be excluded. Safe use of Ganirelix Acetate during pregnancy has not been established ### Precautions - Special care should be taken in women with signs and symptoms of active allergic conditions. Cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported, as early as with the first dose, during post-marketing surveillance . In the absence of clinical experience, Ganirelix Acetate treatment is not advised in women with severe allergic conditions. - The packaging of this product contains natural rubber latex which may cause allergic reactions. - Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed. - Ganirelix Acetate should not be prescribed if the patient is pregnant. - A neutrophil count ≥ 8.3 ( x 109/L) was noted in 11.9% (up to 16.8 x 109/L) of all subjects treated within the adequate and well-controlled clinical trials. In addition, downward shifts within the Ganirelix Acetate Injection group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined. # Adverse Reactions ## Clinical Trials Experience - The safety of Ganirelix Acetate Injection was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Ganirelix Acetate ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Ganirelix Acetate administration until confirmation of pregnancy by ultrasound at an incidence of ≥ 1% in Ganirelix Acetate-treated subjects without regard to causality. - Ongoing clinical follow-up studies of 283 newborns of women administered Ganirelix Acetate Injection were reviewed. There were three neonates with major congenital anomalies and 18 neonates with minor congenital anomalies. The major congenital anomalies were: hydrocephalus/meningocele, omphalocele, and Beckwith-Wiedemann Syndrome. The minor congenital anomalies were: nevus, skin tags, sacral sinus, hemangioma, torticollis/asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis. The causal relationship between these congenital anomalies and Ganirelix Acetate is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may confound ART (Assisted Reproductive Technology) procedures. ## Postmarketing Experience - During post-marketing surveillance, rare cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported, as early as with the first dose # Drug Interactions - No formal drug-drug interaction studies have been performed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Ganirelix Acetate Injection is contraindicated in pregnant women. When administered from Day 7 to near term to pregnant rats and rabbits at doses up to 10 and 30 mcg/day (approximately 0.4 to 3.2 times the human dose based on body surface area), Ganirelix Acetate increased the incidence of litter resorption. There was no increase in fetal abnormalities. No treatment-related changes in fertility, physical, or behavioral characteristics were observed in the offspring of female rats treated with Ganirelix Acetate during pregnancy and lactation. - The effects on fetal resorption are logical consequences of the alteration in hormonal levels brought about by the antigonadotropic properties of this drug and could result in fetal loss in humans. Therefore, this drug should not be used in pregnant women Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ganirelix in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ganirelix during labor and delivery. ### Nursing Mothers - Ganirelix Acetate Injection should not be used by lactating women. It is not known whether this drug is excreted in human milk. ### Pediatric Use There is no FDA guidance on the use of Ganirelix with respect to pediatric patients. ### Geriatic Use - Clinical studies with Ganirelix Acetate Injection did not include a sufficient number of subjects aged 65 and over. ### Gender There is no FDA guidance on the use of Ganirelix with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ganirelix with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ganirelix in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ganirelix in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ganirelix in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ganirelix in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ganirelix Acetate Injection is supplied in a sterile, prefilled syringe and is intended for SUBCUTANEOUS administration only. - Wash hands thoroughly with soap and water. - The most convenient sites for SUBCUTANEOUS injection are in the abdomen around the navel or upper thigh. - The injection site should be swabbed with a disinfectant to remove any surface bacteria. Clean about two inches around the point where the needle will be inserted and let the disinfectant dry for at least one minute before proceeding. - With syringe held upward, remove needle cover. - Pinch up a large area of skin between the finger and thumb. Vary the injection site a little with each injection. - The needle should be inserted at the base of the pinched-up skin at an angle of 45–90° to the skin surface. - When the needle is correctly positioned, it will be difficult to draw back on the plunger. If any blood is drawn into the syringe, the needle tip has penetrated a vein or artery. If this happens, withdraw the needle slightly and reposition the needle without removing it from the skin. Alternatively, remove the needle and use a new, sterile, prefilled syringe. Cover the injection site with a swab containing disinfectant and apply pressure; the site should stop bleeding within one or two minutes. - Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin is not damaged. - Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. - Use the sterile, prefilled syringe only once and dispose of it properly. ### Monitoring There is limited information regarding Monitoring of Ganirelix in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Ganirelix in the drug label. # Overdosage - There have been no reports of overdosage with Ganirelix Acetate Injection in humans. # Pharmacology ## Mechanism of Action - The pulsatile release of GnRH stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The frequency of LH pulses in the mid and late follicular phase is approximately 1 pulse per hour. These pulses can be detected as transient rises in serum LH. At midcycle, a large increase in GnRH release results in an LH surge. The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. Luteinization results in a rise in serum progesterone with an accompanying decrease in estradiol levels. - Ganirelix Acetate acts by competitively blocking the GnRH receptors on the pituitary gonadotroph and subsequent transduction pathway. It induces a rapid, reversible suppression of gonadotropin secretion. The suppression of pituitary LH secretion by Ganirelix Acetate is more pronounced than that of FSH. An initial release of endogenous gonadotropins has not been detected with Ganirelix Acetate, which is consistent with an antagonist effect. Upon discontinuation of Ganirelix Acetate, pituitary LH and FSH levels are fully recovered within 48 hours. ## Structure - Ganirelix Acetate Injection is a synthetic decapeptide with high antagonistic activity against naturally occurring gonadotropin-releasing hormone (GnRH). Ganirelix Acetate is derived from native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, 8, and 10 to form the following molecular formula of the peptide: N-acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-N9,N10-diethyl-D-homoarginyl-L-leucyl-N9,N10-diethyl-L-homoarginyl-L-prolyl-D-alanylamide acetate. The molecular weight for Ganirelix Acetate is 1570.4 as an anhydrous free base. The structural formula is as follows: Ganirelix Acetate - Ganirelix Acetate Injection is supplied as a colorless, sterile, ready-to-use, aqueous solution intended for SUBCUTANEOUS administration only. Each sterile, prefilled syringe contains 250 mcg/0.5 mL of Ganirelix Acetate, 0.1 mg glacial acetic acid, 23.5 mg mannitol, and water for injection adjusted to pH 5.0 with acetic acid, NF and/or sodium hydroxide, NF. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ganirelix in the drug label. ## Pharmacokinetics - The pharmacokinetic parameters of single and multiple injections of Ganirelix Acetate Injection in healthy adult females are summarized in Table I. Steady-state serum concentrations are reached after 3 days of treatment. The pharmacokinetics of Ganirelix Acetate are dose-proportional in the dose range of 125 to 500 mcg. - Ganirelix Acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Ganirelix Acetate following a single 250 mcg subcutaneous injection to healthy female volunteers is 91.1%. - The mean (SD) volume of distribution of Ganirelix Acetate in healthy females following intravenous administration of a single 250-mcg dose is 43.7 (11.4) liters (L). In vitro protein binding to human plasma is 81.9%. - Following single-dose intravenous administration of radiolabeled Ganirelix Acetate to healthy female volunteers, Ganirelix Acetate is the major compound present in the plasma (50–70% of total radioactivity in the plasma) up to 4 hours and urine (17.1–18.4% of administered dose) up to 24 hours. Ganirelix Acetate is not found in the feces. The 1–4 peptide and 1–6 peptide of Ganirelix Acetate are the primary metabolites observed in the feces. - On average, 97.2% of the total radiolabeled Ganirelix Acetate dose is recovered in the feces and urine (75.1% and 22.1%, respectively) over 288 h following intravenous single dose administration of 1 mg [14C]-Ganirelix Acetate. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing. - The pharmacokinetics of Ganirelix Acetate Injection have not been determined in special populations such as geriatric, pediatric, renally impaired and hepatically impaired patients. - Formal in vivo or in vitro drug-drug interaction studies have not been conducted (see PRECAUTIONS). Since Ganirelix Acetate can suppress the secretion of pituitary gonadotropins, dose adjustments of exogenous gonadotropins may be necessary when used during controlled ovarian hyperstimulation (COH). ## Nonclinical Toxicology - Long-term toxicity studies in animals have not been performed with Ganirelix Acetate Injection to evaluate the carcinogenic potential of the drug. Ganirelix Acetate did not induce a mutagenic response in the Ames test (S. typhimurium and E. coli) or produce chromosomal aberrations in in vitro assay using Chinese Hamster Ovary cells. # Clinical Studies - The efficacy of Ganirelix Acetate Injection was established in two adequate and well-controlled clinical studies which included women with normal endocrine and pelvic ultrasound parameters. The studies intended to exclude subjects with polycystic ovary syndrome (PCOS) and subjects with low or no ovarian reserve. One cycle of study medication was administered to each randomized subject. For both studies, the administration of exogenous recombinant FSH [Follistim® (follitropin beta for injection)] 150 IU daily was initiated on the morning of Day 2 or 3 of a natural menstrual cycle. Ganirelix Acetate Injection was administered on the morning of Day 7 or 8 (Day 6 of recombinant FSH administration). The dose of recombinant FSH administered was adjusted according to individual responses starting on the day of initiation of Ganirelix Acetate. Both recombinant FSH and Ganirelix Acetate were continued daily until at least three follicles were 17 mm or greater in diameter at which time hCG [Pregnyl® (chorionic gonadotropin for injection, USP)] was administered. Following hCG administration, Ganirelix Acetate and recombinant FSH administration were discontinued. Oocyte retrieval, followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), was subsequently performed. - In a multicenter, double-blind, randomized, dose-finding study, the safety and efficacy of Ganirelix Acetate Injection were evaluated for the prevention of LH surges in women undergoing COH with recombinant FSH. Ganirelix Acetate Injection doses ranging from 62.5 mcg to 2000 mcg and recombinant FSH were administered to 332 patients undergoing COH for IVF (see TABLE II). Median serum LH on the day of hCG administration decreased with increasing doses of Ganirelix Acetate. Median serum E2 (17β-estradiol) on the day of hCG administration was 1475, 1110, and 1160 pg/mL for the 62.5-, 125-, and 250-mcg doses, respectively. Lower peak serum E2 levels of 823, 703, and 441 pg/mL were seen at higher doses of Ganirelix Acetate 500, 1000, and 2000 mcg, respectively. The highest pregnancy and implantation rates were achieved with the 250-mcg dose of Ganirelix Acetate Injection as summarized in Table II. - Transient LH rises alone were not deleterious to achieving pregnancy with Ganirelix Acetate at doses of 125 mcg (3/6 subjects) and 250 mcg (1/1 subjects). In addition, none of the subjects with LH rises ≥ 10 mIU/mL had premature luteinization indicated by a serum progesterone above 2 ng/mL. - A multicenter, open-label, randomized study was conducted to assess the efficacy and safety of Ganirelix Acetate Injection in women undergoing COH. Follicular phase treatment with Ganirelix Acetate 250 mcg was studied using a luteal phase GnRH agonist as a reference treatment. A total of 463 subjects were treated with Ganirelix Acetate by subcutaneous injection once daily starting on Day 6 of recombinant FSH treatment. Recombinant FSH was maintained at 150 IU for the first 5 days of ovarian stimulation and was then adjusted by the investigator on the sixth day of gonadotropin use according to individual responses. The results for the Ganirelix Acetate arm are summarized in Table III. - The mean number of days of Ganirelix Acetate treatment was 5.4 (2–14). - The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. In 463 subjects administered Ganirelix Acetate Injection 250 mcg, a premature LH surge prior to hCG administration, (LH rise ≥ 10 mIU/mL with a significant rise in serum progesterone > 2 ng/mL, or a significant decline in serum estradiol) occurred in less than 1% of subjects. # How Supplied - Ganirelix Acetate Injection is supplied in: - Disposable, sterile, ready for use, prefilled 1 mL glass syringes containing 250 mcg/0.5 mL aqueous solution of Ganirelix Acetate closed with a rubber piston that does not contain latex. Each Ganirelix Acetate sterile, prefilled syringe is affixed with a 27 gauge × ½-inch needle closed by a needle shield of natural rubber latex and is blister-packed. ## Storage - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 250 MCG/0.5 ML PREFILLED SYRINGE CARTON NDC 0052-0301-51 250 mcg Sterile Prefilled Syringe 27 gauge by 1/2" needle Ganirelix Acetate Injection 250 mcg/0.5 mL For Subcutaneous Use Rx only ### Ingredients and Appearance # Patient Counseling Information - Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see ADVERSE REACTIONS). - Ganirelix Acetate should not be prescribed if the patient is pregnant. # Precautions with Alcohol - Alcohol-Ganirelix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Antagon®[1] # Look-Alike Drug Names There is limited information regarding Ganirelix Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ganirelix
a6461e64e5ac5a973f98f271021607f2b1aa6946	wikidoc	Gefitinib	Gefitinib # 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 Gefitinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Common adverse reactions include diarrhea, rash, acne and dry skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Gefitinib is indicated as monotherapy for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from gefitinib. - The recommended daily dose of gefitinib is one 250 mg tablet with or without food. - Higher doses do not give a better response and cause increased toxicity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gefitinib (patient information) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gefitinib (patient information) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Gefitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gefitinib (patient information) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gefitinib (patient information) in pediatric patients. # Contraindications Is contraindicated in patients with severe hypersensitivity to gefitinib or to any other component of it. # Warnings ### Pulmonary Toxicity Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib at an overall incidence of about 1%. Approximately 1/3 of the cases have been fatal. The reported incidence of ILD was about 2% in the Japanese post-marketing experience, about 0.3% in approximately 23,000 patients treated with gefitinib in a US expanded access program and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups). Reports have described the adverse event as interstitial pneumonia, pneumonitis and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. ILD has occurred in patients who have received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no previous therapy (12% of reported cases). Patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving gefitinib have been observed to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis. In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, gefitinib should be discontinued and the patient treated appropriately. ### Hepatotoxicity Asymptomatic increases in liver transaminases have been observed in gefitinib treated patients; therefore, periodic liver function (transaminases, bilirubin, and alkaline phosphatase) testing should be considered. Discontinuation of gefitinib should be considered if changes are severe. # Adverse Reactions ## Clinical Trials Experience The safety database includes 941 patients from clinical trials and approximately 23,000 patients in the Expanded Access Program. Table 3 includes drug-related adverse events with an incidence of >5% for the 216 patients who received either 250 mg or 500 mg of gefitinib monotherapy for treatment of NSCLC. The most common adverse events reported at the recommended 250 mg daily dose were diarrhea, rash, acne, dry skin, nausea, and vomiting. The 500 mg dose showed a higher rate for most of these adverse events. Table 4 provides drug-related adverse events with an incidence of >5% by CTC grade for the patients who received the 250 mg/day dose of gefitinib monotherapy for treatment of NSCLC. Only 2% of patients stopped therapy due to an adverse drug reaction (ADR). The onset of these ADRs occurred within the first month of therapy. Other adverse events reported at an incidence of <5% in patients who received either 250 mg or 500 mg as monotherapy for treatment of NSCLC (along with their frequency at the 250 mg recommended dose) include the following: peripheral edema (2%), amblyopia (2%), dyspnea (2%), conjunctivitis (1%), vesiculobullous rash (1%), and mouth ulceration (1%). ### Interstitial Lung Disease Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib at an overall incidence of about 1%. Approximately 1/3 of the cases have been fatal. The reported incidence of ILD was about 2% in the Japanese post-marketing experience, about 0.3% in approximately 23,000 patients treated with gefitinib in a US expanded access program and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups). Reports have described the adverse event as interstitial pneumonia, pneumonitis and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. ILD has occurred in patients who have received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no previous therapy (12% of reported cases). Patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving gefitinib have been observed to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis. In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, gefitinib should be discontinued and the patient treated appropriately. In patients receiving gefitinib therapy, there were reports of eye pain and corneal erosion/ulcer, sometimes in association with aberrant eyelash growth. Hemorrhage, such as epistaxis and hematuria have been reported in patients receiving gefitinib. There were also rare reports of pancreatitis and very rare reports of corneal membrane sloughing, ocular ischemia/hemorrhage, toxic epidermal necrolysis, erythema multiforme, and allergic reactions, including angioedema and urticaria. International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. Data from non-clinical (in vitro and in vivo) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarization process (eg, QT interval). The clinical relevance of these findings is unknown. ## Postmarketing Experience There is limited information regarding Gefitinib Postmarketing Experience in the drug label. # Drug Interactions - Substances that are inducers of CYP3A4 activity increase the metabolism of gefitinib and decrease its plasma concentrations. In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500 mg daily should be considered in the absence of severe adverse drug reaction, and clinical response and adverse events should be carefully monitored. - International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. - Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations. This increase may be clinically relevant as adverse experiences are related to dose and exposure; therefore, caution should be used when administering CYP3A4 inhibitors with gefitinib. - Drugs that cause significant sustained elevation in gastric pH (histamine H2-receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of gefitinib and therefore potentially may reduce efficacy. - Phase II clinical trial data, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Gefitinib may cause fetal harm when administered to a pregnant woman. A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m2, about 1/5 the recommended human dose on a mg/m2 basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg and was accompanied by high neonatal mortality soon after parturition. In this study a dose of 1 mg/kg caused no adverse effects. In rabbits, a dose of 20 mg/kg/day (240 mg/m2, about twice the recommended dose in humans on a mg/m2 basis) caused reduced fetal weight. There are no adequate and well-controlled studies in pregnant women using gefitinib. If gefitinib is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gefitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gefitinib during labor and delivery. ### Nursing Mothers It is not known whether gefitinib is excreted in human milk. Following oral administration of carbon-14 labeled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving gefitinib therapy. ### Pediatric Use Gefitinib is not indicated for use in pediatric patients as safety and effectiveness have not been established. In clinical trials of gefitinib alone or with radiation in pediatric patients with primary Central Nervous System (CNS) tumors, cases of CNS hemorrhage and death have been reported. There are insufficient data in pediatric patients to establish a causal relationship. There is no evidence to suggest increased risk of cerebral hemorrhage in adult patients with NSCLC receiving gefitinib. Gefitinib is not indicated for use in pediatric patients as safety and effectiveness have not been established. ### Geriatic Use Of the total number of patients participating in trials of second- and third-line gefitinib treatment of NSCLC, 65% were aged 64 years or less, 30.5 % were aged 65 to 74 years, and 5% of patients were aged 75 years or older. No differences in safety or efficacy were observed between younger and older patients. ### Gender There is no FDA guidance on the use of Gefitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gefitinib with respect to specific racial populations. ### Renal Impairment The effect of severe renal impairment on the pharmacokinetics of gefitinib is not known. Patients with severe renal impairment should be treated with caution when given gefitinib. ### Hepatic Impairment In vitro and in vivo evidence suggest that gefitinib is cleared primarily by the liver. Therefore, gefitinib exposure may be increased in patients with hepatic dysfunction. In patients with liver metastases and moderately to severely elevated biochemical liver abnormalities, however, gefitinib pharmacokinetics were similar to the pharmacokinetics of individuals without liver abnormalities. The influence of non-cancer related hepatic impairment on the pharmacokinetics of gefitinib has not been evaluated. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gefitinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gefitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Gefitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Gefitinib and IV administrations. # Overdosage The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m2 (about 80 times the recommended clinical dose on a mg/m2 basis) was lethal to rats. Half this dose caused no mortality in mice. There is no specific treatment for an gefitinib overdose and possible symptoms of overdose are not established. However, in Phase 1 clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg. An increase in frequency and severity of some adverse reactions was observed, mainly diarrhea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular, severe diarrhea should be managed appropriately. # Pharmacology ## Mechanism of Action The mechanism of the clinical antitumor action of gefitinib is not fully characterized. Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to gefitinib. ## Structure Gefitinib is an anilinoquinazoline with the chemical name 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6- and the following structural formula: ## Pharmacodynamics There is limited information regarding Gefitinib Pharmacodynamics in the drug label. ## Pharmacokinetics Gefitinib is absorbed slowly after oral administration with mean bioavailability of 60%. Elimination is by metabolism (primarily CYP3A4) and excretion in feces. The elimination half-life is about 48 hours. Daily oral administration of gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration. Steady state plasma concentrations are achieved within 10 days. Gefitinib is slowly absorbed, with peak plasma levels occurring 3-7 hours after dosing and mean oral bioavailability of 60%. Bioavailability is not significantly altered by food. Gefitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1400 L following intravenous administration. In vitro binding of gefitinib to human plasma proteins (serum albumin and α1-acid glycoprotein) is 90% and is independent of drug concentrations. Gefitinib undergoes extensive hepatic metabolism in humans, predominantly by CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolites were identified in human plasma. Only O-desmethyl gefitinib has exposure comparable to gefitinib. Although this metabolite has similar EGFR-TK activity to gefitinib in the isolated enzyme assay, it had only 1/14 of the potency of gefitinib in one of the cell-based assays. Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life values of 595 mL/min and 48 hours, respectively, after intravenous administration. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose. ## Nonclinical Toxicology ### Carcinogenesis and Mutagenesis - Gefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the conditions of these assays, gefitinib did not cause genetic damage. - Carcinogenicity studies have not been conducted with gefitinib. # Clinical Studies ### Non-Small Cell Lung Cancer (NSCLC) Refractory Disease Tumor Response Study - A multicenter clinical trial in the United States evaluated the tumor response rate of gefitinib 250 and 500 mg/day in patients with advanced non-small cell lung cancer whose disease had progressed after at least two prior chemotherapy regimens including a platinum drug and docetaxel. gefitinib was taken once daily at approximately the same time each day. Two hundred and sixteen patients received gefitinib, 102 (47%) and 114 (53%) receiving 250 mg and 500 mg daily doses, respectively. Study patient demographics and disease characteristics are summarized in Table 1. Forty-one percent of the patients had received two prior treatment regimens, 33% three prior treatment regimens, and 25% four or more prior treatment regimens. Effectiveness of gefitinib as third line therapy was determined in the 142 evaluable patients with documented disease progression on platinum and docetaxel therapies or who had had unacceptable toxicity on these agents. Table 2 shows tumor response rates and response duration. The overall response rate for the 250 and 500 mg doses combined was 10.6% (95% CI: 6%, 16.8%). Response rates appeared to be highly variable in subgroups of the treated population: 5.1% (4/79) in males, 17.5% (11/63) in females, 4.6% (5/108) in previous or current smokers, 29.4% (10/34) in nonsmokers, 12.4% (12/97) with adenocarcinoma histology, and 6.7% (3/45) with other NSCLC histologies. Similar differences were seen in a multinational study in patients who had received 1 or 2 prior chemotherapy regimens, at least 1 of which was platinum-based. In responders, the median time from diagnosis to study randomization was 16.7 months (range 8 to 34 months). A double-blind, placebo-controlled parallel-group trial randomized 1692 patients with advanced NSCLC to receive either gefitinib 250 mg daily plus Best Supportive Care or placebo plus Best Supportive Care. Patients had received 1 or 2 prior chemotherapy regimens and had progressed while receiving or within 90 days of the last dose of chemotherapy or were intolerant to the most recent prior chemotherapy regimen. The two treatment arms were well-balanced for demographic and disease-related patient characteristics. The primary endpoint of the study was survival. Gefitinib did not significantly prolong survival (stratified log rank HR 0.89, P=0.11, Median 5.6 vs 5.1 months for gefitinib and placebo, respectively). Two large trials were conducted in chemotherapy-naïve patients with stage III and IV non-small cell lung cancer. Two thousand one hundred thirty patients were randomized to receive gefitinib 250 mg daily, gefitinib 500 mg daily, or placebo in combination with platinum-based chemotherapy regimens. The chemotherapies given in these first-line trials were gemcitabine and cis-platinum (N=1093) or carboplatin and paclitaxel (N=1037). The addition of gefitinib did not demonstrate any increase, or trend toward such an increase, in tumor response rates, time to progression, or overall survival. # How Supplied Supplied in tablets of 250 mg - Bottles of 30 Tablets - NDC 0310-0482-30 ## Storage Store at 20-25°C (68-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised to seek medical advice promptly if they develop: - severe or persistent diarrhea, nausea, anorexia, or vomiting, as these have sometimes been associated with dehydration; - an onset or worsening of pulmonary symptoms, ie, shortness of breath or cough; - an eye irritation; or, - any other new symptom. - Women of childbearing potential must be advised to avoid becoming pregnant # Precautions with Alcohol Alcohol-Gefitinib (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Iressa # Look-Alike Drug Names There is limited information regarding Gefitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Gefitinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Gefitinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Common adverse reactions include diarrhea, rash, acne and dry skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Gefitinib is indicated as monotherapy for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from gefitinib. - The recommended daily dose of gefitinib is one 250 mg tablet with or without food. - Higher doses do not give a better response and cause increased toxicity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gefitinib (patient information) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gefitinib (patient information) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Gefitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gefitinib (patient information) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gefitinib (patient information) in pediatric patients. # Contraindications Is contraindicated in patients with severe hypersensitivity to gefitinib or to any other component of it. # Warnings ### Pulmonary Toxicity Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib at an overall incidence of about 1%. Approximately 1/3 of the cases have been fatal. The reported incidence of ILD was about 2% in the Japanese post-marketing experience, about 0.3% in approximately 23,000 patients treated with gefitinib in a US expanded access program and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups). Reports have described the adverse event as interstitial pneumonia, pneumonitis and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. ILD has occurred in patients who have received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no previous therapy (12% of reported cases). Patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving gefitinib have been observed to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis. In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, gefitinib should be discontinued and the patient treated appropriately. ### Hepatotoxicity Asymptomatic increases in liver transaminases have been observed in gefitinib treated patients; therefore, periodic liver function (transaminases, bilirubin, and alkaline phosphatase) testing should be considered. Discontinuation of gefitinib should be considered if changes are severe. # Adverse Reactions ## Clinical Trials Experience The safety database includes 941 patients from clinical trials and approximately 23,000 patients in the Expanded Access Program. Table 3 includes drug-related adverse events with an incidence of >5% for the 216 patients who received either 250 mg or 500 mg of gefitinib monotherapy for treatment of NSCLC. The most common adverse events reported at the recommended 250 mg daily dose were diarrhea, rash, acne, dry skin, nausea, and vomiting. The 500 mg dose showed a higher rate for most of these adverse events. Table 4 provides drug-related adverse events with an incidence of >5% by CTC grade for the patients who received the 250 mg/day dose of gefitinib monotherapy for treatment of NSCLC. Only 2% of patients stopped therapy due to an adverse drug reaction (ADR). The onset of these ADRs occurred within the first month of therapy. Other adverse events reported at an incidence of <5% in patients who received either 250 mg or 500 mg as monotherapy for treatment of NSCLC (along with their frequency at the 250 mg recommended dose) include the following: peripheral edema (2%), amblyopia (2%), dyspnea (2%), conjunctivitis (1%), vesiculobullous rash (1%), and mouth ulceration (1%). ### Interstitial Lung Disease Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib at an overall incidence of about 1%. Approximately 1/3 of the cases have been fatal. The reported incidence of ILD was about 2% in the Japanese post-marketing experience, about 0.3% in approximately 23,000 patients treated with gefitinib in a US expanded access program and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups). Reports have described the adverse event as interstitial pneumonia, pneumonitis and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. ILD has occurred in patients who have received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no previous therapy (12% of reported cases). Patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving gefitinib have been observed to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis. In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, gefitinib should be discontinued and the patient treated appropriately. In patients receiving gefitinib therapy, there were reports of eye pain and corneal erosion/ulcer, sometimes in association with aberrant eyelash growth. Hemorrhage, such as epistaxis and hematuria have been reported in patients receiving gefitinib. There were also rare reports of pancreatitis and very rare reports of corneal membrane sloughing, ocular ischemia/hemorrhage, toxic epidermal necrolysis, erythema multiforme, and allergic reactions, including angioedema and urticaria. International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. Data from non-clinical (in vitro and in vivo) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarization process (eg, QT interval). The clinical relevance of these findings is unknown. ## Postmarketing Experience There is limited information regarding Gefitinib Postmarketing Experience in the drug label. # Drug Interactions - Substances that are inducers of CYP3A4 activity increase the metabolism of gefitinib and decrease its plasma concentrations. In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500 mg daily should be considered in the absence of severe adverse drug reaction, and clinical response and adverse events should be carefully monitored. - International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. - Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations. This increase may be clinically relevant as adverse experiences are related to dose and exposure; therefore, caution should be used when administering CYP3A4 inhibitors with gefitinib. - Drugs that cause significant sustained elevation in gastric pH (histamine H2-receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of gefitinib and therefore potentially may reduce efficacy. - Phase II clinical trial data, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Gefitinib may cause fetal harm when administered to a pregnant woman. A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m2, about 1/5 the recommended human dose on a mg/m2 basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg and was accompanied by high neonatal mortality soon after parturition. In this study a dose of 1 mg/kg caused no adverse effects. In rabbits, a dose of 20 mg/kg/day (240 mg/m2, about twice the recommended dose in humans on a mg/m2 basis) caused reduced fetal weight. There are no adequate and well-controlled studies in pregnant women using gefitinib. If gefitinib is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gefitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gefitinib during labor and delivery. ### Nursing Mothers It is not known whether gefitinib is excreted in human milk. Following oral administration of carbon-14 labeled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving gefitinib therapy. ### Pediatric Use Gefitinib is not indicated for use in pediatric patients as safety and effectiveness have not been established. In clinical trials of gefitinib alone or with radiation in pediatric patients with primary Central Nervous System (CNS) tumors, cases of CNS hemorrhage and death have been reported. There are insufficient data in pediatric patients to establish a causal relationship. There is no evidence to suggest increased risk of cerebral hemorrhage in adult patients with NSCLC receiving gefitinib. Gefitinib is not indicated for use in pediatric patients as safety and effectiveness have not been established. ### Geriatic Use Of the total number of patients participating in trials of second- and third-line gefitinib treatment of NSCLC, 65% were aged 64 years or less, 30.5 % were aged 65 to 74 years, and 5% of patients were aged 75 years or older. No differences in safety or efficacy were observed between younger and older patients. ### Gender There is no FDA guidance on the use of Gefitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gefitinib with respect to specific racial populations. ### Renal Impairment The effect of severe renal impairment on the pharmacokinetics of gefitinib is not known. Patients with severe renal impairment should be treated with caution when given gefitinib. ### Hepatic Impairment In vitro and in vivo evidence suggest that gefitinib is cleared primarily by the liver. Therefore, gefitinib exposure may be increased in patients with hepatic dysfunction. In patients with liver metastases and moderately to severely elevated biochemical liver abnormalities, however, gefitinib pharmacokinetics were similar to the pharmacokinetics of individuals without liver abnormalities. The influence of non-cancer related hepatic impairment on the pharmacokinetics of gefitinib has not been evaluated. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gefitinib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gefitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Gefitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Gefitinib and IV administrations. # Overdosage The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m2 (about 80 times the recommended clinical dose on a mg/m2 basis) was lethal to rats. Half this dose caused no mortality in mice. There is no specific treatment for an gefitinib overdose and possible symptoms of overdose are not established. However, in Phase 1 clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg. An increase in frequency and severity of some adverse reactions was observed, mainly diarrhea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular, severe diarrhea should be managed appropriately. # Pharmacology ## Mechanism of Action The mechanism of the clinical antitumor action of gefitinib is not fully characterized. Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to gefitinib. ## Structure Gefitinib is an anilinoquinazoline with the chemical name 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin) propoxy] and the following structural formula: ## Pharmacodynamics There is limited information regarding Gefitinib Pharmacodynamics in the drug label. ## Pharmacokinetics Gefitinib is absorbed slowly after oral administration with mean bioavailability of 60%. Elimination is by metabolism (primarily CYP3A4) and excretion in feces. The elimination half-life is about 48 hours. Daily oral administration of gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration. Steady state plasma concentrations are achieved within 10 days. Gefitinib is slowly absorbed, with peak plasma levels occurring 3-7 hours after dosing and mean oral bioavailability of 60%. Bioavailability is not significantly altered by food. Gefitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1400 L following intravenous administration. In vitro binding of gefitinib to human plasma proteins (serum albumin and α1-acid glycoprotein) is 90% and is independent of drug concentrations. Gefitinib undergoes extensive hepatic metabolism in humans, predominantly by CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolites were identified in human plasma. Only O-desmethyl gefitinib has exposure comparable to gefitinib. Although this metabolite has similar EGFR-TK activity to gefitinib in the isolated enzyme assay, it had only 1/14 of the potency of gefitinib in one of the cell-based assays. Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life values of 595 mL/min and 48 hours, respectively, after intravenous administration. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose. ## Nonclinical Toxicology ### Carcinogenesis and Mutagenesis - Gefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the conditions of these assays, gefitinib did not cause genetic damage. - Carcinogenicity studies have not been conducted with gefitinib. # Clinical Studies ### Non-Small Cell Lung Cancer (NSCLC) Refractory Disease Tumor Response Study - A multicenter clinical trial in the United States evaluated the tumor response rate of gefitinib 250 and 500 mg/day in patients with advanced non-small cell lung cancer whose disease had progressed after at least two prior chemotherapy regimens including a platinum drug and docetaxel. gefitinib was taken once daily at approximately the same time each day. Two hundred and sixteen patients received gefitinib, 102 (47%) and 114 (53%) receiving 250 mg and 500 mg daily doses, respectively. Study patient demographics and disease characteristics are summarized in Table 1. Forty-one percent of the patients had received two prior treatment regimens, 33% three prior treatment regimens, and 25% four or more prior treatment regimens. Effectiveness of gefitinib as third line therapy was determined in the 142 evaluable patients with documented disease progression on platinum and docetaxel therapies or who had had unacceptable toxicity on these agents. Table 2 shows tumor response rates and response duration. The overall response rate for the 250 and 500 mg doses combined was 10.6% (95% CI: 6%, 16.8%). Response rates appeared to be highly variable in subgroups of the treated population: 5.1% (4/79) in males, 17.5% (11/63) in females, 4.6% (5/108) in previous or current smokers, 29.4% (10/34) in nonsmokers, 12.4% (12/97) with adenocarcinoma histology, and 6.7% (3/45) with other NSCLC histologies. Similar differences were seen in a multinational study in patients who had received 1 or 2 prior chemotherapy regimens, at least 1 of which was platinum-based. In responders, the median time from diagnosis to study randomization was 16.7 months (range 8 to 34 months). A double-blind, placebo-controlled parallel-group trial randomized 1692 patients with advanced NSCLC to receive either gefitinib 250 mg daily plus Best Supportive Care or placebo plus Best Supportive Care. Patients had received 1 or 2 prior chemotherapy regimens and had progressed while receiving or within 90 days of the last dose of chemotherapy or were intolerant to the most recent prior chemotherapy regimen. The two treatment arms were well-balanced for demographic and disease-related patient characteristics. The primary endpoint of the study was survival. Gefitinib did not significantly prolong survival (stratified log rank HR 0.89, P=0.11, Median 5.6 vs 5.1 months for gefitinib and placebo, respectively). Two large trials were conducted in chemotherapy-naïve patients with stage III and IV non-small cell lung cancer. Two thousand one hundred thirty patients were randomized to receive gefitinib 250 mg daily, gefitinib 500 mg daily, or placebo in combination with platinum-based chemotherapy regimens. The chemotherapies given in these first-line trials were gemcitabine and cis-platinum (N=1093) or carboplatin and paclitaxel (N=1037). The addition of gefitinib did not demonstrate any increase, or trend toward such an increase, in tumor response rates, time to progression, or overall survival. # How Supplied Supplied in tablets of 250 mg - Bottles of 30 Tablets - NDC 0310-0482-30 ## Storage Store at 20-25°C (68-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised to seek medical advice promptly if they develop: - severe or persistent diarrhea, nausea, anorexia, or vomiting, as these have sometimes been associated with dehydration; - an onset or worsening of pulmonary symptoms, ie, shortness of breath or cough; - an eye irritation; or, - any other new symptom. - Women of childbearing potential must be advised to avoid becoming pregnant # Precautions with Alcohol Alcohol-Gefitinib (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Iressa [1] # Look-Alike Drug Names There is limited information regarding Gefitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gefitinib
4e6d48de64a3c85cefb8fdc4b8e8ad7f06ba4037	wikidoc	Gemeprost	Gemeprost # Overview Gemeprost (16, 16-dimethyl-trans-delta2 PGE1 methyl ester) is an analogue of prostaglandin E1. # Clinical use It is used as a treatment for obstetric bleeding. It is used with mifepristone to terminate pregnancy up to 24 weeks gestation. # Side effects Vaginal bleeding, cramps, nausea, vomiting, loose stools or diarrhea, headache, muscle weakness; dizziness; flushing; chills; backache; dyspnoea; chest pain; palpitations and mild pyrexia. Rare: Uterine rupture, severe hypotension, coronary spasms with subsequent myocardial infarctions.	Gemeprost Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gemeprost (16, 16-dimethyl-trans-delta2 PGE1 methyl ester) is an analogue of prostaglandin E1. # Clinical use It is used as a treatment for obstetric bleeding. It is used with mifepristone to terminate pregnancy up to 24 weeks gestation. [1] # Side effects Vaginal bleeding, cramps, nausea, vomiting, loose stools or diarrhea, headache, muscle weakness; dizziness; flushing; chills; backache; dyspnoea; chest pain; palpitations and mild pyrexia. Rare: Uterine rupture, severe hypotension, coronary spasms with subsequent myocardial infarctions.	https://www.wikidoc.org/index.php/Gemeprost
f3ce310cbe183ce8255f1cc2d341eb00145e4c26	wikidoc	Genealogy	Genealogy Genealogy (from Greek: γενεα, genea, "family"; and λόγος, logos, "knowledge") is the study and tracing of families. Modern genealogical research is a complex process that involves more than affixing a collection of names to a pedigree chart. Rather, genealogy involves identifying ancestral or descendant families by using historical records to establish biological, genetic, or familial kinship. Reliable conclusions are based on the quality of sources (ideally original records, rather than derivatives), the information within those sources (ideally primary or firsthand information, rather than secondary or secondhand information), and the evidence that can be drawn (directly or indirectly) from that information. In many instances, genealogists must skillfully assemble indirect or circumstantial evidence to build a case for identity and kinship. All evidence and conclusions, together with the documentation that supports them, is then assembled to create a cohesive "genealogy" or "family history." Traditionalists may differentiate between these last two terms, using the former to describe skeletal accounts of kinship (aka family trees) and the latter as a "fleshing out" of lives and personal histories. However, historical, social, and family context is in any case essential to achieving correct identification of individuals and relationships. # Overview In its original form, genealogy was mainly concerned with the kinship and descent of rulers and nobles, often arguing or demonstrating the legitimacy of claims to wealth and power. The term often overlapped with heraldry, in which the ancestry of royalty was reflected in their coats of arms. Many claimed ancestries have been considered fabrications by modern scholars. An example of this puffery would be the Anglo-Saxon chroniclers who traced the ancestry of several English kings back to the god Woden, the English version of the Norse god Odin. This mythological origin of English kings is related in a number of derivative sources, such as The Scyldings, wherein the Anglo-Saxon Chronicle is cited as a primary source. The following passage appears in the entry for A.D. 449: "Their leaders were two brothers, Hengest and Horsa; who were the sons of Wihtgils; Wihtgils was the son of Witta, Witta of Wecta, Wecta of Woden. From this Woden arose all our royal kindred, and that of the Southumbrians also." In this context "royal kindred" refers to English kings. If these descents were true, Queen Elizabeth II would be a descendant of Woden, via the kings of Wessex. In modern times, genealogy became more widespread, with commoners as well as nobility researching and maintaining their family trees. Genealogy received a boost in the late 1970s with the premiere of the television adaptation of Alex Haley's fictionalized account of his family line, Roots: The Saga of an American Family, leading to genealogy becoming popular hobby. With the advent of the Internet, the number of resources available to genealogists has vastly increased, resulting in an explosion of interest in the topic. According to some sources, genealogy is one of the most popular topics on the Internet. Genealogists who are hobbyists typically pursue their own ancestry. Professional genealogists may conduct research for others, publish books on genealogical methods, teach, or work for companies that provide online databases. Both also try to understand not just where and when people lived, but also their lifestyles, biographies, and motivations. This often requires — or leads to — knowledge of antiquated laws, old political boundaries, migration trends, and historical social conditions. Genealogists and family historians often join family history societies where novices can learn from more experienced researchers, indexing projects make records more accessible, and efforts to preserve historical records may be undertaken. The Internet has also become a major source of data, education, and communication for genealogists. Genealogists sometimes specialize in a particular group, e.g. a Scottish clan; a particular surname, such as in a one-name study; a small community, e.g. a single village or parish, such as in a one-place study; or a particular, often famous, person. # The Genealogical Research Process Genealogists begin their research by collecting family documents and stories. This creates a foundation for documentary research, which involves examining and evaluating historical records for evidence about ancestors and other relatives, their kinship ties, and the events that occurred in their lives. ## Genetic analysis With the discovery that a person's DNA contains information that has been passed down relatively unchanged from early ancestors, analysis of DNA has begun to be used for genealogical research. There are two DNA types of particular interest. One is the mitochondrial DNA which we all possess and which is passed down with only minor mutations through the female line. The other is the Y-chromosome, present only in males, which is passed down with only minor mutations through the male line. A genealogical DNA test allows two individuals to estimate the probability that they are, or are not, related within a certain time frame. Individual genetic test results are being collected in various databases to match people descended from a relatively recent common ancestor. See, for example, the Molecular Genealogy Research Project. These tests are limited to either the direct male or the direct female line. On a much longer time scale, genetic methods are being used to trace human migratory patterns and to determine biogeographical and ethnic origin. As this research is unable to identify individuals, families, and specific relationships, most of it is of only tangential interest to genealogists. ## Sharing data among researchers Data sharing among genealogical researchers has grown to be a major use of the Internet. Most genealogy software programs can export information about persons and their relationships in GEDCOM format, so it can be shared with other genealogists by e-mail and Internet forums, added to an online database such as GeneaNet, or converted into a family web site using online genealogical tools such as PhpGedView. Many genealogical software applications also facilitate the sharing of information on CD-ROMs and DVDs made on personal computers. One phenomenon over the last few years has been that of large online genealogical databases attracting such large flash crowds that the database's host server collapses, causing service to be suspended while upgrades are made to accommodate the traffic load. This happened with FamilySearch, the Commonwealth War Graves Commission's database of war graves, and in January 2002 with the much-anticipated British census for 1901. ## Volunteerism Volunteer efforts figure prominently in genealogy. These efforts range from the extremely informal to the highly organized. On the informal side are the many popular and useful message boards and mailing lists regarding particular surnames, regions, and other topics. These forums can be used to try to find relatives, request record lookups, obtain research advice, and much more. Many genealogists participate in loosely organized projects, both online and off. These collaborations take numerous forms, of which only a few are mentioned here. Some projects prepare name indexes for records, such as probate cases, and either publish the indexes or place them online. These indexes can be used as finding aids to locate original records. Other projects transcribe or abstract records, which is especially helpful for searching records by something other than surname. For example, a genealogist using the cluster genealogy research technique might want to search records by land description. For this reason, deeds are a good candidate for transcription. Offering record lookups is another common service, and projects are usually organized by geographic area. Volunteers such as those involved in RAOGK offer to do record lookups in their home areas for researchers who are unable to travel. Those looking for a structured volunteer environment can join one of thousands of genealogical societies worldwide. Like online forums, most societies have a unique area of focus such as a particular surname, ethnicity, geographic area, or descendency from participants in a given historical event. These societies are almost exclusively staffed by volunteers and may offer a broad range of services. It is common for genealogical societies to maintain libraries for members' use, publish newsletters, provide research assistance to the public, offer classes or seminars, and organize efforts such as cemetery transcribing projects. # Records in genealogical research To keep track of their citizens, governments began keeping records of persons who were neither royalty nor nobility. In much of Europe, for example, such record keeping started in the 16th century. As more of the population was recorded, there were sufficient records to follow a family. Major life events were often documented with a license, permit, or report that was stored at a local, regional or national office or archive. Genealogists locate these records and extract information to discover family relationships and recreate timelines of persons' lives. In China and other Asian countries, genealogy books are used to record the names, occupations, and other vitals of family members with some have dating back hundreds or even thousands of years. In the eastern Indian state of Bihar, there is a written tradition of genealogical records among Maithil Brahmins and Karna Kayasthas called "Panjis", dating to the 12th century CE, and are consulted prior to marriages even today. In Ireland, genealogical records were recorded by professional families of senchaidh (historians). This continued until as late as the mid-17th century, when Gaelic civilization died out. Perhaps the most outstanding example of this genre is Leabhar na nGenealach/The Great Book of Irish Genealogies, by Dubhaltach MacFhirbhisigh (d. 1671), which was published in 2004. Records that are used in genealogy research include: - Vital records Birth records Death records Marriage and divorce records - Birth records - Death records - Marriage and divorce records - Adoption records - Biographies and biographical profiles (e.g. Who's Who) - Census records - Church records Baptism or christening Confirmation Bar or bat mitzvah Marriage Funeral or death Membership - Baptism or christening - Confirmation - Bar or bat mitzvah - Marriage - Funeral or death - Membership - City directories and telephone directories - Coroner's reports - Court records Criminal records Civil records - Criminal records - Civil records - Diaries, personal letters and family Bibles - Emigration, immigration and naturalization records - Hereditary & lineage organization records, e.g. Daughters of the American Revolution records - Land and property records, deeds - Medical records - Military and conscription records - Newspaper articles - Obituaries - Occupational records - Oral histories - Passports - Photographs - Poorhouse, workhouse, almshouse, and asylum records - School and alumni association records - Ship passenger lists - Social Security (within the USA) and pension records - Tax records - Tombstones, cemetery records, and funeral home records - Voter registration records - Wills and probate records As a rule, genealogists begin with the present and work backward in time. Written records have the property of hindsight in that they only tell where a person might have lived and who their parents were, not where they and their descendants might subsequently reside. Two exceptions are when genealogists interview living relatives as to who and where their children and grandchildren are, or try to locate relatives who may already have traced their families back to an ancestor they have in common. ## LDS collections The Church of Jesus Christ of Latter-day Saints (LDS) has engaged in large-scale microfilming of available records of genealogical value. It has also compiled indexes of the submissions of its members. This has resulted in several major databases: the International Genealogical Index, or IGI, which includes both data extracted from filmed civil and ecclesiastic records from various worldwide locales and member-submitted information; the Ancestral File, or AF, which includes the contributions of church members; and the Pedigree Resource File, or PRF, compiled from member and non-member submissions. The IGI contains hundreds of millions of records of individuals who lived between 1500 and 1900, primarily in the United States, Canada and Europe. The AF and PRF often contain numerous duplications of IGI records. The LDS Family History Library in Salt Lake City, Utah, houses microfilm and microfiche copies in over 4,000 "Family History Centers" worldwide available for on-site research. Most of these same resources are also available on ther FamilySearch Internet website providing free access to the International Genealogical Index, the Ancestral File, the Pedigree Resource File, 1880 United States federal census index, an 1881 British census index, an 1881 Canadian census index, the U.S. Social Security Death Index, research guides, and genealogical word lists. # Types of genealogical information The classes of information that genealogists seek include: place names, occupations, family names, first names, and dates. Genealogists need to understand such items in their historical context in order to properly evaluate genealogical sources. ## Place names While the locations of ancestors' residences and life events are core elements of the genealogist's quest, they can often be confusing. Place names may be subject to variant spellings by partially literate scribes. Locations may have identical or very similar names. For example, the village name Brocton occurs six times in the border area between the English counties of Shropshire and Staffordshire. Shifts in political borders must also be understood. Parish, county and national borders have frequently been modified, with outlying and detached areas being reassigned. Old records may contain references to farms and villages that have ceased to exist because of disease, famine or wars. Available sources may include vital records (civil or church registration), censuses, and tax assessments. Oral tradition is also an important source, although it must be used with caution. When no source information is available for a location, circumstantial evidence may provide a probable answer based on a person's or a family's place of residence at the time of the event. Maps and gazetteers are important sources for understanding the places researched. They show the relationship of the area to neighboring communities and may help in understanding migration patterns. ## Occupations Occupational information may be important to understanding an ancestor’s life and for distinguishing two people with the same name. A person’s occupation may have been related to his or her social status, political interest, and migration pattern. Since skilled trades are often passed from father to son, occupation may also be indirect evidence of a family relationship. It is important to remember that occupations sometimes changed or may be easily misunderstood. Workmen no longer fit for their primary trade often took less prestigious jobs later in life. Many unskilled ancestors had a variety of jobs depending on the season and local trade requirements. Census returns may contain some embellishment; e.g., from Labourer to Mason, or from journeyman to Master craftsman. Names for old or unfamiliar local occupations may cause confusion if poorly legible. For example, an ostler (a keeper of horses) and a hostler (an innkeeper) could easily be confused for one another. Likewise, descriptions of such occupations may also be problematic. The perplexing description "ironer of rabbit burrows" may turn out to describe an ironer (profession) in the Bristol district named Rabbit Burrows. Several trades have regionally preferred terms. For example, “shoemaker” and “cordwainer” have the same meaning. Finally, many apparently obscure jobs are part of a larger trade community, such as watchmaking, framework knitting or gunmaking. Occupational data may be reported in occupational licenses, tax assessments, membership records of professional organizations, trade directories, census returns, and vital records (civil registration). Occupational dictionaries are available to explain many obscure and archaic trades. ## Family names Family names are simultaneously one of the most important pieces of genealogical information, and a source of significant confusion for researchers. In many cultures, the name of a person references the family to which he or she belongs. This is called the family name, or surname. It is often also called the last name because, for most speakers of English, the family name comes after the given name (or names). However, this is not the case in other cultures, e.g., Chinese family names precede the given name. Patronymics are names that allow identification of an individual based on the father's name, e.g., Marga Olafsdottir or Olaf Thorsson. Many cultures used patronymics before surnames were adopted or came into use. The Dutch in New York, for example, used the patronymic system of names until 1687 when the advent of English rule mandated surname usage. In Iceland, patronymics are used by a majority of the population; surnames made their way into the language in the 19th and 20th century, but are not widely used. In order to protect the patronymics system, it is forbidden by law to introduce a new surname in Iceland. In Norway patronymics were generally in use through the 1800s and beyond, though surnames began to come into fashion toward the end of that century in some parts of the country. Not until 1923 was there a law requiring surnames. The transmission of names across generations, marriages and other relationships, and immigrations also causes significant inaccuracy in genealogical data. For instance, children may sometimes take or be given step-parent, foster parent, or adoptive parent names. Women in many cultures have routinely used their spouse's surnames. When a woman remarried, she may have changed her name and the names of her children; only her name; or changed no names. Her birth name (maiden name) may be reflected in her children's middle names; her own middle name; or dropped entirely. Official records do not capture many kinds of surname changes. For example, fostering, common-law marriage, love affairs, changes in career or location may all result in name changes which are not reflected as such in official records. Surname data may be found in trade directories, census returns, birth, death, and marriage records. ## Given names Genealogical data regarding given names (first names) is subject to many of the same problems as are family names and place names. Additionally, nicknames for personal names are very common — Beth, Lizzie or Betty are common for Elizabeth, which can be confused with Eliza. Patty has been used as a diminutive form for Martha. Also, Amy used for Alice, and Nancy/Ann, and Polly used for a number of feminine names including Mary Ann and Elizabeth. Peggy is often used as a nickname for Margaret. While the feminine names are the most confusing, masculine names can also interchange: Jack, John & Jonathan, Joseph & Josiah, Edward & Edwin, etc. Middle names provide additional information. Middle names may be inherited, or follow naming customs. Middle names may sometimes be treated as part of the family name. For instance, in some Latin cultures, both the mother's family name and the father's family name are used by the children. Official records may record full names in a variety of ways: First, Middle, Last; Last, Middle, First; Last, First Middle; Last, First, M. Historically, naming traditions existed in some places, where the names given to one's children were sometimes influenced by a particular formula. It is important to recognize, however, that naming traditions were not used in all families and did not always follow the same formula. They are just a pattern of naming that was common in a particular area during a particular time. An example is Scotland and Ireland, where: - 1st son - named after paternal grandfather - 2nd son - named after maternal grandfather - 3rd son - named after father - 4th son - named after father's oldest brother - 1st daughter - named after maternal grandmother - 2nd daughter - named after paternal grandmother - 3rd daughter - named after mother - 4th daughter - named after mother's oldest sister Another example is in some areas of Germany, where siblings were given the same first name, often of a favourite saint or local nobility, but different second names and known by their second names (Rufname). If a child died, the next child of the same gender that was born may have been given the same name. It is not uncommon that a list of a particular couple's children will show one or two names repeated. Although this can be confusing, it can also assist a researcher in discovering the date of death for the previous siblings of the same name. Personal names go through periods of popularity, so it is not uncommon to find many similarly-named people in a generation, and even similarly-named families; e.g., "William and Mary and their children David, Mary, and John". Many names may be identified strongly with a particular gender; e.g., William for boys, and Mary for girls. Other names may be ambiguous, e.g., Lee, or have only slightly variant spellings based on gender, e.g., Frances (usually female) and Francis (usually male). ## Dates It is wise to exercise extreme caution and skepticism with information about dates. Dates are more difficult to recall years after an event, and are more easily mistranscribed than other types of genealogical data. Therefore, one should evaluate whether the date was recorded at the time of the event or at a later date. Dates of birth in vital records or civil registrations and in church records at baptism are generally accurate because they were usually recorded near the time of the event. Family Bibles are often a reliable source for dates, but can be written from memory long after the event. When the same ink and handwriting is used for all entries, the dates were probably written at the same time and therefore will be less reliable since the earlier dates, at least, were probably recorded well after the event. The publication date of the Bible also provides a clue about when the dates were recorded since they could not have been recorded at any earlier date. People sometimes reduce their age on marriage, and perhaps those under "full age" may increase their age in order to marry or to join the armed forces. Census returns are notoriously unreliable for ages or for assuming an approximate death date. The 1841 census in the UK is rounded down to the next lower multiple of five years. Also, caution should be used when estimating a date for a husband's death based on his absence from the census. A woman at home while her husband is away could be identified as head of household or assumed to be a widow. Baptismal dates are often used to approximate birth dates; however, some families wait 3-5 years before baptizing children, and adult baptisms are not unknown. In addition, both birth and marriage dates may have been adjusted to cover for pre-wedding pregnancies. It is very common for the first child to be born before or within a few months of a marriage and sometimes baptized in the mother's name, later adopting the father's name after the parents' marriage. The father's name can be used even if no marriage has occurred. Calendar changes must also be considered. In 1752 the date of the new year was changed in England and her American Colonies. Before 1752 the new year started on the 25 March, but in 1752 this was changed to the 1 January. England also made the transition to the Gregorian calendar from the Julian calendar in 1752, several months later, and it is all too easy for some genealogists to assume that these separate changes belong together. Many other European countries had already made the changes, sometimes many decades apart, and by 1751 there was an 11 day discrepancy between the date in England and the date in other European countries. The date continued to be recorded as usual in 1752 until 2 September 1752, the following day became 14 September 1752. Dates that were recorded in the older system can be shown by "double dating". For example: Original date: 24th of March 1750; Modern date: 24 March 1751; Double dating: 24 March 1750/51. A concrete example illustrates the possibilities for confusion. In the year 1715: - France used the Gregorian calendar with the year starting on 01 January - England used the Julian calendar and the year started on 25 March. - In England, 1700 had been a leap year; in France it had not. - 10 June 1715 in England appears to be eleven days "earlier" than the same day, 21 June 1715, in France. - England kept the same year going until far into March, so 15 February 1715 in England was 26 February 1716 in France. - In Scotland, still using the Julian calendar, the same day was 15 February 1716 For events occurring before 1752 in countries where the Julian calendar was still in use, it is best to use double dating whenever the exact year can be ascertained. When transcribing an original record where the exact year is evident but not expressed, the double date can be written as, for example, "24 March 1750". One should also be aware that, in those places using the old Julian calendar, the numbering of months also varied. The "1st month" of the year was considered March, the second April, the third May, and so on. Those 24 days in March which fell before the beginning of the year were generally regarded as being part of the first month. NOTE: The foregoing may be true for British genealogical records but does in no way apply to records in other countries. A notable exception is the Nordic countries, especially Sweden, which have very detailed and mostly accurate records in the form of church records from the 18th century onwards. But there, as in any historical research, a critical review of all information and an assessment of the reliability of each source is required. # Reliability of sources Information found in historical or genealogical sources can be unreliable and it is good practice to evaluate all sources with a critical eye. Factors influencing the reliability of genealogical information include: the knowledge of the informant (or writer); the bias and mental state of the informant (or writer); the passage of time and the potential for copying and compiling errors. ## Knowledge of the informant The informant is the individual who provided the recorded information. Genealogists must carefully consider who provided the information and what he or she knew. In many cases the informant is identified in the record itself. For example, a death certificate usually has two informants: a physician who provides information about the time and cause of death and a family member who provides the birth date, names of parents etc. When the informant is not identified, one can sometimes deduce information about the identity of the person by careful examination of the source. One should first consider who was alive (and nearby) when the record was created. When the informant is also the person recording the information, the handwriting can be compared to other handwriting samples. When a source does not provide clues about the informant, genealogists should treat the source with caution. These sources can be useful if they can be compared with independent sources. For example, a census record by itself cannot be given much weight because the informant is unknown. However, when censuses for several years concur on a piece of information that would not likely be guessed by a neighbor, it is likely that the information in these censuses was provided by a family member or other informed person. On the other hand, information in a single census cannot be confirmed by information in an undocumented compiled genealogy since the genealogy may have used the census record as its source and might therefore be dependent on the same misinformed individual. ## Bias and mental state of the informant Even individuals who had knowledge of the fact, sometimes intentionally or unintentionally provided false or misleading information. A person may have lied in order to obtain a government benefit (such as a military pension), avoid taxation, or cover up an embarrassing situation (such as the existence of a non-marital child). A person with a distressed state of mind may not be able to accurately recall information. Many genealogical records were recorded at the time of a loved one's death, and so genealogists should consider the effect that grief may have had on the informant of these records. ## The effect of time The passage of time often affects a person's ability to recall information. Therefore, as a general rule, data recorded soon after the event is usually more reliable than data recorded many years later. However, different types of data are more difficult to recall after many years than others. A data type especially prone to recollection errors is dates. Also the ability to recall is affected by the significance that the event had to the individual. These values may have been affected by cultural or individual preferences. ## Copying and compiling errors Genealogists must consider the effects that copying and compiling errors may have had on the information in a source. For this purpose, sources are generally categorized in two categories: original and derivative. A derivative source is information taken from another source. An original is one that is not based on another source. Each time a source is copied, information about the record may be lost and errors may creep in from the copyist misreading, mistyping, or miswriting the information. Genealogists should consider the number of times information has been copied and the types of derivation a piece of information has undergone. The types of derivatives include: photocopies, transcriptions, abstracts, translations, extractions, and compilations. In addition to copying errors, compiled sources (such as published genealogies and online pedigree databases) are susceptible to misidentification errors and incorrect conclusions based on circumstantial evidence. Identity errors usually occur when two or more individuals are assumed to be the same person. Circumstantial or indirect is evidence that does not explicitly answer a genealogical question, but either may be used with other sources to answer the question, suggest a probable answer, or eliminate certain possibilities. Compiled sources sometimes draw hasty conclusions from circumstantial evidence without sufficiently examining all available sources, without properly understanding the evidence, and without appropriately indicating the level of uncertainty. # The "maximum relationship" One of the interests in the field of biology in which some genealogists share an interest is in determining the maximum degree of separation that currently exists among all people in the world, that is to say, how many generations back is the most recent common ancestor that the two most distantly related people on earth share. Latest models, taking into account sexual differentiation, monogamy and realistic migration patterns suggest that the most recent common ancestor (MRCA) of all humans probably lived 75-150 generations or 2,000-4,000 years ago. Moreover, according to these models, the MRCA is likely to have lived somewhere in Southeast Asia (increasing the likelihood of his or her descendants reaching the remote islands of the Pacific), is equally likely to be a man or woman, and is not characterized by an unusually large number of children. These models also show that while a large group (indeed all humans) share recent common ancestors, a given person is likely to share the vast majority of his or her genes with a very small local group. # Software Genealogy software is computer software used to collect, store, sort, and display genealogical data. At a minimum, genealogy software tends to accommodate basic information about individuals, including births, marriages, and deaths. Many programs allow for additional biographical information, including occupation, residence and notes. Many genealogy programs also offer an easy method for keeping track of the sources for each fact. Certain programs are geared toward specific religions, and include additional fields relevant to that religion. Other programs focus on certain geographical regions. Some programs allow for the import of digital photographs, and sound files. Other programs focus on the ability to generate kinship charts, family history books and other publications. Some programs are more flexible than others in allowing for the input of same sex marriages and children born out of wedlock. A move is on to incorporate fields for the input of genealogical DNA test results, though this information can be added into the "Notes" field of almost all genealogy software. Most genealogy software allow for the export of data in the GEDCOM format that can be shared with people using different genealogy software. Certain programs allow the user to restrict the information that is shared, usually by removing information about living people out of privacy concerns.	Genealogy Genealogy (from Greek: γενεα, genea, "family"; and λόγος, logos, "knowledge") is the study and tracing of families. Modern genealogical research is a complex process that involves more than affixing a collection of names to a pedigree chart. Rather, genealogy involves identifying ancestral or descendant families by using historical records to establish biological, genetic, or familial kinship. Reliable conclusions are based on the quality of sources (ideally original records, rather than derivatives), the information within those sources (ideally primary or firsthand information, rather than secondary or secondhand information), and the evidence that can be drawn (directly or indirectly) from that information. In many instances, genealogists must skillfully assemble indirect or circumstantial evidence to build a case for identity and kinship. All evidence and conclusions, together with the documentation that supports them, is then assembled to create a cohesive "genealogy" or "family history."[1] Traditionalists may differentiate between these last two terms, using the former to describe skeletal accounts of kinship (aka family trees) and the latter as a "fleshing out" of lives and personal histories. However, historical, social, and family context is in any case essential to achieving correct identification of individuals and relationships. # Overview In its original form, genealogy was mainly concerned with the kinship and descent of rulers and nobles, often arguing or demonstrating the legitimacy of claims to wealth and power. The term often overlapped with heraldry, in which the ancestry of royalty was reflected in their coats of arms. Many claimed ancestries have been considered fabrications by modern scholars. An example of this puffery would be the Anglo-Saxon chroniclers who traced the ancestry of several English kings back to the god Woden, the English version of the Norse god Odin. This mythological origin of English kings is related in a number of derivative sources, such as The Scyldings, wherein the Anglo-Saxon Chronicle is cited as a primary source.[2] The following passage appears in the entry for A.D. 449: "Their leaders were two brothers, Hengest and Horsa; who were the sons of Wihtgils; Wihtgils was the son of Witta, Witta of Wecta, Wecta of Woden. From this Woden arose all our royal kindred, and that of the Southumbrians also." In this context "royal kindred" refers to English kings.[3] If these descents were true, Queen Elizabeth II would be a descendant of Woden, via the kings of Wessex. In modern times, genealogy became more widespread, with commoners as well as nobility researching and maintaining their family trees. Genealogy received a boost in the late 1970s with the premiere of the television adaptation of Alex Haley's fictionalized account of his family line, Roots: The Saga of an American Family,[4][5][6] leading to genealogy becoming popular hobby. With the advent of the Internet, the number of resources available to genealogists has vastly increased, resulting in an explosion of interest in the topic. According to some sources, genealogy is one of the most popular topics on the Internet. Genealogists who are hobbyists typically pursue their own ancestry. Professional genealogists may conduct research for others, publish books on genealogical methods, teach, or work for companies that provide online databases. Both also try to understand not just where and when people lived, but also their lifestyles, biographies, and motivations. This often requires — or leads to — knowledge of antiquated laws, old political boundaries, migration trends, and historical social conditions. Genealogists and family historians often join family history societies where novices can learn from more experienced researchers, indexing projects make records more accessible, and efforts to preserve historical records may be undertaken. The Internet has also become a major source of data, education, and communication for genealogists. Genealogists sometimes specialize in a particular group, e.g. a Scottish clan; a particular surname, such as in a one-name study; a small community, e.g. a single village or parish, such as in a one-place study; or a particular, often famous, person. # The Genealogical Research Process Genealogists begin their research by collecting family documents and stories. This creates a foundation for documentary research, which involves examining and evaluating historical records for evidence about ancestors and other relatives, their kinship ties, and the events that occurred in their lives. ## Genetic analysis With the discovery that a person's DNA contains information that has been passed down relatively unchanged from early ancestors, analysis of DNA has begun to be used for genealogical research. There are two DNA types of particular interest. One is the mitochondrial DNA which we all possess and which is passed down with only minor mutations through the female line. The other is the Y-chromosome, present only in males, which is passed down with only minor mutations through the male line. A genealogical DNA test allows two individuals to estimate the probability that they are, or are not, related within a certain time frame. Individual genetic test results are being collected in various databases to match people descended from a relatively recent common ancestor. See, for example, the Molecular Genealogy Research Project. These tests are limited to either the direct male or the direct female line. On a much longer time scale, genetic methods are being used to trace human migratory patterns and to determine biogeographical and ethnic origin. As this research is unable to identify individuals, families, and specific relationships, most of it is of only tangential interest to genealogists. ## Sharing data among researchers Data sharing among genealogical researchers has grown to be a major use of the Internet. Most genealogy software programs can export information about persons and their relationships in GEDCOM format, so it can be shared with other genealogists by e-mail and Internet forums, added to an online database such as GeneaNet, or converted into a family web site using online genealogical tools such as PhpGedView. Many genealogical software applications also facilitate the sharing of information on CD-ROMs and DVDs made on personal computers. One phenomenon over the last few years has been that of large online genealogical databases attracting such large flash crowds that the database's host server collapses, causing service to be suspended while upgrades are made to accommodate the traffic load. This happened with FamilySearch, the Commonwealth War Graves Commission's database of war graves, and in January 2002 with the much-anticipated British census for 1901. ## Volunteerism Volunteer efforts figure prominently in genealogy. These efforts range from the extremely informal to the highly organized. On the informal side are the many popular and useful message boards and mailing lists regarding particular surnames, regions, and other topics. These forums can be used to try to find relatives, request record lookups, obtain research advice, and much more. Many genealogists participate in loosely organized projects, both online and off. These collaborations take numerous forms, of which only a few are mentioned here. Some projects prepare name indexes for records, such as probate cases, and either publish the indexes or place them online. These indexes can be used as finding aids to locate original records. Other projects transcribe or abstract records, which is especially helpful for searching records by something other than surname. For example, a genealogist using the cluster genealogy research technique might want to search records by land description. For this reason, deeds are a good candidate for transcription. Offering record lookups is another common service, and projects are usually organized by geographic area. Volunteers such as those involved in RAOGK offer to do record lookups in their home areas for researchers who are unable to travel. Those looking for a structured volunteer environment can join one of thousands of genealogical societies worldwide. Like online forums, most societies have a unique area of focus such as a particular surname, ethnicity, geographic area, or descendency from participants in a given historical event. These societies are almost exclusively staffed by volunteers and may offer a broad range of services. It is common for genealogical societies to maintain libraries for members' use, publish newsletters, provide research assistance to the public, offer classes or seminars, and organize efforts such as cemetery transcribing projects. # Records in genealogical research To keep track of their citizens, governments began keeping records of persons who were neither royalty nor nobility. In much of Europe, for example, such record keeping started in the 16th century. As more of the population was recorded, there were sufficient records to follow a family. Major life events were often documented with a license, permit, or report that was stored at a local, regional or national office or archive. Genealogists locate these records and extract information to discover family relationships and recreate timelines of persons' lives. In China and other Asian countries, genealogy books are used to record the names, occupations, and other vitals of family members with some have dating back hundreds or even thousands of years. In the eastern Indian state of Bihar, there is a written tradition of genealogical records among Maithil Brahmins and Karna Kayasthas called "Panjis", dating to the 12th century CE, and are consulted prior to marriages even today.[7][8][9] In Ireland, genealogical records were recorded by professional families of senchaidh (historians). This continued until as late as the mid-17th century, when Gaelic civilization died out. Perhaps the most outstanding example of this genre is Leabhar na nGenealach/The Great Book of Irish Genealogies, by Dubhaltach MacFhirbhisigh (d. 1671), which was published in 2004. Records that are used in genealogy research include: - Vital records Birth records Death records Marriage and divorce records - Birth records - Death records - Marriage and divorce records - Adoption records - Biographies and biographical profiles (e.g. Who's Who) - Census records - Church records Baptism or christening Confirmation Bar or bat mitzvah Marriage Funeral or death Membership - Baptism or christening - Confirmation - Bar or bat mitzvah - Marriage - Funeral or death - Membership - City directories and telephone directories - Coroner's reports - Court records Criminal records Civil records - Criminal records - Civil records - Diaries, personal letters and family Bibles - Emigration, immigration and naturalization records - Hereditary & lineage organization records, e.g. Daughters of the American Revolution records - Land and property records, deeds - Medical records - Military and conscription records - Newspaper articles - Obituaries - Occupational records - Oral histories - Passports - Photographs - Poorhouse, workhouse, almshouse, and asylum records - School and alumni association records - Ship passenger lists - Social Security (within the USA) and pension records - Tax records - Tombstones, cemetery records, and funeral home records - Voter registration records - Wills and probate records As a rule, genealogists begin with the present and work backward in time. Written records have the property of hindsight in that they only tell where a person might have lived and who their parents were, not where they and their descendants might subsequently reside. Two exceptions are when genealogists interview living relatives as to who and where their children and grandchildren are, or try to locate relatives who may already have traced their families back to an ancestor they have in common. ## LDS collections The Church of Jesus Christ of Latter-day Saints (LDS) has engaged in large-scale microfilming of available records of genealogical value. It has also compiled indexes of the submissions of its members. This has resulted in several major databases: the International Genealogical Index, or IGI, which includes both data extracted from filmed civil and ecclesiastic records from various worldwide locales and member-submitted information; the Ancestral File, or AF, which includes the contributions of church members; and the Pedigree Resource File, or PRF, compiled from member and non-member submissions. The IGI contains hundreds of millions of records of individuals who lived between 1500 and 1900, primarily in the United States, Canada and Europe. The AF and PRF often contain numerous duplications of IGI records. The LDS Family History Library in Salt Lake City, Utah, houses microfilm and microfiche copies in over 4,000 "Family History Centers" worldwide available for on-site research. Most of these same resources are also available on ther FamilySearch Internet website providing free access to the International Genealogical Index, the Ancestral File, the Pedigree Resource File, 1880 United States federal census index, an 1881 British census index, an 1881 Canadian census index, the U.S. Social Security Death Index, research guides, and genealogical word lists. # Types of genealogical information The classes of information that genealogists seek include: place names, occupations, family names, first names, and dates. Genealogists need to understand such items in their historical context in order to properly evaluate genealogical sources. ## Place names While the locations of ancestors' residences and life events are core elements of the genealogist's quest, they can often be confusing. Place names may be subject to variant spellings by partially literate scribes. Locations may have identical or very similar names. For example, the village name Brocton occurs six times in the border area between the English counties of Shropshire and Staffordshire. Shifts in political borders must also be understood. Parish, county and national borders have frequently been modified, with outlying and detached areas being reassigned. Old records may contain references to farms and villages that have ceased to exist because of disease, famine or wars. Available sources may include vital records (civil or church registration), censuses, and tax assessments. Oral tradition is also an important source, although it must be used with caution. When no source information is available for a location, circumstantial evidence may provide a probable answer based on a person's or a family's place of residence at the time of the event. Maps and gazetteers are important sources for understanding the places researched. They show the relationship of the area to neighboring communities and may help in understanding migration patterns. ## Occupations Occupational information may be important to understanding an ancestor’s life and for distinguishing two people with the same name. A person’s occupation may have been related to his or her social status, political interest, and migration pattern. Since skilled trades are often passed from father to son, occupation may also be indirect evidence of a family relationship. It is important to remember that occupations sometimes changed or may be easily misunderstood. Workmen no longer fit for their primary trade often took less prestigious jobs later in life. Many unskilled ancestors had a variety of jobs depending on the season and local trade requirements. Census returns may contain some embellishment; e.g., from Labourer to Mason, or from journeyman to Master craftsman. Names for old or unfamiliar local occupations may cause confusion if poorly legible. For example, an ostler (a keeper of horses) and a hostler (an innkeeper) could easily be confused for one another. Likewise, descriptions of such occupations may also be problematic. The perplexing description "ironer of rabbit burrows" may turn out to describe an ironer (profession) in the Bristol district named Rabbit Burrows. Several trades have regionally preferred terms. For example, “shoemaker” and “cordwainer” have the same meaning. Finally, many apparently obscure jobs are part of a larger trade community, such as watchmaking, framework knitting or gunmaking. Occupational data may be reported in occupational licenses, tax assessments, membership records of professional organizations, trade directories, census returns, and vital records (civil registration). Occupational dictionaries are available to explain many obscure and archaic trades. ## Family names Family names are simultaneously one of the most important pieces of genealogical information, and a source of significant confusion for researchers. In many cultures, the name of a person references the family to which he or she belongs. This is called the family name, or surname. It is often also called the last name because, for most speakers of English, the family name comes after the given name (or names). However, this is not the case in other cultures, e.g., Chinese family names precede the given name. Patronymics are names that allow identification of an individual based on the father's name, e.g., Marga Olafsdottir or Olaf Thorsson. Many cultures used patronymics before surnames were adopted or came into use. The Dutch in New York, for example, used the patronymic system of names until 1687 when the advent of English rule mandated surname usage.[10] In Iceland, patronymics are used by a majority of the population; surnames made their way into the language in the 19th and 20th century, but are not widely used. In order to protect the patronymics system, it is forbidden by law to introduce a new surname in Iceland.[11] In Norway patronymics were generally in use through the 1800s and beyond, though surnames began to come into fashion toward the end of that century in some parts of the country. Not until 1923 was there a law requiring surnames.[12] The transmission of names across generations, marriages and other relationships, and immigrations also causes significant inaccuracy in genealogical data. For instance, children may sometimes take or be given step-parent, foster parent, or adoptive parent names. Women in many cultures have routinely used their spouse's surnames. When a woman remarried, she may have changed her name and the names of her children; only her name; or changed no names. Her birth name (maiden name) may be reflected in her children's middle names; her own middle name; or dropped entirely.[citation needed] Official records do not capture many kinds of surname changes. For example, fostering, common-law marriage, love affairs, changes in career or location may all result in name changes which are not reflected as such in official records.[citation needed] Surname data may be found in trade directories, census returns, birth, death, and marriage records. ## Given names Genealogical data regarding given names (first names) is subject to many of the same problems as are family names and place names. Additionally, nicknames for personal names are very common — Beth, Lizzie or Betty are common for Elizabeth, which can be confused with Eliza. Patty has been used as a diminutive form for Martha. Also, Amy used for Alice, and Nancy/Ann, and Polly used for a number of feminine names including Mary Ann and Elizabeth. Peggy is often used as a nickname for Margaret. While the feminine names are the most confusing, masculine names can also interchange: Jack, John & Jonathan, Joseph & Josiah, Edward & Edwin, etc. Middle names provide additional information. Middle names may be inherited, or follow naming customs. Middle names may sometimes be treated as part of the family name. For instance, in some Latin cultures, both the mother's family name and the father's family name are used by the children. Official records may record full names in a variety of ways: First, Middle, Last; Last, Middle, First; Last, First Middle; Last, First, M. Historically, naming traditions existed in some places, where the names given to one's children were sometimes influenced by a particular formula. It is important to recognize, however, that naming traditions were not used in all families and did not always follow the same formula. They are just a pattern of naming that was common in a particular area during a particular time. An example is Scotland and Ireland, where: - 1st son - named after paternal grandfather - 2nd son - named after maternal grandfather - 3rd son - named after father - 4th son - named after father's oldest brother - 1st daughter - named after maternal grandmother - 2nd daughter - named after paternal grandmother - 3rd daughter - named after mother - 4th daughter - named after mother's oldest sister Another example is in some areas of Germany, where siblings were given the same first name, often of a favourite saint or local nobility, but different second names and known by their second names (Rufname). If a child died, the next child of the same gender that was born may have been given the same name. It is not uncommon that a list of a particular couple's children will show one or two names repeated. Although this can be confusing, it can also assist a researcher in discovering the date of death for the previous siblings of the same name. Personal names go through periods of popularity, so it is not uncommon to find many similarly-named people in a generation, and even similarly-named families; e.g., "William and Mary and their children David, Mary, and John". Many names may be identified strongly with a particular gender; e.g., William for boys, and Mary for girls. Other names may be ambiguous, e.g., Lee, or have only slightly variant spellings based on gender, e.g., Frances (usually female) and Francis (usually male). ## Dates It is wise to exercise extreme caution and skepticism with information about dates. Dates are more difficult to recall years after an event, and are more easily mistranscribed than other types of genealogical data. Therefore, one should evaluate whether the date was recorded at the time of the event or at a later date. Dates of birth in vital records or civil registrations and in church records at baptism are generally accurate because they were usually recorded near the time of the event. Family Bibles are often a reliable source for dates, but can be written from memory long after the event. When the same ink and handwriting is used for all entries, the dates were probably written at the same time and therefore will be less reliable since the earlier dates, at least, were probably recorded well after the event. The publication date of the Bible also provides a clue about when the dates were recorded since they could not have been recorded at any earlier date. People sometimes reduce their age on marriage, and perhaps those under "full age" may increase their age in order to marry or to join the armed forces. Census returns are notoriously unreliable for ages or for assuming an approximate death date. The 1841 census in the UK is rounded down to the next lower multiple of five years. Also, caution should be used when estimating a date for a husband's death based on his absence from the census. A woman at home while her husband is away could be identified as head of household or assumed to be a widow. Baptismal dates are often used to approximate birth dates; however, some families wait 3-5 years before baptizing children, and adult baptisms are not unknown. In addition, both birth and marriage dates may have been adjusted to cover for pre-wedding pregnancies. It is very common for the first child to be born before or within a few months of a marriage and sometimes baptized in the mother's name, later adopting the father's name after the parents' marriage. The father's name can be used even if no marriage has occurred. Calendar changes must also be considered. In 1752 the date of the new year was changed in England and her American Colonies. Before 1752 the new year started on the 25 March, but in 1752 this was changed to the 1 January. England also made the transition to the Gregorian calendar from the Julian calendar in 1752, several months later, and it is all too easy for some genealogists to assume that these separate changes belong together. Many other European countries had already made the changes, sometimes many decades apart, and by 1751 there was an 11 day discrepancy between the date in England and the date in other European countries. The date continued to be recorded as usual in 1752 until 2 September 1752, the following day became 14 September 1752. Dates that were recorded in the older system can be shown by "double dating". For example: Original date: 24th of March 1750; Modern date: 24 March 1751; Double dating: 24 March 1750/51. A concrete example illustrates the possibilities for confusion. In the year 1715: - France used the Gregorian calendar with the year starting on 01 January - England used the Julian calendar and the year started on 25 March. - In England, 1700 had been a leap year; in France it had not. - 10 June 1715 in England appears to be eleven days "earlier" than the same day, 21 June 1715, in France. - England kept the same year going until far into March, so 15 February 1715 in England was 26 February 1716 in France. - In Scotland, still using the Julian calendar, the same day was 15 February 1716 For events occurring before 1752 in countries where the Julian calendar was still in use, it is best to use double dating whenever the exact year can be ascertained. When transcribing an original record where the exact year is evident but not expressed, the double date can be written as, for example, "24 March 1750[/51]". One should also be aware that, in those places using the old Julian calendar, the numbering of months also varied. The "1st month" of the year was considered March, the second April, the third May, and so on. Those 24 days in March which fell before the beginning of the year were generally regarded as being part of the first month. NOTE: The foregoing may be true for British genealogical records but does in no way apply to records in other countries. A notable exception is the Nordic countries, especially Sweden, which have very detailed and mostly accurate records in the form of church records from the 18th century onwards. But there, as in any historical research, a critical review of all information and an assessment of the reliability of each source is required. # Reliability of sources Information found in historical or genealogical sources can be unreliable and it is good practice to evaluate all sources with a critical eye. Factors influencing the reliability of genealogical information include: the knowledge of the informant (or writer); the bias and mental state of the informant (or writer); the passage of time and the potential for copying and compiling errors. ## Knowledge of the informant The informant is the individual who provided the recorded information. Genealogists must carefully consider who provided the information and what he or she knew. In many cases the informant is identified in the record itself. For example, a death certificate usually has two informants: a physician who provides information about the time and cause of death and a family member who provides the birth date, names of parents etc. When the informant is not identified, one can sometimes deduce information about the identity of the person by careful examination of the source. One should first consider who was alive (and nearby) when the record was created. When the informant is also the person recording the information, the handwriting can be compared to other handwriting samples. When a source does not provide clues about the informant, genealogists should treat the source with caution. These sources can be useful if they can be compared with independent sources. For example, a census record by itself cannot be given much weight because the informant is unknown. However, when censuses for several years concur on a piece of information that would not likely be guessed by a neighbor, it is likely that the information in these censuses was provided by a family member or other informed person. On the other hand, information in a single census cannot be confirmed by information in an undocumented compiled genealogy since the genealogy may have used the census record as its source and might therefore be dependent on the same misinformed individual. ## Bias and mental state of the informant Even individuals who had knowledge of the fact, sometimes intentionally or unintentionally provided false or misleading information. A person may have lied in order to obtain a government benefit (such as a military pension), avoid taxation, or cover up an embarrassing situation (such as the existence of a non-marital child). A person with a distressed state of mind may not be able to accurately recall information. Many genealogical records were recorded at the time of a loved one's death, and so genealogists should consider the effect that grief may have had on the informant of these records. ## The effect of time The passage of time often affects a person's ability to recall information. Therefore, as a general rule, data recorded soon after the event is usually more reliable than data recorded many years later. However, different types of data are more difficult to recall after many years than others. A data type especially prone to recollection errors is dates. Also the ability to recall is affected by the significance that the event had to the individual. These values may have been affected by cultural or individual preferences. ## Copying and compiling errors Genealogists must consider the effects that copying and compiling errors may have had on the information in a source. For this purpose, sources are generally categorized in two categories: original and derivative. A derivative source is information taken from another source. An original is one that is not based on another source. Each time a source is copied, information about the record may be lost and errors may creep in from the copyist misreading, mistyping, or miswriting the information. Genealogists should consider the number of times information has been copied and the types of derivation a piece of information has undergone. The types of derivatives include: photocopies, transcriptions, abstracts, translations, extractions, and compilations. In addition to copying errors, compiled sources (such as published genealogies and online pedigree databases) are susceptible to misidentification errors and incorrect conclusions based on circumstantial evidence. Identity errors usually occur when two or more individuals are assumed to be the same person. Circumstantial or indirect is evidence that does not explicitly answer a genealogical question, but either may be used with other sources to answer the question, suggest a probable answer, or eliminate certain possibilities. Compiled sources sometimes draw hasty conclusions from circumstantial evidence without sufficiently examining all available sources, without properly understanding the evidence, and without appropriately indicating the level of uncertainty. # The "maximum relationship" One of the interests in the field of biology in which some genealogists share an interest is in determining the maximum degree of separation that currently exists among all people in the world, that is to say, how many generations back is the most recent common ancestor that the two most distantly related people on earth share. Latest models, taking into account sexual differentiation, monogamy and realistic migration patterns suggest that the most recent common ancestor (MRCA) of all humans probably lived 75-150 generations or 2,000-4,000 years ago.[13] Moreover, according to these models, the MRCA is likely to have lived somewhere in Southeast Asia (increasing the likelihood of his or her descendants reaching the remote islands of the Pacific), is equally likely to be a man or woman, and is not characterized by an unusually large number of children. These models also show that while a large group (indeed all humans) share recent common ancestors, a given person is likely to share the vast majority of his or her genes with a very small local group. # Software Genealogy software is computer software used to collect, store, sort, and display genealogical data. At a minimum, genealogy software tends to accommodate basic information about individuals, including births, marriages, and deaths. Many programs allow for additional biographical information, including occupation, residence and notes. Many genealogy programs also offer an easy method for keeping track of the sources for each fact. Certain programs are geared toward specific religions, and include additional fields relevant to that religion. Other programs focus on certain geographical regions. Some programs allow for the import of digital photographs, and sound files. Other programs focus on the ability to generate kinship charts, family history books and other publications. Some programs are more flexible than others in allowing for the input of same sex marriages and children born out of wedlock. A move is on to incorporate fields for the input of genealogical DNA test results, though this information can be added into the "Notes" field of almost all genealogy software. Most genealogy software allow for the export of data in the GEDCOM format that can be shared with people using different genealogy software. Certain programs allow the user to restrict the information that is shared, usually by removing information about living people out of privacy concerns.	https://www.wikidoc.org/index.php/Genealogy
3bec5f443d6c16b7c02f0cc6b7468a9628c55085	wikidoc	Paralysis	Paralysis # Overview Paralysis is the complete loss of muscle function for one or more muscle groups. Paralysis often includes loss of feeling in the affected area. # Pathophysiology Paralysis is most often caused by damage to the nervous system or brain, especially the spinal cord. Partial paralysis can also occur in the REM stage of sleep. Paralysis may be localized, or generalized, or it may follow a certain pattern. For example, localized paralysis occurs in Bell's palsy where one side of the face may be paralyzed due to inflammation of the facial nerve on that side. Patients with stroke may be weak throughout their body (global paralysis) or have hemiplegia (weakness on one side of the body) or other patterns of paralysis depending on the area of damage in the brain. Other patterns of paralysis arise due to different lesions and their sequelae. For example, lower spinal cord damage from a severe back injury may result in paraplegia, while an injury higher up on the spinal cord, such as a neck injury, can cause quadriplegia. Patients with paraplegia or quadriplegia often use equipment such as a wheelchair or standing frame for mobility and to regain some independence. Most paralyses caused by nervous system damage are constant in nature; however, there are forms of periodic paralysis, including sleep paralysis, which are caused by other factors. # Causes ## Common Causes - Amyotrophic lateral sclerosis (ALS) - Botulism - Drugs Amikacin sulfate Iodixanol Pergolide - Amikacin sulfate - Iodixanol - Pergolide - Guillain-Barré syndrome - Multiple sclerosis - Poisons that interfere with nerve function, such as curare - Poliomyelitis - Spina bifida - Stroke - trauma ## Causes by Organ System ## Causes in Alphabetical Order - Acetylandromedol - Acute disseminated encephalomyelitis - Acute fulminant multiple sclerosis - Adrenal adenoma - Adrenal cancer - Adrenal cortex neoplasms - Adrenal gland hyperfunction - Adrenal incidentaloma - Adrenocortical carcinoma - Adrenoleukodystrophy - Alexander disease - Amikacin sulfate - Amnesic shellfish poisoning - Amyotrophic lateral sclerosis - Andromedotoxin - Apricot seed poisoning - Arachnoiditis - Arbovirosis - Arteriovenous malformation - Asphyxia - Ataxic cerebral palsy - Autoimmune diseases of the nervous system - Azinphos-methyl - Back tumor - Balo's concentric sclerosis - Bell's palsy - Benign astrocytoma - Bird cherry seed poisoning - Bitter almond seed poisoning - Blue-ringed octopus poisoning - Bog rosemary poisoning - Bottlebrush buckeye poisoning - Botulism - Brachial plexus injury - Broken neck - Bromide - Brown snake poisoning - Buckeye poisoning - Bush lily poisoning - Calcification of basal ganglia - California buckeye poisoning - California encephalitis - Canavan disease - Carbamate insecticide poisoning - Cerebral cavernous malformations - Cerebral palsy - Cerebral sarcoma - Cerebrotendinous xanthomatosis - Cerebrovascular accident - Chediak-higashi syndrome - Cherry seed poisoning - Chiari malformation - China tree poisoning - Chokecherry seed poisoning - Chronic inflammatory demyelinating polyneuropathy - Classical hodgkin disease - Clupeotoxism - Coastal leucothoe poisoning - Cobra poisoning - Compartment syndrome - Congenital defects - Conium maculatum - Conversion disorder - Corn lily poisoning - Curare - Cutaneomeningospinal angiomatosis - Cytisine - Decompression sickness - Delphinium poisoning - Desmoplastic cerebral astrocytoma of infancy - Desmoplastic infantile ganglioma - Dimethyl phthalate - Donepezil toxicity - Dysbarism - Dyskinetic cerebral palsy - Elapid poisoning - Electrical burns - Encephalitis - Encephalomyelitis - Enterovirus antenatal infection - Everlasting pea poisoning - Extradural hematoma - Familial infantile metachromatic leukodystrophy - Fetterbush poisoning - Flax poisoning - Flecainide - Flecatab - Florida leucothoe poisoning - Fowl paralyses - Fractures - Friedreich’s ataxia - Functioning pancreatic endocrine tumor - Fungal meningitis - Gm2-gangliosidosis - Golden chain tree poisoning - Grayanotoxin - Guillain-barre syndrome - Hemorrhagic stroke - Hendra virus - Hereditary peripheral nervous disorder - Hip cancer - Hodgkin's disease - Homocystinuria syndrome - Hydrocephalus - Hyperadrenalism - Hypokalemia - Insulinoma - Intercostal neuralgia - Intracranial hemorrhage - Iodixanol - Ischemic stroke - Japanese andromeda poisoning - Japanese encephalitis - Jessamine poisoning - Juvenile paget's disease - Krabbe disease - Leprosy - Leptomeningitis - Lobelia poisoning - Lobeline - Lyme disease - Lymphocyte depletion hodgkin's disease - Lymphocytic choriomeningitis - Malignant astrocytoma - Marburg multiple sclerosis - Mareck's disease - Marine toxins - Mayapple poisoning - Mercury poisoning - Mesothelioma - Metachromatic leukodystrophy - Metastatic insulinoma - Mixed cellularity hodgkin's disease - Monkshood poisoning - Monocrotophos - Motor neurone disease - Mountain andromeda poisoning - Mountain laurel poisoning - Movement disorders - Moyamoya syndrome - Multiple myeloma - Multiple sclerosis - Muscular dystrophy - Neuroblastoma - Neurofibromatosis - Neurosyphilis - Nicotiana tabacum - Nodular sclerosing hodgkin's lymphoma - Nyssen-van bogaert syndrome - Organophosphate insecticide poisoning - Paget's disease of bone - Pathological fracture - Peach seed poisoning - Pelizaeus-merzbacher disease - Pergolide - Peripheral neuritis - Pernettya poisoning - Persian violet poisoning - Poliomyelitis - Porphyria - Post-polio syndrome - Post-vaccinial encephalitis - Potassium deficiency - Primary hyperaldosteronism - Progressive multifocal leukoencephalopathy - Rabies - Rasmussen's encephalitis - Red buckeye poisoning - Refsum disease - Rhodotoxin - Rib tumor - Schistosomiasis japonica - Schistosomiasis mansoni - Sea wasp poisoning - Selected encephalitides - Sheep laurel poisoning - Simian b virus infection - Sleep - Spastic cerebral palsy - Spina bifida - Spinal cord injury - Spinal muscular atrophy - Spinal tumor - Staggerbush poisoning - Stroke - Subarachnoid hemorrhage - Subdural hematoma - Sweetshrub poisoning - Syphilis - Syringomyelia - Systemic lupus erythematosus - Tacrine toxicity - Tambocor - Tay sachs disease - Temodar - Temozolomide - Tetanus - Tetranortriterpene - Tetraodon poisoning - Thiram - Tick-borne encephalitis - Transverse myelitis - Trauma - Trumpet flower poisoning - Vanishing white matter leukodystrophy - Wild cherry seed poisoning - Zellweger syndrome # Differential diagnosis # Related Chapters - Spinal cord injury - Paraplegia - Quadriplegia - Muscle relaxant - Ptosis - Sleep paralysis - Hemiparesis - Beriberi - Neuroprosthetics - Brain-computer interface - Tonic immobility - Cerebral palsy - ↑ Talukder RK, Sutradhar SR, Rahman KM, Uddin MJ, Akhter H (2011). "Guillian-Barre syndrome". Mymensingh Med J. 20 (4): 748–56. PMID 22081202.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} - ↑ Merino-Ramírez MÁ, Bolton CF (2016). "Review of the Diagnostic Challenges of Lambert-Eaton Syndrome Revealed Through Three Case Reports". Can J Neurol Sci. 43 (5): 635–47. doi:10.1017/cjn.2016.268. PMID 27412406. - ↑ Gilhus NE (2016). "Myasthenia Gravis". N Engl J Med. 375 (26): 2570–2581. doi:10.1056/NEJMra1602678. PMID 28029925. - ↑ Ozono K (2016). "". Clin Calcium. 26 (2): 215–22. doi:CliCa1602215222 Check \|doi= value (help). PMID 26813501. - ↑ Kamanyire R, Karalliedde L (2004). "Organophosphate toxicity and occupational exposure". Occup Med (Lond). 54 (2): 69–75. PMID 15020723. - ↑ Pecina CA (2012). "Tick paralysis". Semin Neurol. 32 (5): 531–2. doi:10.1055/s-0033-1334474. PMID 23677663. - ↑ Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A (2014). "Tetrodotoxin: chemistry, toxicity, source, distribution and detection". Toxins (Basel). 6 (2): 693–755. doi:10.3390/toxins6020693. PMC 3942760. PMID 24566728.CS1 maint: Multiple names: authors list (link) - ↑ Kuntzer T, Hirt L, Bogousslavsky J (1996). "". Rev Med Suisse Romande. 116 (8): 605–9. PMID 8848683.CS1 maint: Multiple names: authors list (link) - ↑ Laffont I, Julia M, Tiffreau V, Yelnik A, Herisson C, Pelissier J (2010). "Aging and sequelae of poliomyelitis". Ann Phys Rehabil Med. 53 (1): 24–33. doi:10.1016/j.rehab.2009.10.002. PMID 19944665.CS1 maint: Multiple names: authors list (link) - ↑ West TW (2013). "Transverse myelitis--a review of the presentation, diagnosis, and initial management". Discov Med. 16 (88): 167–77. PMID 24099672. - ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430. - ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697. - ↑ Falzarano MS, Scotton C, Passarelli C, Ferlini A (2015). "Duchenne Muscular Dystrophy: From Diagnosis to Therapy". Molecules. 20 (10): 18168–84. doi:10.3390/molecules201018168. PMID 26457695.CS1 maint: Multiple names: authors list (link) - ↑ Filippi M, Preziosa P, Rocca MA (2016). "Multiple sclerosis". Handb Clin Neurol. 135: 399–423. doi:10.1016/B978-0-444-53485-9.00020-9. PMID 27432676.CS1 maint: Multiple names: authors list (link) - ↑ Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group". Arch Neurol. 51 (1): 61–6. PMID 8274111.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Riva N, Agosta F, Lunetta C, Filippi M, Quattrini A (2016). "Recent advances in amyotrophic lateral sclerosis". J Neurol. 263 (6): 1241–54. doi:10.1007/s00415-016-8091-6. PMC 4893385. PMID 27025851.CS1 maint: Multiple names: authors list (link) - ↑ Michelle EH, Mammen AL (2015). "Myositis Mimics". Curr Rheumatol Rep. 17 (10): 63. doi:10.1007/s11926-015-0541-0. PMID 26290112.	Paralysis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S. # Overview Paralysis is the complete loss of muscle function for one or more muscle groups. Paralysis often includes loss of feeling in the affected area. # Pathophysiology Paralysis is most often caused by damage to the nervous system or brain, especially the spinal cord. Partial paralysis can also occur in the REM stage of sleep. Paralysis may be localized, or generalized, or it may follow a certain pattern. For example, localized paralysis occurs in Bell's palsy where one side of the face may be paralyzed due to inflammation of the facial nerve on that side. Patients with stroke may be weak throughout their body (global paralysis) or have hemiplegia (weakness on one side of the body) or other patterns of paralysis depending on the area of damage in the brain. Other patterns of paralysis arise due to different lesions and their sequelae. For example, lower spinal cord damage from a severe back injury may result in paraplegia, while an injury higher up on the spinal cord, such as a neck injury, can cause quadriplegia. Patients with paraplegia or quadriplegia often use equipment such as a wheelchair or standing frame for mobility and to regain some independence. Most paralyses caused by nervous system damage are constant in nature; however, there are forms of periodic paralysis, including sleep paralysis, which are caused by other factors. # Causes ## Common Causes - Amyotrophic lateral sclerosis (ALS) - Botulism - Drugs Amikacin sulfate Iodixanol Pergolide - Amikacin sulfate - Iodixanol - Pergolide - Guillain-Barré syndrome - Multiple sclerosis - Poisons that interfere with nerve function, such as curare - Poliomyelitis - Spina bifida - Stroke - trauma ## Causes by Organ System ## Causes in Alphabetical Order - Acetylandromedol - Acute disseminated encephalomyelitis - Acute fulminant multiple sclerosis - Adrenal adenoma - Adrenal cancer - Adrenal cortex neoplasms - Adrenal gland hyperfunction - Adrenal incidentaloma - Adrenocortical carcinoma - Adrenoleukodystrophy - Alexander disease - Amikacin sulfate - Amnesic shellfish poisoning - Amyotrophic lateral sclerosis - Andromedotoxin - Apricot seed poisoning - Arachnoiditis - Arbovirosis - Arteriovenous malformation - Asphyxia - Ataxic cerebral palsy - Autoimmune diseases of the nervous system - Azinphos-methyl - Back tumor - Balo's concentric sclerosis - Bell's palsy - Benign astrocytoma - Bird cherry seed poisoning - Bitter almond seed poisoning - Blue-ringed octopus poisoning - Bog rosemary poisoning - Bottlebrush buckeye poisoning - Botulism - Brachial plexus injury - Broken neck - Bromide - Brown snake poisoning - Buckeye poisoning - Bush lily poisoning - Calcification of basal ganglia - California buckeye poisoning - California encephalitis - Canavan disease - Carbamate insecticide poisoning - Cerebral cavernous malformations - Cerebral palsy - Cerebral sarcoma - Cerebrotendinous xanthomatosis - Cerebrovascular accident - Chediak-higashi syndrome - Cherry seed poisoning - Chiari malformation - China tree poisoning - Chokecherry seed poisoning - Chronic inflammatory demyelinating polyneuropathy - Classical hodgkin disease - Clupeotoxism - Coastal leucothoe poisoning - Cobra poisoning - Compartment syndrome - Congenital defects - Conium maculatum - Conversion disorder - Corn lily poisoning - Curare - Cutaneomeningospinal angiomatosis - Cytisine - Decompression sickness - Delphinium poisoning - Desmoplastic cerebral astrocytoma of infancy - Desmoplastic infantile ganglioma - Dimethyl phthalate - Donepezil toxicity - Dysbarism - Dyskinetic cerebral palsy - Elapid poisoning - Electrical burns - Encephalitis - Encephalomyelitis - Enterovirus antenatal infection - Everlasting pea poisoning - Extradural hematoma - Familial infantile metachromatic leukodystrophy - Fetterbush poisoning - Flax poisoning - Flecainide - Flecatab - Florida leucothoe poisoning - Fowl paralyses - Fractures - Friedreich’s ataxia - Functioning pancreatic endocrine tumor - Fungal meningitis - Gm2-gangliosidosis - Golden chain tree poisoning - Grayanotoxin - Guillain-barre syndrome - Hemorrhagic stroke - Hendra virus - Hereditary peripheral nervous disorder - Hip cancer - Hodgkin's disease - Homocystinuria syndrome - Hydrocephalus - Hyperadrenalism - Hypokalemia - Insulinoma - Intercostal neuralgia - Intracranial hemorrhage - Iodixanol - Ischemic stroke - Japanese andromeda poisoning - Japanese encephalitis - Jessamine poisoning - Juvenile paget's disease - Krabbe disease - Leprosy - Leptomeningitis - Lobelia poisoning - Lobeline - Lyme disease - Lymphocyte depletion hodgkin's disease - Lymphocytic choriomeningitis - Malignant astrocytoma - Marburg multiple sclerosis - Mareck's disease - Marine toxins - Mayapple poisoning - Mercury poisoning - Mesothelioma - Metachromatic leukodystrophy - Metastatic insulinoma - Mixed cellularity hodgkin's disease - Monkshood poisoning - Monocrotophos - Motor neurone disease - Mountain andromeda poisoning - Mountain laurel poisoning - Movement disorders - Moyamoya syndrome - Multiple myeloma - Multiple sclerosis - Muscular dystrophy - Neuroblastoma - Neurofibromatosis - Neurosyphilis - Nicotiana tabacum - Nodular sclerosing hodgkin's lymphoma - Nyssen-van bogaert syndrome - Organophosphate insecticide poisoning - Paget's disease of bone - Pathological fracture - Peach seed poisoning - Pelizaeus-merzbacher disease - Pergolide - Peripheral neuritis - Pernettya poisoning - Persian violet poisoning - Poliomyelitis - Porphyria - Post-polio syndrome - Post-vaccinial encephalitis - Potassium deficiency - Primary hyperaldosteronism - Progressive multifocal leukoencephalopathy - Rabies - Rasmussen's encephalitis - Red buckeye poisoning - Refsum disease - Rhodotoxin - Rib tumor - Schistosomiasis japonica - Schistosomiasis mansoni - Sea wasp poisoning - Selected encephalitides - Sheep laurel poisoning - Simian b virus infection - Sleep - Spastic cerebral palsy - Spina bifida - Spinal cord injury - Spinal muscular atrophy - Spinal tumor - Staggerbush poisoning - Stroke - Subarachnoid hemorrhage - Subdural hematoma - Sweetshrub poisoning - Syphilis - Syringomyelia - Systemic lupus erythematosus - Tacrine toxicity - Tambocor - Tay sachs disease - Temodar - Temozolomide - Tetanus - Tetranortriterpene - Tetraodon poisoning - Thiram - Tick-borne encephalitis - Transverse myelitis - Trauma - Trumpet flower poisoning - Vanishing white matter leukodystrophy - Wild cherry seed poisoning - Zellweger syndrome # Differential diagnosis # Related Chapters - Spinal cord injury - Paraplegia - Quadriplegia - Muscle relaxant - Ptosis - Sleep paralysis - Hemiparesis - Beriberi - Neuroprosthetics - Brain-computer interface - Tonic immobility - Cerebral palsy Template:Cerebral palsy and other paralytic syndromes Template:Skin and subcutaneous tissue symptoms and signs Template:Nervous and musculoskeletal system symptoms and signs Template:Urinary system symptoms and signs Template:Cognition, perception, emotional state and behaviour symptoms and signs Template:Speech and voice symptoms and signs Template:General symptoms and signs Template:WikiDoc Sources - ↑ Talukder RK, Sutradhar SR, Rahman KM, Uddin MJ, Akhter H (2011). "Guillian-Barre syndrome". Mymensingh Med J. 20 (4): 748–56. PMID 22081202.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} - ↑ Merino-Ramírez MÁ, Bolton CF (2016). "Review of the Diagnostic Challenges of Lambert-Eaton Syndrome Revealed Through Three Case Reports". Can J Neurol Sci. 43 (5): 635–47. doi:10.1017/cjn.2016.268. PMID 27412406. - ↑ Gilhus NE (2016). "Myasthenia Gravis". N Engl J Med. 375 (26): 2570–2581. doi:10.1056/NEJMra1602678. PMID 28029925. - ↑ Ozono K (2016). "[Diagnostic criteria for vitamin D-deficient rickets and hypocalcemia-]". Clin Calcium. 26 (2): 215–22. doi:CliCa1602215222 Check \|doi= value (help). PMID 26813501. - ↑ Kamanyire R, Karalliedde L (2004). "Organophosphate toxicity and occupational exposure". Occup Med (Lond). 54 (2): 69–75. PMID 15020723. - ↑ Pecina CA (2012). "Tick paralysis". Semin Neurol. 32 (5): 531–2. doi:10.1055/s-0033-1334474. PMID 23677663. - ↑ Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A (2014). "Tetrodotoxin: chemistry, toxicity, source, distribution and detection". Toxins (Basel). 6 (2): 693–755. doi:10.3390/toxins6020693. PMC 3942760. PMID 24566728.CS1 maint: Multiple names: authors list (link) - ↑ Kuntzer T, Hirt L, Bogousslavsky J (1996). "[Neuromuscular involvement and cerebrovascular accidents]". Rev Med Suisse Romande. 116 (8): 605–9. PMID 8848683.CS1 maint: Multiple names: authors list (link) - ↑ Laffont I, Julia M, Tiffreau V, Yelnik A, Herisson C, Pelissier J (2010). "Aging and sequelae of poliomyelitis". Ann Phys Rehabil Med. 53 (1): 24–33. doi:10.1016/j.rehab.2009.10.002. PMID 19944665.CS1 maint: Multiple names: authors list (link) - ↑ West TW (2013). "Transverse myelitis--a review of the presentation, diagnosis, and initial management". Discov Med. 16 (88): 167–77. PMID 24099672. - ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430. - ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697. - ↑ Falzarano MS, Scotton C, Passarelli C, Ferlini A (2015). "Duchenne Muscular Dystrophy: From Diagnosis to Therapy". Molecules. 20 (10): 18168–84. doi:10.3390/molecules201018168. PMID 26457695.CS1 maint: Multiple names: authors list (link) - ↑ Filippi M, Preziosa P, Rocca MA (2016). "Multiple sclerosis". Handb Clin Neurol. 135: 399–423. doi:10.1016/B978-0-444-53485-9.00020-9. PMID 27432676.CS1 maint: Multiple names: authors list (link) - ↑ Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group". Arch Neurol. 51 (1): 61–6. PMID 8274111.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Riva N, Agosta F, Lunetta C, Filippi M, Quattrini A (2016). "Recent advances in amyotrophic lateral sclerosis". J Neurol. 263 (6): 1241–54. doi:10.1007/s00415-016-8091-6. PMC 4893385. PMID 27025851.CS1 maint: Multiple names: authors list (link) - ↑ Michelle EH, Mammen AL (2015). "Myositis Mimics". Curr Rheumatol Rep. 17 (10): 63. doi:10.1007/s11926-015-0541-0. PMID 26290112.	https://www.wikidoc.org/index.php/General_paralysis
0063f52948b54446b82ee26112a3c8e4b12013ce	wikidoc	Genistein	Genistein Genistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants, with soybeans and soy products like tofu and textured vegetable protein being the primary food source. Soy isoflavones are a group of compounds found in and isolated from the soybean. Besides functioning as antioxidants, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen. Soy isoflavones also produce non-hormonal effects. Isoflavones act as antioxidants to counteract damaging effects of free radicals in tissues. Isoflavones can act like estrogen in stimulating development and maintenance of female characteristics or they can block cells from using other forms of estrogen. Isoflavones also have been found to have antiangiogenic effects (blocking formation of new blood vessels), and may block the uncontrolled cell growth associated with cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival (growth factors). Studies show that groups of people who eat large amounts of soy-based products have lower incidences of breast, colon, endometrial, and prostate cancers than the general (US) population. Initial studies of soy isoflavone mixtures containing genistein, daidzein, and glycitein have found them safe for human use. Laboratory studies using animals models have shown that both soy and isoflavones can be protective against cancer when given during early life but can stimulate response to cancer-causing chemicals when given during fetal development or when circulating levels of estrogen are low (menopause). # Cancer link Some recent studies have raised the concern that genistein might potentially increase the risk of leukemia, because it can inhibit an enzyme (topoisomerase) that protects DNA from mutations. Some cancer patients whose chemotherapy drugs inhibited topoisomerase later developed leukemia. NCI researchers have completed animal studies on genistein with no adverse effects being seen. Clinical trials with people are in progress. # Molecular function Genistein influences several targets in living cells. One important function is the inhibition of several tyrosine kinases. Genistein also inhibits the mammalian hexose transporter GLUT1 and contraction of several types of smooth muscles. Genistein can bind to CFTR receptors. This binding causes the channel to become permanently open causing "free-flow" of chloride ions through the channel. de:Genistein	Genistein Genistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants, with soybeans and soy products like tofu and textured vegetable protein being the primary food source. Soy isoflavones are a group of compounds found in and isolated from the soybean. Besides functioning as antioxidants, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen. Soy isoflavones also produce non-hormonal effects. Isoflavones act as antioxidants to counteract damaging effects of free radicals in tissues. Isoflavones can act like estrogen in stimulating development and maintenance of female characteristics or they can block cells from using other forms of estrogen. Isoflavones also have been found to have antiangiogenic effects (blocking formation of new blood vessels), and may block the uncontrolled cell growth associated with cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival (growth factors). Studies show that groups of people who eat large amounts of soy-based products have lower incidences of breast, colon, endometrial, and prostate cancers than the general (US) population. Initial studies of soy isoflavone mixtures containing genistein, daidzein, and glycitein have found them safe for human use. Laboratory studies using animals models have shown that both soy and isoflavones can be protective against cancer when given during early life but can stimulate response to cancer-causing chemicals when given during fetal development or when circulating levels of estrogen are low (menopause). # Cancer link Some recent studies have raised the concern that genistein might potentially increase the risk of leukemia, because it can inhibit an enzyme (topoisomerase) that protects DNA from mutations[citation needed]. Some cancer patients whose chemotherapy drugs inhibited topoisomerase later developed leukemia. NCI researchers have completed animal studies on genistein with no adverse effects being seen. Clinical trials with people are in progress. # Molecular function Genistein influences several targets in living cells. One important function is the inhibition of several tyrosine kinases. Genistein also inhibits the mammalian hexose transporter GLUT1 and contraction of several types of smooth muscles. Genistein can bind to CFTR receptors. This binding causes the channel to become permanently open causing "free-flow" of chloride ions through the channel. [verification needed] Template:Verify credibility de:Genistein Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Genistein

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