TRACLEER (Tablet, Film Coated)
General: TRACLEER' treatment should be initiated at a dose of 62.5 mg b.i.d. for 4 weeks and then increased to the maintenance dose of 125 mg b.i.d. Doses above 125 mg b.i.d. did not appear to confer additional benefit sufficient to offset the increased risk of liver injury. Tablets should be administered morning and evening with or without food. If TRACLEER' is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin���2��ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER' in these circumstances.<br/>Use in Women of Child-bearing Potential: TRACLEER' treatment should only be initiated in women of child-bearing potential following a negative pregnancy test and only in those who practice adequate contraception that does not rely solely upon hormonal contraceptives, including oral, injectable, transdermal, or implantable contraceptives . Input from a gynecologist or similar expert on adequate contraception should be sought as needed. Urine or serum pregnancy tests should be obtained monthly in women of childbearing potential takingTRACLEER'.<br/>Dosage Adjustment in Renally Impaired Patients: The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment.<br/>Dosage Adjustment in Geriatric Patients: Clinical studies of TRACLEER' did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between elderly and younger patients. In general, caution should be exercised in dose selection for elderly patients given the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group.<br/>Dosage Adjustment in Hepatically Impaired Patients: Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (Cand AUC) of bosentan. Mild liver impairment was shown not to impact the pharmacokinetics of bosentan. The influence of moderate or severe liver impairment on the pharmacokinetics of TRACLEER' has not been evaluated. There are no specific data to guide dosing in hepatically impaired patients ; caution should be exercised in patients with mildly impaired liver function. TRACLEER' should generally be avoided in patients with moderate or severe liver impairment.<br/>Dosage Adjustment in Children: Safety and efficacy in pediatric patients have not been established.<br/>Dosage Adjustment in Patients with Low Body Weight: In patients with a body weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg b.i.d.<br/>Discontinuation of Treatment: There is limited experience with abrupt discontinuation of TRACLEER'. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg b.i.d. for 3 to 7 days) should be considered.
Bosentan is the first of a new drug class, an endothelin receptor antagonist. TRACLEER' (bosentan) belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula: Bosentan has a molecular weight of 569.64 and a molecular formula of CHNOS���HO. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not lightsensitive. TRACLEER' is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each TRACLEER' 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each TRACLEER' 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan.
Mechanism of Action: Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETand ETreceptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ETand ET. Bosentan has a slightly higher affinity for ETreceptors than for ETreceptors.<br/>Pharmacokinetics:<br/>General: After oral administration, maximum plasma concentrations of bosentan are attained within 3���5 hours and the terminal elimination half-life (t) is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about 2-fold greater in adult patients with pulmonary arterial hypertension than in healthy adult subjects.<br/>Absorption and Distribution: The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food. The volume of distribution is about 18 L. Bosentan is highly bound (>98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.<br/>Metabolism and Elimination: Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10%���20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19. Total clearance after a single intravenous dose is about 4 L/hr in patients with pulmonary arterial hypertension. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine.<br/>Special Populations: It is not known whether bosentan's pharmacokinetics is influenced by gender, body weight, race, or age.<br/>Clinical Studies:
See BOX WARNING for CONTRAINDICATION to use in pregnancy.<br/>Pregnancy Category X: TRACLEER' is expected to cause fetal harm if administered to pregnant women. Bosentan was teratogenic in rats given oral doses���60 mg/kg/day (twice the maximum recommended human oral dose of 125 mg, b.i.d., on a mg/ mbasis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day (2 and 10 times, respectively, the maximum recommended human dose on a mg/mbasis). Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no data on the use of TRACLEER' in pregnant women. Pregnancy must be excluded before the start of treatment with TRACLEER' and prevented thereafter by use of reliable contraception. It has been demonstrated that hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives may not be reliable in the presence of TRACLEER' and should not be used as the sole contraceptive method in patients receiving TRACLEER' (see Drug Interactions: Hormonal Contraceptives, Including Oral, Injectable, Transdermal and Implantable Contraceptives). Input from a gynecologist or similar expert on adequate contraception should be sought as needed. TRACLEER' should be started only in patients known not to be pregnant. For female patients of childbearing potential, a prescription for TRACLEER' should not be issued by the prescriber unless the patient assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse. Follow-up urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking TRACLEER'. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician and patient must discuss the risk to the pregnancy and to the fetus.<br/>Cyclosporine A: Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER' and cyclosporine A is contraindicated.<br/>Glyburide: An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and TRACLEER' is contraindicated.<br/>Hypersensitivity: TRACLEER' is also contraindicated in patients who are hypersensitive to bosentan or any component of the medication.
62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking "62,5", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap. NDC 66215-101-06: Bottle containing 60 tablets. 125 mg film-coated, oval, biconvex, orange-white tablets, embossed with identification marking "125", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap. NDC 66215-102-06: Bottle containing 60 tablets. Rx only.<br/>STORAGE: Store at 20��C���25��C (68��F���77��F). Excursions are permitted between 15��C and 30��C (59��F and 86��F). [See USP Controlled Room Temperature].
Use of TRACLEER' requires attention to two significant concerns: 1) potential for serious liver injury, and 2) potential damage to a fetus.<br/>WARNING: Potential liver injury: TRACLEER' causes at least 3-fold (upper limit of normal; ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious liver injury, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly . In the post-marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy with TRACLEER' in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of TRACLEER' in these cases could not be excluded. In at least one case the initial presentation (after>20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of TRACLEER'. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping TRACLEER' with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction. . Elevations in aminotransferases require close attention . TRACLEER' should generally be avoided in patients with elevated aminotransferases (>3��ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin���2��ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER' in these circumstances.<br/>CONTRAINDICATION: Pregnancy: TRACLEER' (bosentan) is very likely to produce major birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals . Therefore, pregnancy must be excluded before the start of treatment with TRACLEER' and prevented thereafter by the use of a reliable method of contraception. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving TRACLEER' (see Precautions: Drug Interactions). Therefore, effective contraception through additional forms of contraception must be practiced. Monthly pregnancy tests should be obtained. Because of potential liver injury and in an effort to make the chance of fetal exposure to TRACLEER' (bosentan) as small as possible, TRACLEER' may be prescribed only through the TRACLEER' Access Program by calling 1 866 228 3546. Adverse events can also be reported directly via this number.
dailymed-ingredient:corn_starch, dailymed-ingredient:ethylcellulose, dailymed-ingredient:glyceryl_behenate, dailymed-ingredient:hydroxypropylmethylcellulose, dailymed-ingredient:iron_oxide_red, dailymed-ingredient:iron_oxide_yellow, dailymed-ingredient:magnesium_stearate, dailymed-ingredient:povidone, dailymed-ingredient:pregelatinized_starch, dailymed-ingredient:sodium_starch_glycolate, dailymed-ingredient:talc, dailymed-ingredient:titanium_dioxide, dailymed-ingredient:triacetin
Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.
TRACLEER (Tablet, Film Coated)
Adverse Events: See BOX WARNING for discussion of liver injury and PRECAUTIONS for discussion of hemoglobin and hematocrit abnormalities. Safety data on bosentan were obtained from 12 clinical studies (8 placebo-controlled and 4 open-label) in 777 patients with pulmonary arterial hypertension, and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg b.i.d.) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (N=89 for 1 year; N=61 for 1.5 years and N=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (N=235) to bosentan ranged from 1 day to 1.7 years (N=126 more than 6 months and N=28 more than 12 months). Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension were more frequent on bosentan (5%; 8/165 patients) than on placebo (3%; 2/80 patients). In this database the only cause of discontinuations>1%, and occurring more often on bosentan was abnormal liver function. The adverse drug reactions that occurred in���3% of the bosentan-treated patients and were more common on bosentan in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg b.i.d. are shown in Table 4: In placebo-controlled studies of bosentan in pulmonary arterial hypertension and for other diseases (primarily chronic heart failure), a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients were treated with placebo. The duration of treatment ranged from 4 weeks to 6 months. For the adverse drug reactions that occurred in���3% of bosentan-treated patients, the only ones that occurred more frequently on bosentan than on placebo (���2% difference) were headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function (6% vs. 2%), leg edema (5% vs. 1%), and anemia (3% vs. 1%).<br/>Post-Marketing Experience: Hypersensitivity, Rash, Thrombocytopenia. There have been several post-marketing reports of angioneurotic edema associated with the use of bosentan. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing TRACLEER'. In the post-marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy with TRACLEER' in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of TRACLEER' in these cases could not be excluded .<br/>Laboratory Abnormalities: Increased Liver Aminotransferases . Decreased Hemoglobin and Hematocrit
TRACLEER' is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening (see Clinical Studies).