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BosentanTRACLEER® [bosentan] 62.5 mg and 125 mg film-coated tablets
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´] monohydrate. Bosentan has a molecular weight of 569.64 and a molecular formula of C27H29N5O6S•H 2O. 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 light sensitive. 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 ETA and ETB receptors 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 ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. Pharmacokinetics General After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life (t1/2) 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. 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. 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. Special Populations It is not known whether bosentan’s pharmacokinetics is influenced by gender, body weight, race, or age. Liver Function Impairment In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure of bosentan. In a study comparing 8 patients with mild liver impairment (as indicated by the Child-Pugh method) to 8 controls, the single- and multiple -dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment. The influence of moderate or severe liver impairment on the pharmacokinetics of bosentan has not been evaluated. Bosentan should generally be avoided in patients with moderate or severe liver abnormalities and/or elevated aminotransferases > 3 x ULN (See DOSAGE AND ADMINISTRATION & WARNINGS). Renal Impairment In patients with severe renal impairment (creatinine clearance 15–30 ml/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to people with normal renal function. These differences do not appear to be clinically important (See DOSAGE AND ADMINISTRATION). Clinical Studies Pulmonary Arterial Hypertension Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg b.i.d. and 250 mg b.i.d.) of TRACLEER® with placebo. The smaller study (Study 351) compared 125 mg b.i.d. with placebo. Patients had severe (WHO functional Class III–IV) pulmonary arterial hypertension: primary pulmonary hypertension (72%) or pulmonary hypertension secondary to scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with pulmonary hypertension secondary to other conditions such as HIV disease, or recurrent pulmonary emboli. In both studies, TRACLEER® or placebo was added to could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. TRACLEER® was given at a dose of 62.5 mg b.i.d. for 4 weeks and then at 125 mg b.i.d. or 250 mg b.i.d. for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351. The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years. Submaximal Exercise Capacity Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 1.
In both trials, treatment with TRACLEER® resulted in a significant increase in exercise capacity. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg b.i.d.) and fully developed by about 2 months of treatment. It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg b.i.d., but the potential for increased liver injury causes this dose not to be recommended (See DOSAGE AND ADMINISTRATION). There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences. Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined bosentan (125 mg b.i.d. and 250 mg b.i.d.) groups. Values are expressed as mean ± standard error of the mean.
Symptoms and Functional Status Symptoms of pulmonary arterial hypertension were assessed by Borg dyspnea score, WHO functional class, and rate of "clinical worsening." Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in TRACLEER®-treated patients. There was a significant reduction in the rate of clinical worsening (Table 3).
Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (N=144 in the bosentan group and N=69 in the placebo group) participated in the first 16 weeks of the study. A subset of this population (N=35 in the bosentan group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks. Congestive Heart Failure (CHF) In a pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction <35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or TRACLEER® (62.5 mg bid titrated as tolerated to 125 mg bid) and followed for up to 70 weeks. Use of TRACLEER® was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first 4 to 8 weeks after bosentan was initiated. Based on these results, bosentan is not effective in the treatment of congestive heart failure with left ventricular dysfunction. TRACLEER® is indicated for the treatment of pulmonary arterial hypertension in patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening (see CLINICAL PHARMACOLOGY: Clinical Studies). 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. Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Abnormalities
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 ³ 2 x ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER® in these circumstances. 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 or implantable contraceptives (see DRUG INTERACTIONS: Hormonal contraceptives, Including Oral, Injectable and 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 taking TRACLEER®. Dosage Adjustment in Renally Impaired Patients The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment. 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. 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 (Cmax and 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 TRACLEERÒ has not been evaluated. There are no specific data to guide dosing in hepatically impaired patients (See WARNINGS); caution should be exercised in patients with mildly impaired liver function. TRACLEERÒ should generally be avoided in patients with moderate or severe liver impairment. Dosage Adjustment in Children Safety and efficacy in pediatric patients have not been established. 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. 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. 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. STORAGE Store at 20ºC – 25ºC (68ºF – 77ºF). Excursions are permitted between 15°C and
30°C (59°F and 86°F). [See USP Controlled Room Temperature].
*Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. 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 3% of bosentan-treated patients, the only ones that occurred more frequently on bosentan than on placebo (³ 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%). 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®. Laboratory Abnormalities Increased Liver Aminotransferases (see BOX WARNING and WARNINGS). Decreased Hemoglobin and Hematocrit (see PRECAUTIONS) Long-term Treatment The long term follow-up of the patients who were treated with TRACLEER® in the two pivotal studies and their open-label extensions (N=235) shows that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment with TRACLEER®. These estimates may be influenced by the presence of epoprostenol treatment, which was administered to 43/235 patients. Without a control group, these data must be interpreted cautiously and cannot be interpreted as an improvement in survival. Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole). Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently, plasma concentrations of drugs metabolized by these two isoenzymes will be decreased when TRACLEER® is co-administered. Bosentan had no relevant inhibitory effect on any CYP isoenzymes tested (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Consequently, TRACLEER® is not expected to increase the plasma concentrations of drugs metabolized by these enzymes. Hormonal Contraceptives, Including Oral, Injectable, and Implantable Contraceptives: Specific interaction studies have not been performed to evaluate the effect of co-administration of bosentan and hormonal contraceptives, including oral, injectable or implantable contraceptives. Since many of these drugs are metabolized by CYP3A4, there is a possibility of failure of contraception when TRACLEER® is co-administered. Women should not rely on hormonal contraception alone when taking TRACLEER®. Specific interaction studies have demonstrated the following: Cyclosporine A: During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. The concomitant administration of bosentan and cyclosporine A is contraindicated (see CONTRAINDICATIONS). Co-administration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A4 substrate) by approximately 50%. Tacrolimus: Co-administration of tacrolimus and bosentan has not been studied in man. Co-administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and bosentan are used together. Glyburide: An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of TRACLEER® and glyburide is contraindicated, and alternative hypoglycemic agents should be considered (see CONTRAINDICATIONS). Co-administration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Bosentan is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A4. The possibility of worsened glucose control in patients using these agents should be considered. Ketoconazole: Co-administration of bosentan 125 mg b.i.d. and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold. No dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered. Simvastatin and Other Statins: Co-administration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A4 substrate), and its active ß-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Bosentan is also expected to reduce plasma concentrations of other statins that have significant metabolism by CYP3A4, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A4 metabolized statins should have cholesterol levels monitored after TRACLEER® is initiated to see whether the statin dose needs adjustment. Warfarin: Co-administration of bosentan 500 mg b.i.d. for 6 days decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients. Digoxin, Nimodipine and Losartan: Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan. Potential Liver Injury (see BOX WARNING) Elevations in ALT or AST by more than 3 x ULN were observed in 11% of bosentan-treated patients (N = 658) compared to 2% of placebo-treated patients (N = 280). Threefold increases were seen in 12% of 95 PAH patients on 125 mg b.i.d. and 14% of 70 PAH patients on 250 mg b.i.d. Eight-fold increases were seen in 2% of PAH patients on 125 mg b.i.d. and 7% of PAH patients on 250 mg b.i.d. Bilirubin increases to ³ 3 x ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. The combination of hepatocellular injury (increases in aminotransferases of > 3 x ULN) and increases in total bilirubin (³ 3 x ULN) is a marker for potential serious liver injury.1 Elevations of AST and/or ALT associated with bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and to date have been reversible after treatment interruption or cessation. These aminotransferase elevations may reverse spontaneously while continuing treatment with TRACLEER®. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated (see DOSAGE AND ADMINISTRATION). 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 ³ 2 x ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER® in these circumstances. Pre-existing Liver Impairment Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. TRACLEER® should generally be avoided in patients with moderate or severe liver impairment (see Clinical Pharmacology and DOSAGE AND ADMINISTRATION). In addition, TRACLEER® should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) because monitoring liver injury in these patients may be more difficult (see BOX WARNING). Hematologic Changes Treatment with TRACLEER® caused a dose-related decrease in hemoglobin and hematocrit. Hemoglobin levels should be monitored after 1 and 3 months of treatment and then every 3 months. The overall mean decrease in hemoglobin concentration for bosentan-treated patients was 0.9 g/dl (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan treatment and hemoglobin levels stabilized by 4–12 weeks of bosentan treatment. In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dl) were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. In patients with pulmonary arterial hypertension treated with doses of 125 and 250 mg b.i.d., marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 1 g/dl was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dl, the decrease occurred during the first 6 weeks of bosentan treatment. During the course of treatment the hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment. Fluid retention In a placebo controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks of treatment with TRACLEER®. In addition, there have been numerous post-marketing reports of fluid retention in patients with pulmonary hypertension, occurring, within weeks after starting TRACLEER®. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure (see CLINICAL PHARMACOLOGY: Clinical Studies; Congestive Heart Failure). INFORMATION FOR PATIENTS Patients are advised to consult the TRACLEER® Medication Guide on the safe use of TRACLEER®. The physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases and urine or serum pregnancy testing and of avoidance of pregnancy. The physician should discuss options for effective contraception and measures to prevent pregnancy with their female patients. Input from a gynecologist or similar expert on adequate contraception should be sought as needed. Carcinogenesis, Mutagenesis, Impairment of Fertility
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