Tracleer

Tracleer

bosentan

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Bosentan.
Description
Each Tracleer 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan.
Tracleer is the proprietary name for bosentan, an endothelin receptor antagonist that 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.
Bosentan has a molecular weight of 569.64 and a molecular formula of C27H29N5O6S·H2O. 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 125 mg film-coated tablets for oral administration.
Excipients/Inactive Ingredients: 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.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: 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. The clinical impact of dual endothelin blockage is unknown.
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.
Clinical Studies: Pulmonary Arterial Hypertension: WHO Functional Class III-IV: 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 twice daily and 250 mg twice daily) of Tracleer with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (WHO functional Class III-IV) pulmonary arterial hypertension: idiopathic or heritable pulmonary arterial hypertension (72%) or pulmonary arterial hypertension associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with pulmonary arterial hypertension associated with other conditions such as HIV disease or recurrent pulmonary emboli.
In both studies, Tracleer or placebo was added to patients' current therapy, which 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 twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily 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 Ability: Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 1. (See Table 1.)

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In both trials, treatment with Tracleer resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 1). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, twice daily but the potential for increased liver injury causes this dose not to be recommended (See DOSAGE & 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. (See Figure 1.)

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Haemodynamic Changes: Invasive hemodynamic parameters were assessed in Study 351. Treatment with Tracleer led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 2).
The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown. (See Table 2.)

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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 and Figure 2). Figure 2 shows the log-rank test reflecting clinical worsening over 28 weeks. (See Table 3 and Figure 2.)

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WHO Functional Class II: In a randomized, double-blind, multicenter, placebo-controlled trial, 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received Tracleer 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or placebo (n = 92) for 6 months. Enrolled patients were treatment-naÏve (n = 156) or on a stable dose of sildenafil (n = 29). The coprimary endpoints were change from baseline to month 6 in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO functional class and hemodynamics were assessed as secondary endpoints.
Compared with placebo, Tracleer treatment was associated with a reduced incidence of worsening of at least one functional class (3% Tracleer vs. 13% placebo, p = 0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO2; p < 0.05). The + 19 m mean (+14 m median) increase in 6-minute walk distance with Tracleer vs. placebo was not significant (p = 0.08). There was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with Tracleer compared with placebo (hazard ratio 0.2, p = 0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline.
Long-term Treatment of PAH: Long-term follow-up of patients with Class III and IV PAH who were treated with Tracleer in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment.
These uncontrolled observations do not allow comparison with a group not given Tracleer and cannot be used to determine the long-term effect of Tracleer on mortality.
Pulmonary Arterial Hypertension related to Congenital Heart Disease with Left-to-Right Shunts: A small study (N=54) and its open label extension (N=37) of up to 40 weeks with patients with Eisenmenger physiology demonstrated effects of Tracleer on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).
Lack of Benefit in Congestive Heart Failure: Tracleer is not effective in the treatment of congestive heart failure with left ventricular dysfunction. 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 twice daily titrated as tolerated to 125 mg twice daily) 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 Tracleer was initiated. 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. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
Pharmacokinetics: General: After oral administration, maximum plasma concentrations of bosentan are attained within 3-5 hours and the terminal elimination half-life (t½) 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 CYP3A 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, 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 (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan was not altered in patients with mild hepatic impairment.
In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and pulmonary arterial hypertension associated with portal hypertension than in 3 patients with normal liver function and pulmonary arterial hypertension of other etiologies.
The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child-Pugh Class C) (see CONTRAINDICATIONS).
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 & ADMINISTRATION).
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg twice daily., on a mg/m2 basis). In the same study, doses greater than 2,000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan.
Reproductive and Developmental Toxicology: Bosentan was teratogenic in rats given oral doses ≥60 mg/kg/day. 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. 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.
Impairment of Fertility/Testicular Function: The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.
Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).
Indications/Uses
Treatment of pulmonary arterial hypertension (PAH) in patients with WHO Class II-IV.
Considerations for use: Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in WHO Class II patients, which may preclude future use as their disease progresses.
Dosage/Direction for Use
General: TRACLEER treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily. 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.
In the case of clinical deterioration (e.g., decrease in 6-minute walk test distance by at least 10% compared with pre-treatment measurement) despite Tracleer treatment for at least 8 weeks (target dose for at least 4 weeks), alternative therapies should be considered. However, some patients who show no response after 8 weeks of treatment with Tracleer may respond favourably after an additional 4 to 8 weeks of treatment. In the case of alte clinical deterioration despite treatment with Tracleer (i.e. after several months of treatment), the treatment should be re-assessed. Some patients not responding well to 125mg twice daily of Tracleer may slightly improve their exercise capacity when the dose is increased to 250mg twice daily. A careful benefit/risk assessment should be made, taking into consideration that the liver toxicity is dose dependent.
Required Monitoring: 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.
Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Abnormalities: The table as follows summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations >3 X ULN during therapy with Tracleer. 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 x ULN, treatment with Tracleer should be stopped. There is no experience with the re-introduction of Tracleer in these circumstances. (See Table 4.)

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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 as previously mentioned.
Use in Women of Child-bearing Potential: Initiate treatment in females of child-bearing potential only after a negative pregnancy test and only in females who are using two reliable methods of contraception. Females who have had a tubal sterilization or a Copper T 380A IUD or LNg 20 IUS inserted do not require other forms of contraception. Effective contraception must be practiced throughout treatment and for one month after stopping Tracleer. Females should seek contraceptive advice as needed from a gynecologist or similar expert. Urine or serum pregnancy tests should be obtained monthly in females 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.
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 TRACLEER 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. TRACLEER should generally be avoided in patients with moderate or severe liver impairment.
Dosage Adjustment in Children: Safety and efficacy in paediatric 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 twice daily. There is limited information about the safety and efficacy of Tracleer in children between the ages of 12 and 18 years.
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 twice daily for 3 to 7 days) should be considered.
Overdosage
Bosentan has been given as a single dose of up to 2,400 mg in normal volunteers, or up to 2,000 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 1,000 mg twice daily 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.
Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. In the post-marketing period there was one reported overdose of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating and blurred vision. He recovered completely within 24 hours with blood pressure support. Note: dialysis is not possible with bosentan overdose.
Contraindications
See WARNINGS for CONTRAINDICATION to use in pregnancy.
Pregnancy Category X: Use of Tracleer is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of childbearing potential must use two reliable forms of contraception during treatment and for one month after stopping Tracleer. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
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. (see INTERACTIONS.)
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. (see INTERACTIONS.)
Hypersensitivity: TRACLEER is also contraindicated in patients who are hypersensitive to bosentan or any component of the medication. Observed reactions include rash and angioedema. (see INTERACTIONS.)
The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. Tracleer should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan was not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) (see Pharmacology: PHARMACOKINETICS under Actions).
Warnings
Potential liver injury: In clinical trials 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 (see Potential Liver Injury as follows and DOSAGE & ADMINISTRATION). 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 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. (see DOSAGE & ADMINISTRATION).
Elevations in aminotransferases require close attention (see DOSAGE & ADMINISTRATION). Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 x 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 x ULN, treatment with Tracleer should be stopped. There is no experience with the re-introduction of Tracleer in these circumstances.
Teratogenicity: Tracleer is likely to cause major birth defects if used by pregnant females based on animal data. Therefore, pregnancy must be excluded before the start of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of childbearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. 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. Obtain monthly pregnancy tests.
Potential Liver Injury (see WARNING as previously mentioned):
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). Three-fold increases were seen in 12% of 95 PAH patients on 125 mg twice daily. and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily. and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥ 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 x ULN) is a marker for potential serious liver injury.
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, usually have been reversible after treatment interruption or cessation. Aminotransferase elevations may reverse spontaneously while continuing treatment with TRACLEER.
Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN.
Patients with Pre-existing Liver Impairment: Tracleer is not recommended in patients with moderate or severe liver impairment. In addition, initiation of Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult (see Warning as previously mentioned and DOSAGE & ADMINISTRATION).
Special Precautions
Haematologic Changes: Treatment with Tracleer can cause a dose-related decrease in hemoglobin and hematocrit. 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.
The overall mean decrease in hemoglobin concentration for Tracleer-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 Tracleer treatment and hemoglobin levels stabilized by 4-12 weeks of Tracleer treatment. In placebo-controlled studies of all uses of Tracleer, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of Tracleer-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, 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 Tracleer-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 Tracleer treatment.
During the course of treatment the hemoglobin concentration remained within normal limits in 68% of Tracleer-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.
Fluid Retention: Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of Tracleer and other endothelin receptor antagonists. In PAH clinical trials with Tracleer, combined adverse events of fluid retention or edema were reported in 1.7 percent (placebo-corrected) of patients.
In addition, there have been numerous postmarketing 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.
If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as Tracleer or underlying heart failure, and the possible need for treatment or discontinuation of Tracleer therapy.
Pulmonary Veno-Occlusive Disease (PVOD): Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether Tracleer should be discontinued.
Decreased Sperm Counts: Study AC-052-402 evaluated the effect on testicular function of TRACLEER 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily. for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled; 23 completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with Tracleer. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. TRACLEER was discontinued and after two months the sperm count had returned to baseline levels.
Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Tracleer have an adverse effect on spermatogenesis.
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 gynaecologist or similar expert on adequate contraception should be sought as needed.
Use In Pregnancy & Lactation
Pregnancy, Teratogenic Effects: Category X (See CONTRAINDICATIONS).
Use of Tracleer is contraindicated in females who are or may become pregnant. While there are no adequate and well controlled studies in pregnant females, animal studies show that Tracleer is likely to cause major birth defects when administered during pregnancy. Bosentan caused teratogenic effects in animals including malformations of the head, mouth, face, and large blood vessels. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Females of childbearing potential should have a negative pregnancy test before starting treatment with Tracleer. The prescriber should not dispense a prescription for Tracleer without documenting a negative 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 females of childbearing potential taking Tracleer. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus.
Drug interaction studies show that Tracleer reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using Tracleer and should not be used as a patient's only contraceptive method. (See INTERACTIONS.) Females of childbearing potential using Tracleer must use two reliable forms of contraception unless she has a tubal sterilization or has a Copper T 380A IUD or LNg 20 IUS. In these cases, no additional contraception is needed. Contraception should be continued until one month after completing Tracleer therapy. Females of childbearing potential using Tracleer should seek contraception counseling from a gynecologist or other expert as needed.
Bosentan was teratogenic in rats given oral doses two times the maximum recommended human dose [MRHD] (on a mg/m2 basis). 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 2 and 10 times the MRHD (on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, 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 (See Pharmacology: Toxicology: Preclinical safety data under Actions).
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Tracleer, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Adverse Events: See WARNINGS for discussion of liver injury and PRECAUTIONS for discussion of haemoglobin and haematocrit abnormalities.
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 data on bosentan were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 patients with pulmonary arterial hypertension and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily.) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (N=94 for 1 year; N=61 for 1.5 years and N=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (N=328) to bosentan ranged from 1 day to 1.7 years (N=174 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 (6 %; 15/258 patients) than on placebo (3%; 5/172 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 twice daily are shown in Table 5: See Table 5.

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Post-Marketing Experience: There have been several post-marketing reports of angioneurotic oedema 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.
The following additional adverse reactions have been reported during the post approval use of TRACLEER. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to TRACLEER exposure: Unexplained hepatic cirrhosis (see Warnings), Liver failure (see Warnings), Hypersensitivity (see Contraindications), Thrombocytopenia, Rash, Jaundice, Anemia requiring transfusion, Neutropenia and leukopenia, Nasal congestion.
Laboratory Abnormalities: Increased Liver Aminotransferases (see WARNINGS).
Decreased Haemoglobin and Haematocrit (see PRECAUTIONS).
Drug Interactions
Cytochrome P450 Summary: Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan (see Ketoconazole as follows). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with Tracleer will likely lead to large increases in plasma concentrations of bosentan. Coadministration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with Tracleer is not recommended.
Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when Tracleer is coadministered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, Tracleer is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.
Hormonal Contraceptives: Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Tracleer is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Tracleer.
An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.
Specific interaction studies have demonstrated the following: Cyclosporine A: The concomitant administration of bosentan and cyclosporine A is contraindicated. During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. 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%.
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 twice daily and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. No dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered.
Lopinavir+Ritonavir (and other boosted protease inhibitors): Co-administration of Tracleer 125 mg twice daily and lopinavir+ritonavir 400+100mg twice daily during 9.5 days in healthy volunteers, resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher than those measured after Tracleer administered alone. On day 9, plasma concentrations of bosentan were approximately 5-fold higher than with Tracleer administered alone. Inhibition by ritonavir of transport protein mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of bosentan, most likely causes this interaction. When administered concomitantly with lopinavir+ritonavir or other ritonavir-boosted protease inhibitors, the patient's tolerability of Tracleer should be monitored.
After co-administration of Tracleer for 9.5 days, the plasma exposures to lopinavir and ritonavir decreased to a clinically non significant extent (by approximately 14% and 17%, respectively). However, full induction by bosentan might not have been reached and further decrease of protease inhibitors cannot be excluded. Appropriate monitoring of the HIV therapy is recommended. Similar effects would be expected with other ritonavir-boosted protease inhibitors.
Simvastatin and Other Statins: Co-administration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A4 substrate), and its active β-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 twice daily for 6 days in normal volunteers 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.
Sildenafil: In normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg t.i.d. sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. A dose adjustment of neither drug is necessary. This recommendation holds true when sildenafil is used for the treatment of pulmonary arterial hypertension or erectile dysfunction.
Tacrolimus: Coadministration of tacrolimus and bosentan has not been studied in humans. Coadministration 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.
Rifampicin: Coadministration of bosentan and rifampicin in normal volunteers resulted in a mean 6-fold increase in bosentan trough levels after the first concomitant dose (likely due to inhibition of OATP by rifampin), but about a 60% decrease in bosentan levels at steady state. The effect of bosentan on rifampicin levels has not been assessed. When consideration of the potential benefits and known and unknown risks leads to concomitant use, measure LFTs weekly for the first 4 weeks before reverting to normal monitoring.
Iloprost: In a small, randomized, double-blind, placebo-controlled study, 34 patients treated with bosentan 125 mg twice daily for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6.
Storage
Store below 30°C.
Shelf-Life: 60 MONTHS.
ATC Classification
C02KX01 - bosentan ; Belongs to the class of other antihypertensives. Used in the treatment of pulmonary arterial hypertension.
Presentation/Packing
FC tab 125 mg (oval, biconvex, orange-white, embossed with identification marking "125") x 60's.
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