Tracleer Drug Information

TRACLEER is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%). in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.

Required Monitoring

Healthcare professionals who prescribe TRACLEER must enroll in the Bosentan REMS and must comply with the required monitoring to minimize the risks associated with TRACLEER. Measure liver aminotransferase levels prior to initiation of treatment and then monthly. Exclude pregnancy before initiating treatment with TRACLEER in females of reproductive potential.

Recommended Dosage Administer

TRACLEER orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity. Table 1: Dosing Recommendations

Administration

TRACLEER film-coated tablets and tablets for oral suspension (dispersible tablets) should be administered orally twice daily. Disperse tablets for oral suspension, or dispersible tablet half, in a minimal amount of water immediately before administration. 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 bilirubin ≥2 × Upper Limit of Normal (ULN).

There is no experience with the reintroduction of TRACLEER in these circumstances. Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3×ULN

Use with Ritonavir Co-administration of TRACLEER in Patients on Ritonavir In patients who have been receiving ritonavir for at least 10 days, start TRACLEER at the recommended initial dose once daily or every other day based upon individual tolerability. Co-administration of Ritonavir in Patients on TRACLEER Discontinue use of TRACLEER at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume TRACLEER at the recommended initial dose once daily or every other day based upon individual tolerability.

Use in Patients with Pre-existing Hepatic Impairment

Avoid initiation of TRACLEER in patients with aminotransferases >3 × ULN. No dose adjustment is required in patients with mildly impaired liver function.

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. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with PAH were more frequent on TRACLEER (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 TRACLEER was abnormal liver function. The adverse drug events that occurred in ≥3% of the TRACLEER-treated patients and were more common on TRACLEER in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3: Table 3: Adverse Events 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.

Occurring in ≥3% of Patients Treated with TRACLEER 125-250 mg Twice Daily and More Common on TRACLEER in Placebo-Controlled Studies in Pulmonary Arterial Hypertension - - TRACLEER was evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled.

Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. 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 2 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. Decreases in Hemoglobin and Hematocrit 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 adult 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. 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. In a pooled analysis of pediatric patients (N=100) with PAH treated with TRACLEER, a decrease in hemoglobin levels to <10 g/dL from baseline was reported in 11% of patients.

There was no decrease to <8 g/dL.

Postmarketing Experience There have been several postmarketing reports of angioedema associated with the use of TRACLEER. 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 Liver failure Hypersensitivity, DRESS, and anaphylaxis Thrombocytopenia Rash Jaundice Anemia requiring transfusion Neutropenia and leukopenia Nasal congestion Autoimmune hepatitis

Cytochrome P450 Drug Interactions Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan. 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.

Co-administration 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 co-administered.

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. Figure 1.

CYP3A induction-mediated effect of bosentan on other drugs Figure 2. Effect of other drugs on bosentan Figure 1 Figure 2

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.

Pregnancy Risk Summary Based on data from animal reproduction studies, TRACLEER may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy. Available data from postmarketing reports and published literature over decades of use with endothelin receptor antagonists (ERA) in the same class as TRACLEER have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data.

These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on a mg/m 2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data Animal Data Bosentan was teratogenic in rats given oral doses two times the MRHD (on a mg/m 2 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/m 2 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 embryo-fetal toxicity is a class effect of these drugs.

Pediatric Use The efficacy of TRACLEER in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with TRACLEER. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with TRACLEER. Safety in pediatric patients is supported by data from 100 pediatric patients treated with TRACLEER for a median of 17 months.

Juvenile Animal Toxicity Data In a juvenile rat toxicity study, rats were treated from Day 4 postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen.

No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, 7 times the therapeutic exposure in children with PAH.

Pregnancy Use of TRACLEER is contraindicated in females who are pregnant.

Use with 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.

Use with 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.

Hypersensitivity TRACLEER is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema.

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 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. In the postmarketing period, there was one reported overdose of 10,000 mg of TRACLEER taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision.

He recovered within 24 hours with blood pressure support. Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.