2.1 Required Monitoring

Healthcare professionals who prescribe TRACLEER must enroll in the Bosentan REMS Program and must comply with the required monitoring to minimize the risks associated with TRACLEER [see Warnings and Precautions (5.3)] .

Obtain a pregnancy test in females of reproductive potential prior to TRACLEER treatment, monthly during treatment and one month after stopping TRACLEER. Initiate treatment with TRACLEER in females of reproductive potential only after a negative pregnancy test [see Boxed Warning, Contraindications (4.1), Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)] .

Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Warnings and Precautions (5.1)] .

2.2 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.

2.3 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.

Store divided dispersible tablet pieces at 20ºC to 25ºC (68ºF to 77ºF) in the opened blister for up to 7 days.

2.4 Dosage Adjustments for Aminotransferase Elevations

If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2.

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.

2.5 Use with Ritonavir

2.6 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 [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .

4.1 Pregnancy

Use of TRACLEER is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2), Use in Specific Populations (8.1)] .

4.2 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 [see Cytochrome P450 Drug Interactions (7.1)] .

4.3 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 [see Cytochrome P450 Drug Interactions (7.1)] .

4.4 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 [see Adverse Reactions (6.2), Description (11)] .

5.1 Hepatotoxicity

ALT or AST >3 ×ULN were observed in 11% of TRACLEER-treated patients (n=658) compared to 2% of placebo-treated patients (n=280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (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 ×ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with TRACLEER. In a pooled analysis of four pediatric studies conducted in PAH (n =100), elevations in liver aminotransferases ≥3×ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3 ×ULN) and increases in total bilirubin (≥2 ×ULN) is a marker for potential serious hepatotoxicity.

Elevations of AST or ALT associated with TRACLEER 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 also 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 [see Dosage and Administration (2.1, 2.4)] . 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 ×ULN.

Avoid initiation of TRACLEER in patients with elevated aminotransferases (>3 ×ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning, Dosage and Administration (2.6), Use in Specific Populations (8.6)] .

In WHO Functional Class II patients, consider whether the benefits of TRACLEER are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses.

5.2 Embryo-fetal Toxicity

Based on data from animal reproduction studies, TRACLEER may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test prior to TRACLEER treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with TRACLEER and for at least one month after the last dose [see Dosage and Administration (2), Use in Specific Populations (8.1, 8.3)] .

TRACLEER is only available for females through a restricted program under REMS [see Warnings and Precautions (5.3)] .

5.3 Prescribing and Distribution Program for Bosentan

Because of the risks of hepatotoxicity and birth defects, TRACLEER is available only through a restricted program called the Bosentan REMS Program. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions (5.1, 5.2), Contraindications (4.1)] .

Required components of the Bosentan REMS are:

• Healthcare professionals who prescribe TRACLEER must review the prescriber educational materials, enroll in the Bosentan REMS Program and comply with its requirements.
• Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of reproductive potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.
• To receive TRACLEER, all patients must understand the risks and benefits, and complete a patient enrollment form.
• Pharmacies that dispense TRACLEER must enroll in the program and agree to comply with the Bosentan REMS Program requirements.

Further information about TRACLEER and the Bosentan REMS Program is available at www.BosentanREMSProgram.com or 1-866-359-2612.

5.4 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% (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 [see Adverse Reactions (6.1), Clinical Studies (14.2)] .

5.5 Pulmonary Veno-Occlusive Disease

If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether TRACLEER should be discontinued.

5.6 Decreased Sperm Counts

Decreased sperm counts have been observed in patients receiving TRACLEER. Preclinical data also suggest that TRACLEER, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)] .

5.7 Decreases in Hemoglobin and Hematocrit

Treatment with TRACLEER can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. 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 [see Adverse Reactions (6.1)] .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data on TRACLEER were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with PAH 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 TRACLEER 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 PAH patients (n=328) to TRACLEER 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 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:

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.

6.2 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 postapproval 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 Boxed Warning]
• Liver failure [see Boxed Warning]
• Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4)]
• Thrombocytopenia
• Rash
• Jaundice
• Anemia requiring transfusion
• Neutropenia and leukopenia
• Nasal congestion

7.1 Cytochrome P450 Drug Interactions

Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see Pharmacokinetics (12.3)] . 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

7.2 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 [see Use in Specific Populations (8.3)] .

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 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 [see Pulmonary Arterial Hypertension (14.1)] . Safety in pediatric patients is supported by data from 100 pediatric patients treated with TRACLEER for a median of 17 months [see Clinical Studies Experience (6.1), Pulmonary Arterial Hypertension (14.1)] .

8.5 Geriatric Use

Clinical studies of TRACLEER did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

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 (C max and AUC) of bosentan. The pharmacokinetics of TRACLEER have 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 were not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) [see Dosage and Administration (2.6), Warnings and Precautions (5.1), Pharmacokinetics (12.3)] .

8.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics (12.3)] .

12.3 Pharmacokinetics

12.1 Mechanism of Action

Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. Bosentan has a slightly higher affinity for ET A receptors than for ET B 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 ET A and ET B receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disease.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Pulmonary Arterial Hypertension

14.2 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.

Store at 20ºC to 25ºC (68ºF to 77ºF). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]. These storage temperatures apply to both film-coated and dispersible tablets. Divided dispersible tablets should be stored under the same conditions and used within 7 days. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to 7 days.

Keep out of reach of children.

Restricted access

Advise the patient that TRACLEER is only available through a restricted access program called the Bosentan REMS Program.

As a component of the Bosentan REMS, prescribers must review the contents of the TRACLEER Medication Guide with the patient before initiating TRACLEER.

Instruct patients that the risks associated with TRACLEER include:

• Hepatotoxicity
  Discuss with the patient the requirement to measure serum aminotransferases monthly.
• Embryo-fetal toxicity
  Educate and counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with TRACLEER and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use two different forms of contraception while taking TRACLEER and for one month after discontinuing TRACLEER [see Use in Specific Populations (8.1)] .
  Females who have intrauterine devices (IUD) or tubal sterilization can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.
  Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.
  Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.
  Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected.
  Advise the patient that TRACLEER is available only from certified pharmacies that are enrolled in the Bosentan REMS Program.
  Patients must sign the Bosentan REMS Program Patient Enrollment Form to confirm that they understand the risks of TRACLEER.
• Lactation
  Advise women not to breastfeed during treatment with TRACLEER [see Use in Specific Populations (8.2)].
• Infertility
  Advise males of reproductive potential that TRACLEER may impair fertility [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
• Phenylketonurics
  TRACLEER dispersible tablets contain phenylalanine, a component of aspartame. Each dispersible tablet contains 1.87 mg of phenylalanine.

Other Risks Associated with TRACLEER

Instruct patients that the risks associated with TRACLEER also include the following:

• Decreases in hemoglobin and hematocrit – advise patients of the importance of hemoglobin testing,
• Decreases in sperm count,
• Fluid retention.

Administration Considerations

Advise patients that TRACLEER dispersible tablets should not be split into quarters.