Bosentan

Bosentan
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Black Box Warning

WARNING: RISKS OF HEPATOTOXICITY and TERATOGENICITY See full prescribing information for complete Boxed Warning. * Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted program called the Tracleer Access Program (T.A.P.). T.A.P. is a component of the Tracleer Risk Evaluation and Mitigation Strategy (REMS). Under the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program. Hepatotoxicity: In clinical studies, Tracleer caused 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 hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. In the postmarketing 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 comorbidities 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. Elevations in aminotransferases require close attention. Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) at baseline because monitoring for hepatotoxicity may be more difficult. 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, treatment with Tracleer should be stopped. There is no experience with the reintroduction 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.

Overview

Bosentan is an endothelin receptor antagonist that is FDA approved for the {{{indicationType}}} of pulmonary arterial hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, hypotension, palpitations, flushing, and headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Pulmonary Arterial Hypertension

• Tracleer® is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA 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%).

• 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 hepatotoxicity in WHO Class II patients, which may preclude future use as their disease progresses.

• Healthcare professionals who prescribe Tracleer must enroll in the Tracleer Access Program (T.A.P.) and must comply with the required monitoring to minimize the risks associated with Tracleer.

• Dosing Information

• Initiate treatment at 62.5 mg twice daily for 4 weeks and then increase 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 hepatotoxicity.
• Tracleer should be administered in the morning and evening with or without food.

Dosage Adjustments for Patients Developing Aminotransferase Elevations

• Measure liver aminotransferase levels prior to initiation of treatment and then monthly. If aminotransferase levels increase, revise the monitoring and treatment plan. The table below summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations >3 × ULN during therapy with Tracleer. 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. There is no experience with the reintroduction of Tracleer in these circumstances. Information.

This image is provided by the National Library of Medicine.

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.

Use with Ritonavir

• Coadministration of Tracleer in Patients on Ritonavir

• In patients who have been receiving ritonavir for at least 10 days, start Tracleer at 62.5 mg once daily or every other day based upon individual tolerability.

• Coadministration 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 62.5 mg once daily or every other day based upon individual tolerability.

Use in Patients with Pre-existing Hepatic Impairment

• Tracleer should generally be avoided in patients with moderate or severe liver impairment. Initiation of Tracleer should generally be avoided in patients with elevated aminotransferases >3 × ULN. No dose adjustment is required in patients with mildly impaired liver function.

Treatment Discontinuation

• 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.

There is limited information regarding Off-Label Guideline-Supported Use of Bosentan in adult patients.

Off-Label Use and Dosage (Adult)

Non–Guideline-Supported Use

Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

• Dosing Information

• 62.5 mg orally twice daily for 4 weeks, followed by 125 mg twice daily or 62.5 mg twice daily in patients weighing less than 40 kilograms.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• Safety and efficacy in pediatric patients have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Bosentan in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Bosentan in pediatric patients.

Contraindications

• Pregnancy

• 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.

• Use with Cyclosporine A

• Coadministration 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 coadministration 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 rash and angioedema

Warnings

WARNING: RISKS OF HEPATOTOXICITY and TERATOGENICITY See full prescribing information for complete Boxed Warning. * Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted program called the Tracleer Access Program (T.A.P.). T.A.P. is a component of the Tracleer Risk Evaluation and Mitigation Strategy (REMS). Under the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program. Hepatotoxicity: In clinical studies, Tracleer caused 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 hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. In the postmarketing 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 comorbidities 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. Elevations in aminotransferases require close attention. Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) at baseline because monitoring for hepatotoxicity may be more difficult. 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, treatment with Tracleer should be stopped. There is no experience with the reintroduction 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.

• Description

Precautions

• Description

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Bosentan in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Bosentan in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bosentan in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Bosentan during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Bosentan with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Bosentan with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Bosentan with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Bosentan with respect to specific gender populations.

Race

There is no FDA guidance on the use of Bosentan with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Bosentan in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Bosentan in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Bosentan in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Bosentan in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Bosentan in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Bosentan in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Bosentan in the drug label.

Pharmacology

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Bosentan in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Bosentan in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Bosentan in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Bosentan in the drug label.

How Supplied

Storage

There is limited information regarding Bosentan Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Bosentan in the drug label.

Precautions with Alcohol

• Alcohol-Bosentan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Tracleer®

Look-Alike Drug Names

• Tracleer® — Tricor®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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