Bosentan

BOSENTAN — bosentan tablet, film coated
Alembic Pharmaceuticals Limited

WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY

Because of the risks of hepatotoxicity and birth defects, bosentan tablets is available only through a restricted program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.3)].

Hepatotoxicity
In clinical studies, bosentan tablets 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 [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with bosentan tablets in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan tablets 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 bosentan tablets. 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 bosentan tablets with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.4)].

Elevations in aminotransferases require close attention [see Dosage and Administration (2.4)]. Bosentan tablets should generally be avoided in patients with elevated aminotransferases (> 3 x 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 x ULN, treatment with bosentan tablets should be stopped. There is no experience with the reintroduction of bosentan tablets in these circumstances.

Embryo-Fetal Toxicity

Bosentan tablets are likely to cause major birth defects if used by pregnant females based on animal data [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]. Therefore, pregnancy must be excluded before the start of treatment with bosentan tablets. Throughout treatment and for one month after stopping bosentan tablets, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, 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 bosentan tablets [see Drug Interactions (7.2)]. Obtain monthly pregnancy tests.

1 INDICATIONS AND USAGE

Bosentan tablets are 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%) [see Clinical Studies (14.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Required Monitoring

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

Obtain a pregnancy test in females of reproductive potential prior to bosentan tablets treatment, monthly during treatment and one month after stopping bosentan tablets. Initiate treatment with bosentan tablets 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 bosentan tablets 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

Initial 4 weeks Maintenance (after 4 weeks)
Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily
Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily

2.3 Administration

Bosentan tablets film-coated tablets should be administered orally twice daily.

2.4 Dosage Adjustments for Aminotransferase Elevations

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

Discontinue bosentan tablets 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 x Upper Limit of Normal (ULN). There is no experience with the reintroduction of bosentan tablets in these circumstances.

Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3 x ULN

ALT/AST levels Treatment and monitoring recommendations
> 3 and ≤ 5 x ULN Confirm by another aminotransferase test; if confirmed, –in patients >12 years and >40 kg, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pretreatment values, treatment may continue or be reintroduced at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days.– in patients >12 years and <40 kg, interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days.
> 5 and ≤ 8 x ULN Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, –in patients >12 years, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days.
> 8 x ULN Stop treatment permanently. There is no experience with reintroduction of bosentan tablets in these circumstances.

2.5 Use with Ritonavir

Co-administration of Bosentan Tablets in Patients on Ritonavir

In patients who have been receiving ritonavir for at least 10 days, start bosentan tablets at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1)].

Co-administration of Ritonavir in Patients on Bosentan Tablets

Discontinue use of bosentan tablets at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan tablets at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1)].

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