Bosentan (Page 2 of 8)

2.5 Use with Ritonavir

Coadministration 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)].

Coadministration 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)].

2.6 Use in Patients with Pre-existing Hepatic Impairment

Avoid initiation of bosentan tablets in patients with aminotransferases greater than 3 x 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)].

3 DOSAGE FORMS AND STRENGTHS

Bosentan Tablets for oral administration are available as follows:

62.5 mg — Light orange, round, biconvex, film-coated tablets, debossed with ‘WPI’ on one side and ‘62.5’ on the other side contains 64.541 mg of bosentan monohydrate, equivalent to 62.5 mg of bosentan base.

125 mg — Light orange, oval, biconvex, film-coated tablets, debossed with ‘WPI’ on one side and ‘125’ on the other side contains 129.082 mg of bosentan monohydrate, equivalent to 125 mg of bosentan base.

4 CONTRAINDICATIONS

4.1 Pregnancy

Use of bosentan 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 bosentan [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2), Use in Specific Populations (8.1)].

4.2 Use with Cyclosporine A

Coadministration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan 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 coadministration of glyburide and bosentan is contraindicated [see Cytochrome P450 Drug Interactions (7.1)].

4.4 Hypersensitivity

Bosentan 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 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

ALT or AST greater 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 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 greater than or equal 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 greater than 3 x ULN) and increases in total bilirubin (greater than or equal to 2 x ULN) is a marker for potential serious hepatotoxicity.

Elevations of AST 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 also may reverse spontaneously while continuing treatment with bosentan.

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 bosentan 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 greater than or equal to 2 x ULN.

Avoid initiation of bosentan in patients with elevated aminotransferases (greater than 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning, D osage and Administration (2.6), Use in Specific Populations (8.6)].

In WHO Functional Class II patients, consider whether the benefits of bosentan 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, bosentan 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 bosentan 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 bosentan and for at least one month after the last dose [see Dosage and Administration (2), Use in Specific Populations (8.1, 8.3)].

Bosentan 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 Tablets

Because of the risks of hepatotoxicity and birth defects, bosentan tablets are 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 bosentan tablets 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 bosentan tablets, all patients must understand the risks and benefits, and complete a patient enrollment form.
  • Pharmacies that dispense bosentan tablets must enroll in the program and agree to comply with the Bosentan REMS Program requirements.

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

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