BOSENTAN Drug Interactions: What You Need to Know

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Drug Interactions (FDA Label)

INTERACTIONS Cytochrome P450: Coadministration of bosentan with drugs metabolized by CYP2C9 and CYP3A can increase exposure to bosentan and/or the coadministered drug ( 4.2 , 4.3 , 7.1 ). Hormonal contraceptives: Bosentan use decreases contraceptive exposure and reduces effectiveness ( 7.2 ).

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 Clinical Pharmacology ( 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 bosentan will likely lead to large increases in plasma concentrations of bosentan. Coadministration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with bosentan 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 bosentan is coadministered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, bosentan 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 bosentan is coadministered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan [see Use in Specific Populations ( 8.3 )] . An interaction study demonstrated that coadministration 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. CYP3A induction-mediated effect of bosentan on other drugs CYP3A induction-mediated effect of bosentan on other drugs Effect of other drugs on bosentan

Contraindications

4. CONTRAINDICATIONS

Pregnancy ( 4.1 )
Use with Cyclosporine A ( 4.2 )
Use with Glyburide ( 4.3 )
Hypersensitivity ( 4.4 )

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 Co-administration 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 co-administration 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) ] .

Related Warnings

5. WARNINGS AND PRECAUTIONS

Fluid retention: May require intervention ( 5.4 ).
Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing bosentan ( 5.5 ).
Decreased sperm counts ( 5.6 ).
Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter ( 5.7 ).

5.1 Hepatotoxicity ALT or AST > 3xULN 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 ≥3xULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. 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 > 3xULN) and increases in total bilirubin (≥2xULN) 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 ≥2xULN. Avoid initiation of bosentan in patients with elevated aminotransferases (>3xULN) 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 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 tablets for oral suspension 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, bosentan tablets for oral suspension 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 tablets for oral suspension REMS are: Healthcare professionals who prescribe bosentan tablets for oral suspension 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 for oral suspension, all patients must understand the risks and benefits, and complete a patient enrollment form. Pharmacies that dispense bosentan tablets for oral suspension must enroll in the program and agree to comply with the Bosentan REMS Program requirements. Further information about Bosentan and Bosentan 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 bosentan and other endothelin receptor antagonists. In PAH clinical trials with bosentan, 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 bosentan. 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 bosentan or underlying heart failure, and the possible need for treatment or discontinuation of bosentan [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 bosentan should be discontinued.

5.6 Decreased Sperm Counts Decreased sperm counts have been observed in patients receiving bosentan. Preclinical data also suggest that bosentan, 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 bosentan 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) ] .

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