Tracleer (Bosentan) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole). Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently, plasma concentrations of drugs metabolized by these two isoenzymes will be decreased when TRACLEER® is co-administered. Bosentan had no relevant inhibitory effect on any CYP isoenzymes tested (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Consequently, TRACLEER® is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.

Hormonal Contraceptives, Including Oral, Injectable, and Implantable Contraceptives:    Specific interaction studies have not been performed to evaluate the effect of co-administration of bosentan and hormonal contraceptives, including oral, injectable or implantable contraceptives. Since many of these drugs are metabolized by CYP3A4, there is a possibility of failure of contraception when TRACLEER® is co-administered. Women should not rely on hormonal contraception alone when taking TRACLEER®.

Specific interaction studies have demonstrated the following:

Cyclosporine A:    During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. The concomitant administration of bosentan and cyclosporine A is contraindicated (see CONTRAINDICATIONS). Co-administration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A4 substrate) by approximately 50%.

Tacrolimus:    Co-administration of tacrolimus and bosentan has not been studied in man. Co-administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and bosentan are used together.

Glyburide:    An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of TRACLEER® and glyburide is contraindicated, and alternative hypoglycemic agents should be considered (see CONTRAINDICATIONS).

Co-administration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Bosentan is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A4. The possibility of worsened glucose control in patients using these agents should be considered.

Ketoconazole:    Co-administration of bosentan 125 mg b.i.d. and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold. No dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered.

Simvastatin and Other Statins:    Co-administration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A4 substrate), and its active (beta)-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Bosentan is also expected to reduce plasma concentrations of other statins that have significant metabolism by CYP3A4, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A4 metabolized statins should have cholesterol levels monitored after TRACLEER® is initiated to see whether the statin dose needs adjustment.

Warfarin:    Co-administration of bosentan 500 mg b.i.d. for 6 days decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients.

Digoxin, Nimodipine and Losartan:    Bosentan has been shown to have no pharmacokinetic interactions with digoxin and nimodipine, and losartan has no effect on plasma levels of bosentan.

OVERDOSAGE

Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.

There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

CONTRAINDICATIONS

See BOX WARNING above for CONTRAINDICATION to use in pregnancy.

Pregnancy Category X.    TRACLEER® is expected to cause fetal harm if administered to pregnant women. Bosentan was teratogenic in rats given oral doses >/= 60 mg/kg/day (twice the maximum recommended human oral dose of 125 mg, b.i.d., on a mg/m² basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day (2 and 10 times, respectively, the maximum recommended human dose on a mg/m² basis). Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no data on the use of TRACLEER® in pregnant women.

Pregnancy must be excluded before the start of treatment with TRACLEER® and prevented thereafter by use of reliable contraception. Hormonal contraceptives, including oral, injectable, and implantable contraceptives may not be reliable in the presence of TRACLEER® and should not be used as the sole contraceptive method in patients receiving TRACLEER® (see Drug Interactions: Hormonal Contraceptives, Including Oral, Injectable, and Implantable Contraceptives). Input from a gynecologist or similar expert on adequate contraception should be sought as needed.

TRACLEER® should be started only in patients known not to be pregnant. For female patients of childbearing potential, a prescription for TRACLEER® should not be issued by the prescriber unless the patient assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse.

Follow-up urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking TRACLEER®. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician and patient must discuss the risk to the pregnancy and to the fetus.

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.

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.

Hypersensitivity:    TRACLEER® is also contraindicated in patients who are hypersensitive to bosentan or any component of the medication.