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Bosentan

Pronunciation: (boe-SEN-tan)
Class: Endothelin receptor antagonist

Trade Names:
Tracleer
- Tablets 62.5 mg
- Tablets 125 mg

Pharmacology

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Antagonizes endothelin (ET) receptor by binding to ET _A and ET _B receptors in the endothelium and vascular smooth muscle.

Pharmacokinetics

Absorption

T _max is 3 to 5 h.

Distribution

Vd is about 18 L. Bosentan is more than 98% protein bound (mainly albumin).

Metabolism

Liver

There are 3 metabolites, one of which contributes 10% to 20% of bosentan's effects. Bosentan induces CYP2C9, CYP3A4, and possibly CYP2C19; it may induce its own metabolism.

Elimination

The t _½ is about 5 h. Bosentan is eliminated by biliary excretion; less than 3% is recovered in urine. Cl is 8 L/h.

Special Populations

Renal Function Impairment

In those with severe renal function impairment (Ccr 15 to 30 mL/min), concentrations of the 3 metabolites may increase 2-fold, although not clinically significant.

Hepatic Function Impairment

Exposure to bosentan would be significantly increased; avoid use in those with moderate or severe liver impairment or elevated aminotransferases more than 3 times the ULN.

Severe chronic heart failure

Exposure to bosentan may be increased 30% to 40%. Similar effects are expected in those with pulmonary arterial hypertension.

Indications and Usage

Treatment of pulmonary arterial hypertension in patients with WHO Class III and IV symptoms, to improve exercise ability and decrease the rate of clinical worsening.

Contraindications

Pregnancy; coadministration of cyclosporine or glyburide; hypersensitivity to bosentan or any component of the product.

Dosage and Administration

Adults and Children older than 12 yr of age Initial dose

PO 62.5 mg twice daily for 4 wk; then increase to maintenance dose of 125 mg twice daily. If bosentan therapy is reintroduced, it should be at the starting dose.

Patients under 40 kg but older than 12 yr of age Initial and maintenance dose

PO 62.5 mg twice daily. If bosentan therapy is reintroduced, it should be at the starting dose.

General Advice

This medication is available only through the Tracleer Access Program.
Give prescribed dose twice daily, in the morning and evening, with or without food.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F).

Drug Interactions

Cyclosporine

Bosentan trough concentrations may be increased, while cyclosporine plasma levels may be decreased; coadministration is contraindicated.

Glyburide

Plasma concentrations of both glyburide and bosentan may be decreased; coadministration is contraindicated.

Ketoconazole

Plasma concentrations of bosentan may be increased.

Hormonal contraceptives (ie, oral, injectable, implantable), HMG-CoA reductase inhibitors (eg, simvastatin), warfarin

Plasma concentrations of these agents may be decreased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension; palpitations; edema.

CNS

Headache; fatigue.

Dermatologic

Pruritus.

EENT

Nasopharyngitis.

GI

Dyspepsia.

Hepatic

Abnormal hepatic function.

Miscellaneous

Flushing.

Precautions

Warnings

Hepatotoxicity

At least 3-fold increase in ALT or AST occurs in approximately 11% of patients and requires close monitoring.

Teratogenicity

Use is contraindicated in pregnancy.

Monitor

Ensure that liver enzymes are measured before starting therapy and monthly during treatment. Notify health care provider if any elevations are noted. Ensure that Hgb is measured after 1 and 3 mo of therapy and then every 3 mo for duration of treatment. Document baseline disease state activity (eg, exercise capacity, walking distance). Reassess periodically to document response to therapy. Monitor for signs of liver injury (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue). Discontinue medication and notify health care provider immediately if noted.

Pregnancy

Category X . Pregnancy must be excluded before starting bosentan.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Select dose with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function and comorbidity.

Hepatic Function

In general, because monitoring liver injury may be more difficult in patients with hepatic function impairment, avoid bosentan in patients with elevated aminotransferases (greater than 3 times the ULN).

Hepatotoxicity

At least a 3-fold elevation of liver ALT and AST may occur in 11% of patients, which may indicate serious liver injury.

Hematologic

Dose-related decreases in hemoglobin and hematocrit may occur.

Overdosage

Symptoms

Headache, nausea, vomiting, decreased blood pressure, increased heart rate.

Patient Information

Advise patient to read the Medication Guide before beginning therapy.
Advise patient to take morning and evening as prescribed, without regard to meals.
Advise patient that monthly liver enzyme tests and pregnancy tests (in women of childbearing potential) will be required to use this medication safely.
Inform patient that drug controls, but does not cure pulmonary hypertension, and to continue taking drug as prescribed.
Caution patient not to change the dose or stop taking the drug unless advised to do so by health care provider.
Caution patient that if drug is stopped for any period of time and then restarted, the lower initial dose should be used again.
Instruct women of childbearing potential that reliable contraceptive measures must be used during treatment. Advise patient using hormonal contraception (eg, oral, injectable, implantable) that another nonhormonal contraceptive needs to be used.
Instruct women to notify health care provider immediately if pregnancy is suspected (eg, delay in menses, have any other reason to suspect pregnancy), they are planning on becoming pregnant, or are breast-feeding.
Instruct patient to stop taking drug and immediately report any of these symptoms to health care provider: nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy, fatigue.