Bosentan

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

Trade Names

Tracleer
- Tablets, oral 62.5 mg
- Tablets, oral 125 mg

Pharmacology

Antagonizes endothelin receptor by binding to endothelin A and endothelin B receptors in the endothelium and vascular smooth muscle.

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Pharmacokinetics

Absorption

T max is 3 to 5 h. Absolute bioavailability is approximately 50%. Steady state is reached in 3 to 5 days.

Distribution

Vd is approximately 18 L. More than 98% protein bound (mainly albumin).

Metabolism

Metabolized in the 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

Half-life is approximately 5 h. Eliminated by biliary excretion; less than 3% is recovered in urine. Cl is 4 L/h.

Special Populations

Renal Function Impairment

In patients with severe renal impairment (CrCl 15 to 30 mL/min), concentrations of the 3 metabolites may increase 2-fold, although it is 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.

Elderly

It is not known whether bosentan pharmacokinetics are influenced by age.

Children

It is not known whether bosentan pharmacokinetics are influenced by age.

Gender

It is not known whether bosentan pharmacokinetics are influenced by gender.

Race

It is not known whether bosentan pharmacokinetics are influenced by race.

Body weight

It is not known whether bosentan pharmacokinetics are influenced by body weight.

Indications and Usage

Treatment of pulmonary arterial hypertension (WHO group 1) to improve exercise ability and decrease the rate of clinical worsening.

Unlabeled Uses

Prevention of digital ulcers in systemic sclerosis; prevention of Raynaud phenomenon.

Contraindications

Coadministration of cyclosporine or glyburide; hypersensitivity to bosentan or any component of the product; pregnancy.

Dosage and Administration

Pulmonary Arterial Hypertension
Adults

PO 62.5 mg twice daily for 4 wk, then increase to maintenance dosage of 125 mg twice daily. In patients with a body weight less than 40 kg, the recommended maintenance dosage is 62.5 mg twice daily.

Dosage adjustment

If ALT/AST is more than 3 and 5 or less times the ULN, confirm by another aminotransferase test. If confirmed, reduce the daily dosage to 62.5 mg twice daily or interrupt treatment and monitor aminotransferase levels at least every 2 wk. If the aminotransferase levels return to pretreatment values, continue or reintroduce the treatment as appropriate. If ALT/AST is more than 5 and 8 or less times the ULN, confirm by another aminotransferase test. If confirmed, stop treatment and monitor aminotransferase levels at least every 2 wk. Once the aminotransferase levels return to pretreatment values, consider reintroduction of the treatment. If ALT/AST is more than 8 times the ULN, treatments should be stopped and reintroduction of bosentan should not be considered.

Discontinuation of therapy

When discontinuing therapy, consider a gradual dose reduction (62.5 mg twice daily for 3 to 7 days) to avoid the potential for clinical deterioration.

Concomitant therapy
Adults

PO Discontinue use of bosentan at least 36 h prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.

General Advice

  • This medication is available only through the Tracleer Access Program.
  • May be taken with or without food.
  • If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting) or increases in bilirubin of 2 times the ULN or more, stop treatment.
  • If therapy is reintroduced, it should be at the starting dose and aminotransferase levels should be checked within 3 days and thereafter at least every 2 wk.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Clarithromycin

The risk of bosentan hepatotoxicity may be increased. Close clinical and laboratory monitoring is warranted. If an interaction is suspected, stop one or both drugs.

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.

HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, simvastatin)

Plasma concentrations of simvastatin and its metabolite may be decreased when coadministered with bosentan. Bosentan is also expected to reduce plasma concentrations of other HMG-CoA reductase inhibitors metabolized by CYP3A4 (ie, atorvastatin, lovastatin). Monitor cholesterol levels and adjust the HMG-CoA reductase inhibitor dose accordingly.

Hormonal contraceptives (ie, implantable, injectable, oral, transdermal)

Plasma concentrations may be reduced by bosentan, decreasing the effectiveness. Women should not rely on hormonal contraception alone when taking bosentan.

Ketoconazole

Plasma concentrations of bosentan may be increased. No dosage adjustment is necessary, but consider increased effects of bosentan. Addition monitoring is warranted.

Phosphodiesterase type 5 inhibitors (eg, sildenafil)

Coadministration may elevate bosentan plasma concentrations, increasing the pharmacologic effects and risk of toxicity. Phosphodiesterase type 5 inhibitor concentrations may be reduced, decreasing the pharmacologic effects. Coadminister these agents with caution. Closely monitor the clinical response and for adverse reactions. Adjust therapy as needed.

Rifampin

Coadministration may increase bosentan trough concentrations after the first concomitant dose and decrease bosentan trough concentrations at steady state. Measure liver function weekly for the first 4 wk of concurrent use before reverting to normal monitoring.

Ritonavir-containing regimens

Coadministration may increase bosentan trough concentrations. In patients receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on tolerability. In patients receiving bosentan, stop bosentan at least 36 h before starting ritonavir. At least 10 days after starting ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon tolerability.

Tacrolimus

Although not studied in humans, coadministration resulted in markedly increased plasma concentrations of bosentan in animals. Use with caution.

Warfarin

Warfarin plasma concentrations may be decreased by bosentan. Clinically important changes in INR or warfarin dose were not seen in patients with pulmonary arterial hypertension during clinical trials. Because warfarin has a narrow therapeutic index, monitor coagulation parameters and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Syncope (5%); flushing, hypotension, palpitations (4%).

CNS

Headache (15%).

Dermatologic

Rash (postmarketing).

Hematologic

Anemia (3%); anemia requiring transfusion, leukopenia, neutropenia, thrombocytopenia (postmarketing).

Hepatic

Abnormal hepatic function test (4%); hepatic cirrhosis, jaundice, liver failure (postmarketing).

Respiratory

Respiratory tract infection (22%); sinusitis (4%).

Miscellaneous

Edema (11%); arthralgia (4%); angioneurotic edema, hypersensitivity (postmarketing).

Precautions

Warnings

Distribution program

Because of the risk of liver injury and birth defects, bosentan is available only through a special restricted distribution program called the Tracleer Access Program (TAP), by calling 1-866-228-3546. Only health care providers and pharmacies registered with TAP may prescribe and distribute bosentan. In addition, bosentan may be dispensed only to patients who are enrolled in and meet all conditions of TAP.

Liver injury

At least a 3-fold ULN elevation of liver aminotransferases (ALT and AST) occurred in approximately 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious liver injury, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. Rare cases of unexplained hepatic cirrhosis were reported after prolonged (more than 12 mo) therapy with bosentan in patients with multiple comorbidities and drug therapies. There have also been rare reports of liver failure.

Avoid using bosentan in patients with elevated aminotransferases (greater than 3 times the ULN) at baseline because monitoring liver injury may be more difficult. Stop treatment if liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting) or increases in bilirubin 2 times or more the ULN.

Pregnancy

Bosentan is likely to cause major birth defects if used by pregnant women based on animal data. Pregnancy must be excluded before the start of treatment with bosentan. Throughout treatment and for 1 mo after stopping bosentan, women of childbearing potential must use 2 reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A intrauterine device or levonorgestrel 20 mcg/day intrauterine system inserted, 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. Obtain monthly pregnancy tests.


Monitor

Ensure that liver enzymes are measured before starting therapy and monthly during treatment. Ensure that Hgb is measured after 1 and 3 mo of therapy and then every 3 mo for duration of treatment. Obtain monthly follow-up urine or serum pregnancy tests in women of childbearing potential.


Pregnancy

Category X . May cause fetal harm. 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.

Hypersensitivity

May occur, including rash and angioedema.

Hepatic Function

Avoid use in patients with moderate or severe hepatic impairment or elevated aminotransferases (more than 3 times the ULN); use with caution in patients with mild hepatic impairment.

Fertility

There was a decline in sperm count of at least 50% in 25% of patients after 3 or 6 mo of treatment with bosentan.

Fluid retention

Fluid retention or edema may occur.

Hematologic

Dose-related decreases in Hgb and Hct may occur.

Pulmonary edema

If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and discontinue bosentan.

Overdosage

Symptoms

Blurred vision, decreased BP, dizziness, headache, increased heart rate, nausea, sweating, vomiting.

Patient Information

  • Advise patient to read the Medication Guide before beginning therapy and with each refill.
  • Advise patient to take in the 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.
  • 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, implantable, injectable) that another nonhormonal contraceptive needs to be used.
  • Instruct women to notify health care provider immediately if pregnancy is suspected (eg, delay in menses, any other reason to suspect pregnancy), they are planning on becoming pregnant, or they are breast-feeding.
  • Instruct patient to stop taking drug and immediately report any of these symptoms to health care provider: abdominal pain, fatigue, fever, nausea, jaundice, unusual lethargy, vomiting.

Copyright © 2009 Wolters Kluwer Health.

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