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Drugs reference index «Bosentan»

Bosentan

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

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

Pharmacology

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. 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 those 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.

Body weight

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

Indications and Usage

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

Contraindications

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

Dosage and Administration

Pulmonary Arterial HypertensionAdults

PO 62.5 mg twice daily for 4 wk; then increase to maintenance dosage of 125 mg twice daily.

Dosage Adjustment

If ALT/AST is more than 3 and less than or equal to 5 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 less than or equal to 8 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

Consider gradual dose reduction (62.5 mg twice daily for 3 to 7 days).

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

PO 62.5 mg twice daily.

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.
  • 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.
  • 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.
  • If therapy is reintroduced, it should be at the starting dose.

Storage/Stability

Store at 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.

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, oral, injectable, implantable, 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 hours 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 PAH during clinical trials. Because warfarin has a narrow therapeutic index, monitor coagulation parameters and adjust the warfarin dose as needed.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Syncope (5%); 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%); chest pain (5%); arthralgia, flushing (4%); angioneurotic edema, hypersensitivity (postmarketing).

Precautions

Warnings

Potential liver injury

At least 3-fold increase in ALT or AST occurs in approximately 11% of patients, accompanied by elevated bilirubin in a small number of cases. Serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid use in patients with aminotransferases elevations (greater than 3 times ULN) at baseline. 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 greater than or equal to 2 times ULN, stop treatment.

Pregnancy

Bosentan is very likely to produce major birth defects if used by pregnant women; this effect has been seen consistently when it is administered to animals. Therefore, pregnancy must be excluded before the start of treatment with bosentan and prevented thereafter by the use of a reliable method of contraception. Do not use hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, as the sole means of contraception because these may not be effective in patients receiving bosentan. Therefore, effective contraception through additional forms of contraception must be practiced. Obtain monthly pregnancy tests.

Distribution program

Because of potential liver injury and in an effort to make the chance of fetal exposure to bosentan as small as possible, bosentan may be prescribed only through the Tracleer Access Program by calling 1-866-228-3546. Only prescribers and pharmacies registered may prescribe and distribute bosentan. In addition, bosentan may be dispensed only to patients who are enrolled in and meet all the conditions of the program.

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. Document baseline disease state activity (eg, exercise capacity, walking distance). Reassess periodically to document response to therapy. Monitor for signs of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting). Discontinue medication 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

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

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

May occur.

Hematologic

Dose-related decreases in hemoglobin and hematocrit may occur.

Pulmonary edema

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

Overdosage

Symptoms

Blurred vision, decreased blood pressure, 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 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, 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.

  • Bosentan MedFacts Consumer Leaflet (Wolters Kluwer)
  • bosentan Concise Consumer Information (Cerner Multum)
  • bosentan Advanced Consumer (Micromedex) - Includes Dosage Information
  • Tracleer Prescribing Information (FDA)

See Also...

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