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Bosentan

Class: Vasodilating Agents
VA Class: CV900
Chemical Name: 4-(1,1-Dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2′-bipyrimidin]-4-yl]-benzenesulfonamide monohydrate
Molecular Formula: C27H29N5O6S•H2O
CAS Number: 157212-55-0
Brands: Tracleer

Medically reviewed by Drugs.com on May 17, 2021. Written by ASHP.

Warning

    Hepatotoxicity
  • Risk of serious hepatic injury. Elevations in serum aminotransferase (AST/ALT) concentrations and liver failure reported. (See Hepatotoxicity under Cautions.)

  • Measure AST/ALT concentrations prior to initiation of therapy and monthly thereafter.

  • Discontinue therapy if AST/ALT elevations are accompanied by manifestations of liver injury (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) or bilirubin concentrations ≥2 times ULN. (See Patients with Adverse Hepatic Effects under Dosage and Administration.)

  • Generally avoid in patients with elevated aminotransferases (>3 times ULN) at baseline (because monitoring for liver injury may be more difficult) and in those with preexisting moderate to severe hepatic impairment.

    Teratogenicity
  • May cause fetal harm; contraindicated in women who are or may become pregnant.

  • Must exclude pregnancy before start of treatment and prevent thereafter by using 2 reliable forms of contraception during and for 1 month following discontinuance of therapy. (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

  • Oral, injectable, transdermal, and implantable hormonal contraceptives may not be reliable when used concomitantly with bosentan and should not be the sole contraceptive method. (See Specific Drugs under Interactions.)

    Restricted Distribution
  • Distribution of bosentan is restricted because of risks of hepatotoxicity and major birth defects. (See Restricted Distribution Program under Dosage and Administration.)

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for bosentan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of bosentan and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/. Also see Restricted Distribution Program under Dosage and Administration: General.

Introduction

Vasodilator; an endothelin receptor antagonist.

Uses for Bosentan

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and slow clinical worsening. Efficacy established principally in patients with NYHA/WHO functional class II–IV PAH (idiopathic, heritable, or associated with connective tissue diseases or congenital systemic-to-pulmonary shunts).

Endothelin-receptor antagonists (e.g., ambrisentan, bosentan, macitentan) are recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy has failed. Individualize choice of PAH therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.

When considering use in patients with mild (NYHA/WHO class II) PAH, determine whether benefits are sufficient to outweigh risk of hepatotoxicity; liver injury could preclude future use of the drug.

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid, phosphodiesterase (PDE) type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially). By targeting different pathophysiologic pathways of the disease, combination therapy may provide additive and/or synergistic benefits.

Has been designated an orphan drug by FDA for treatment of PAH.

CHF

Not effective in treatment of CHF with left ventricular dysfunction.

Bosentan Dosage and Administration

General

Restricted Distribution Program

  • Bosentan can only be obtained through a restricted distribution program (Tracleer Access Program [TAP]); not available through community pharmacies. (See Boxed Warning and also see REMS.) Contact manufacturer at 866-228-3546 for specific information.

  • Dispense no more than a 30-day supply of bosentan at one time; confirm with patient that required pregnancy and liver function tests were completed prior to dispensing.

  • Distribute medication guide each time bosentan is dispensed and review with patient.

Administration

Oral Administration

Administer orally twice daily (morning and evening) without regard to meals.

Dosage

Pediatric Patients

PAH
Oral

Patients >12 years of age: Initially, 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily. If patient weighs <40 kg, recommended dosage for both initial and maintenance therapy is 62.5 mg twice daily.

Whenever therapy is discontinued, consider gradual dosage reduction (e.g., 62.5 mg twice daily for 3–7 days) to minimize risk of clinical deterioration.

Adults

PAH
Oral

Initially, 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily. If patient weighs <40 kg, recommended dosage for both initial and maintenance therapy is 62.5 mg twice daily.

Whenever therapy is discontinued, consider gradual dosage reduction (e.g., 62.5 mg twice daily for 3–7 days) to minimize risk of clinical deterioration.

Special Populations

Patients with Adverse Hepatic Effects

If elevations in AST and ALT are accompanied by manifestations of hepatic disease (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) or bilirubin are ≥2 times ULN, discontinue bosentan by gradually reducing dosage (e.g., 62.5 mg twice daily for 3–7 days).

If confirmed (i.e., upon a repeat test) AST or ALT elevations of >3 but ≤5 times ULN develop during bosentan therapy, reduce dosage or interrupt therapy.

If confirmed AST or ALT concentrations of >5 times ULN, discontinue bosentan by gradually reducing dosage.

Monitor serum AST/ALT at least every 2 weeks following dosage reduction or discontinuance.

May consider reinitiation of bosentan at starting dosage of 62.5 mg twice daily following return of AST/ALT to pretreatment levels if AST/ALT elevations did not exceed 8 times ULN; check serum AST/ALT within 3 days of reinitiating therapy and every 2 weeks thereafter.

Manufacturer states that reinitiation of bosentan therapy should not be considered if AST/ALT exceeded 8 times ULN. Clinical experience with reinitiation of bosentan therapy is lacking in such patients, as well as in those with AST/ALT elevations accompanied by manifestations of hepatic disease or by increases in bilirubin concentrations of ≥2 times ULN.

Hepatic Impairment

Dosage adjustment not necessary in patients with preexisting mild hepatic impairment (Child-Pugh class A).

Avoid use in patients with preexisting moderate or severe hepatic impairment (Child-Pugh class B or C). (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustments necessary.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Bosentan

Contraindications

  • Known or suspected pregnancy.

  • Concomitant therapy with cyclosporine or glyburide.

  • Known hypersensitivity to bosentan or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hepatotoxicity

With close monitoring, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged (i.e., >12 months) bosentan therapy. (See Boxed Warning.)

Manufacturer reinforces importance of strict adherence to monthly monitoring schedule and to dosage adjustment and monitoring guidelines throughout bosentan therapy. (See Patients with Adverse Hepatic Effects under Dosage and Administration.)

Dose-dependent elevations in AST or ALT of >3 times ULN were observed in 11% of patients receiving bosentan (<2 g daily) in clinical trials; occasionally accompanied by elevations in bilirubin, indicating potentially serious hepatic injury.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. Teratogenicity appears to be a class effect of endothelin-receptor antagonists.

Exclude pregnancy (i.e., negative results on a urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and ≥11 days after the last unprotected act of sexual intercourse) prior to initiating bosentan therapy in women of childbearing potential. Perform urine or serum pregnancy tests monthly.

Women of childbearing potential must use 2 reliable contraceptive methods (including a nonhormonal method) during and for 1 month following cessation of therapy, unless patient has a Copper T380A or LNg 20 IUD or has undergone tubal sterilization, in which case no other contraceptive method required. (See Specific Drugs under Interactions.)

If used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.

Sensitivity Reactions

Hypersensitivity Reactions

Angioedema (occurring 8 hours to 21 days after initiating therapy) reported.

General Precautions

Fluid Retention

Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported. Peripheral edema a known class effect of endothelin-receptor antagonists and also a consequence of PAH.

If clinically important fluid retention occurs, evaluate further to determine cause; initiate specific treatment or discontinue bosentan if necessary.

Fertility in Males

Reduced sperm counts observed in men with PAH receiving usual dosages of bosentan; cannot exclude possibility of adverse effects on spermatogenesis.

Hematologic Effects

Possible dose-related decreases in hemoglobin and hematocrit. Monitor hemoglobin 1 and 3 months after initiation of therapy and every 3 months thereafter.

Pulmonary Effects

Consider possibility of associated pulmonary veno-occlusive disease (PVOD) and discontinue bosentan if manifestations of pulmonary edema occur.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Lactation

Not known whether bosentan is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <12 years of age. Evaluated in a limited number of pediatric patients 3–15 years of age; safety, efficacy, and pharmacokinetics of bosentan were similar to those parameters reported in adults.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Extensively metabolized by liver; hepatic impairment expected to increase exposure to bosentan. Use not recommended in patients with preexisting moderate to severe hepatic impairment or AST/ALT >3 times ULN.

Renal Impairment

Minimal effect of severe renal impairment (Scr 15–30 mL/minute) on bosentan pharmacokinetics.

Common Adverse Effects

Headache, nasopharyngitis, flushing, abnormal hepatic function, lower limb edema, hypotension, palpitations, dyspepsia, edema, fatigue, pruritus, rash, anemia.

Interactions for Bosentan

Induces and is metabolized by CYP2C9 and CYP3A4; may possibly induce CYP2C19.

Drugs Affecting Hepatic Microsomal Enzymes

CYP2C9 and CYP3A inhibitors: Potential pharmacokinetic interaction (increased plasma bosentan concentrations). Concomitant administration of both a CYP2C9 inhibitor and a potent or moderate CYP3A inhibitor with bosentan is not recommended.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2C9 and CYP3A, and possibly CYP2C19: Potential pharmacokinetic interaction (decreased plasma substrate concentrations).

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A in vitro; therefore, not expected to increase plasma concentrations of drugs metabolized by these enzymes.

Drugs Affecting the Organic Anion Transport Protein (OATP)

Potential pharmacokinetic interaction with drugs that inhibit OATP.

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Potential for increased plasma bosentan concentrations

Concomitant use of both amiodarone and a potent/moderate CYP3A inhibitor with bosentan not recommended

Amprenavir (no longer commercially available in the US)

Potential for increased plasma bosentan concentrations

Concomitant use of both amprenavir and a CYP2C9 inhibitor with bosentan not recommended

Cyclosporine

Increased plasma bosentan and decreased plasma cyclosporine concentrations

Concomitant use contraindicated

Digoxin

Clinically important pharmacokinetic interaction unlikely

Diltiazem

Potential for increased plasma bosentan concentrations

Concomitant use of both diltiazem and a CYP2C9 inhibitor with bosentan not recommended

Erythromycin

Potential for increased plasma bosentan concentrations

Concomitant use of both erythromycin and a CYP2C9 inhibitor with bosentan not recommended

Fluconazole

Potential for increased plasma bosentan concentrations

Concomitant use of both fluconazole and a CYP2C9 inhibitor with bosentan not recommended

Concomitant use of both fluconazole and a potent/moderate CYP3A inhibitor with bosentan not recommended

Glyburide

Increased risk of elevated serum aminotransferase concentrations; decreased plasma glyburide and bosentan concentrations

Concomitant use contraindicated; consider alternative hypoglycemic agents

HIV protease inhibitors (PIs)

Substantially increased plasma trough bosentan concentrations observed with concomitant lopinavir/ritonavir; increases in bosentan concentrations also expected with other PIs

Atazanavir (without ritonavir): Possible decreased atazanavir concentrations

In patients already receiving a PI for ≥10 days, initiate bosentan at 62.5 mg once daily or every other day based on individual patient tolerance

In patients currently receiving bosentan, discontinue bosentan for ≥36 hours prior to PI initiation; after ≥10 days of PI therapy, resume bosentan at 62.5 mg once daily or every other day based on individual patient tolerance

Atazanavir (without ritonavir): Avoid concomitant use with bosentan

HMG-CoA reductase inhibitors (statins)

Simvastatin: Decreased plasma concentrations of simvastatin and active metabolite

Lovastatin, atorvastatin: Decreased plasma statin concentrations also expected

Monitor serum cholesterol concentrations when initiating bosentan; adjust statin dosage if necessary

Hormonal contraceptives

Decreased plasma norethindrone and ethinyl estradiol concentrations and systemic exposure; possible contraceptive failure

Use concomitant nonhormonal contraceptive method; do not use hormonal contraceptive as sole contraceptive method

Iloprost

Concomitant therapy appears well tolerated

Combination may be used to therapeutic advantage

Itraconazole

Potential for increased plasma bosentan concentrations

Concomitant use of both itraconazole and a CYP2C9 inhibitor with bosentan not recommended

Ketoconazole

Increased plasma bosentan concentrations

Bosentan dosage adjustment not necessary, but consider potential for increased effects

Concomitant use of both ketoconazole and a CYP2C9 inhibitor with bosentan not recommended

Losartan

Pharmacokinetic interaction unlikely

Nimodipine

Pharmacokinetic interaction unlikely

PDE type 5 inhibitors

Sildenafil: Decreased plasma sildenafil and increased plasma bosentan concentrations

Tadalafil: Decreased exposure to tadalafil, but no substantial alteration in bosentan exposure

Sildenafil: Manufacturer states dosage adjustments not necessary

Rifampin

Healthy individuals: Plasma bosentan concentrations increased by about sixfold after first concurrent dose, then decreased with continued coadministration

If concomitant use necessary, monitor liver function tests weekly for first 4 weeks, then resume usual monthly testing schedule

Tacrolimus

Markedly increased plasma bosentan concentrations in animals

Use concomitantly with caution

Treprostinil

Healthy individuals: Pharmacokinetic interaction not noted with an oral formulation of treprostinil

Warfarin

Decreased plasma warfarin concentrations and anticoagulant effects

Monitor INR closely when bosentan is initiated or discontinued

Bosentan Pharmacokinetics

Absorption

Bioavailability

Healthy individuals: Following oral administration, peak plasma concentrations attained within approximately 2–5 hours. Absolute bioavailability about 50%.

Food

Food does not affect bioavailability.

Special Populations

Increased (twofold) exposure to bosentan following oral or IV administration in patients with PAH compared with healthy individuals.

Distribution

Extent

Does not penetrate into erythrocytes.

Plasma Protein Binding

>98% (mainly albumin).

Elimination

Metabolism

Metabolized by CYP2C9 and CYP3A4; appears to induce its own metabolism following multiple-dose administration.

Elimination Route

Biliary excretion following metabolism in the liver. Less than 3% of dose excreted in urine.

Half-life

Healthy adults: Terminal elimination half-life about 5 hours.

Special Populations

Because of extensive hepatic metabolism, hepatic impairment may increase exposure to the drug.

Pharmacokinetics not affected in patients with mild hepatic impairment (Child-Pugh class A). Increased exposure to bosentan and its active metabolite observed in patients with moderate hepatic impairment (Child-Pugh class B) and PAH associated with portal hypertension; not evaluated in those with severe hepatic impairment (Class-Pugh class C).

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

  • Exhibits specific and competitive antagonism of both endothelin type A and type B receptors in the endothelium and vascular smooth muscle.

  • Improves exercise capacity and hemodynamics in patients with PAH by inhibiting vasoconstricting effects of endothelin-1.

Advice to Patients

  • Risk of liver injury. Importance of patients promptly informing clinicians of any nausea, vomiting, fever, unusual tiredness, abdominal pain, or yellowing of the skin or whites of the eyes.

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Risk of fetal harm. Importance of avoiding pregnancy; importance of using reliable (including nonhormonal) methods of contraception. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Importance of monthly monitoring of serum aminotransferases and monthly pregnancy testing.

  • Importance of patients taking bosentan as prescribed.

  • Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.

  • Importance of carefully reading the patient information (medication guide) provided by the manufacturer before initiating therapy and each time the prescription is refilled.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of bosentan is restricted. (See Restricted Distribution Program under Dosage and Administration.)

Bosentan

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

62.5 mg (of anhydrous bosentan)

Tracleer

Actelion

125 mg (of anhydrous bosentan)

Tracleer

Actelion

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 27, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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