Bosentan (Monograph)

Brand name: Tracleer
Drug class: Endothelin receptor antagonists
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

Medically reviewed by Drugs.com on Mar 27, 2023. Written by ASHP.

Introduction

Vasodilator; an endothelin receptor antagonist.

Uses for Bosentan

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) in adults 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).

Management of PAH in pediatric patients ≥3 years of age with idiopathic or congenital PAH to improve pulmonary vascular resistance, which is expected to result in an improvement in exercise ability.

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications. Endothelin-receptor antagonists such as bosentan are recommended among several options for treatment of WHO/NYHA class II or III PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

In pediatric patients, bosentan monotherapy is a recommended option in patients with lower-risk PAH and negative acute vasoreactivity testing.

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

Related/similar drugs

sildenafil, tadalafil, Adcirca, ambrisentan, Revatio, Opsumit

Bosentan Dosage and Administration

General

Pretreatment Screening

• Obtain a pregnancy test in females of reproductive potential prior to starting treatment with bosentan; initiate treatment only after a negative pregnancy test is obtained.

• Measure liver function tests (AST/ALT and bilirubin) prior to starting treatment with bosentan.

Patient Monitoring

• In all patients, monitor liver function tests (AST/ALT and bilirubin) monthly during treatment.

• In females of reproductive potential, obtain pregnancy tests monthly during treatment and 1 month after discontinuing bosentan.

• Monitor the reproductive status of prepubertal females during treatment with bosentan; verify reproductive status at least annually in prepubertal patients ≥8 years of age.

• Monitor for signs and symptoms of fluid retention or pulmonary edema.

• Monitor hemoglobin 1 month and 3 months after starting bosentan therapy, then every 3 months thereafter.

Dispensing and Administration Precautions

• To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for bosentan on the prescription order form.

• Handling and disposal: Bosentan is a hazardous drug based on reproductive concerns; follow procedures for proper handling (e.g. use of gloves) when handling oral tablets.

REMS

• Because of the risks of hepatotoxicity and birth defects, bosentan is only available through a restricted distribution program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS) Program. Prescribers, patients, and pharmacies must enroll in the program and agree to comply with its requirements prior to prescribing, receiving, or dispensing bosentan. For additional information about the REMS program, clinicians may consult [Web].

• As a condition of the Bosentan REMS program, all patients must have liver function tests (ALT/AST and bilirubin) monitored at baseline and monthly while receiving bosentan.

• Females of reproductive potential must undergo pregnancy testing prior to starting bosentan therapy, monthly while on therapy, and 1 month after stopping therapy.

• Prepubertal female patients should contact the prescriber immediately when menstruation begins. Reproductive status must be verified at least annually in prepubertal female patients ≥8 years of age; prescribers must report any changes in reproductive status to the Bosentan REMS program within 10 days of becoming aware of the change.

Administration

Oral Administration

Administer orally twice daily (morning and evening) without regard to meals. Available as a film-coated tablet or dispersible tablet for oral suspension.

Disperse tablet for oral suspension, or half of the dispersible tablet, in a minimal amount of water immediately before administration.

Dosage

Pediatric Patients

PAH

Oral

Patients >12 years of age weighing >40 kg: Initially, 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily.

Patients >12 years of age weighing <40 kg: Initially, 62.5 mg twice daily for 4 weeks, followed by 62.5 mg twice daily.

Patients 3–12 years of age weighing ≥4–8 kg: 16 mg twice daily for initial and maintenance therapy.

Patients 3–12 years of age weighing >8–16 kg: 32 mg twice daily for initial and maintenance therapy.

Patients 3–12 years of age weighing >16–24 kg: 48 mg twice daily for initial and maintenance therapy.

Patients 3–12 years of age weighing >24–40 kg: 64 mg twice daily for initial and maintenance therapy.

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.

Dosage Modification for Toxicity

Hepatotoxicity

If aminotransferase levels increase to >3 times ULN without clinical symptoms of hepatotoxicity, temporary interruption of therapy, dosage reduction, and/or discontinuance of bosentan may be necessary.

If aminotransferase levels increase to >3 but ≤5 times ULN without clinical symptoms of hepatotoxicity, retest aminotransferase levels to confirm the result. In adults and pediatric patients >12 years of age and >40 kg with confirmed aminotransferase elevation, reduce bosentan dosage to 62.5 mg twice daily or interrupt treatment. Monitor aminotransferase levels at least every 2 weeks. If aminotransferase levels return to pretreatment values, may continue treatment or reintroduce at 62.5 mg twice daily; re-assess aminotransferase levels within 3 days. In pediatric patients ≤12 years of age and/or ≤40 kg with confirmed aminotransferase elevation, interrupt treatment. If aminotransferase levels return to pretreatment levels, reintroduce bosentan at the dosage used prior to treatment interruption; reassess aminotransferase levels within 3 days.

If aminotransferase levels increase to >5 but ≤8 times ULN without clinical symptoms of hepatotoxicity, retest aminotransferase levels to confirm the result; if confirmed, interrupt bosentan treatment and monitor aminotransferase levels at least every 2 weeks. Once aminotransferase levels return to pretreatment levels, may resume bosentan therapy. In adults and pediatric patients >12 years of age and >40 kg, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. In pediatric patients ≤12 years of age and/or ≤40 kg, consider reintroduction at the dosage used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days.

If aminotransferase levels increase to >8 times ULN without clinical symptoms of hepatotoxicity, discontinue bosentan; no experience with reintroduction of bosentan in these circumstances.

If aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue), or if bilirubin elevations ≥2 times ULN, discontinue bosentan; no experience with reintroduction of bosentan in these circumstances.

Concomitant Use with Ritonavir

When bosentan therapy is initiated in patients who have been receiving ritonavir for ≥10 days, initiate bosentan at the recommended initial dosage once daily or every other day based on individual patient tolerance.

When therapy with ritonavir is initiated in patients receiving bosentan, discontinue bosentan ≥36 hours prior to initiating ritonavir; after ≥10 days of ritonavir therapy, may resume bosentan at the recommended initial dosage once daily or every other day based on patient tolerance.

Special Populations

Hepatic Impairment

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

Avoid use in patients with aminotransferases >3 times ULN at baseline and/or preexisting moderate or severe hepatic impairment (Child-Pugh class B or C).

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

Elevations in serum aminotransferase (AST/ALT) concentrations reported in both adults and pediatric patients, sometimes accompanied by elevated bilirubin. Combined elevation of aminotransferases and total bilirubin is a marker for potential serious hepatotoxicity. (See Boxed Warning.)

Elevations in aminotransferase concentrations are dose-dependent, may occur at any point during treatment, are typically asymptomatic, and generally progress slowly. In most cases reversible after treatment interruption or cessation; may also reverse spontaneously during continued treatment.

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

Manufacturer reinforces importance of strict adherence to monthly monitoring schedule for the duration of bosentan therapy and to dosage adjustment and monitoring guidelines.

Measure serum aminotransferase concentrations prior to initiation of therapy and then monthly thereafter. Dosage reduction or discontinuance of the drug may be necessary depending on the degree of hepatic impairment. If liver aminotransferase elevations are accompanied by bilirubin levels ≥2 times ULN and/or clinical symptoms of hepatotoxicity (e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue), discontinue bosentan.

Avoid initiation of bosentan in patients with elevated aminotransferases (>3 times ULN) at baseline, because monitoring hepatotoxicity may be more difficult in these patients.

In patients with WHO functional class II PAH, consider whether benefits of bosentan are sufficient to outweigh risks of hepatotoxicity.

Fetal/Neonatal Morbidity and Mortality

Based on data from animal studies, bosentan may cause fetal harm, including birth defects and fetal death.

Exclude pregnancy prior to initiating bosentan therapy in females of childbearing potential. (See Pregnancy under Cautions.)

Women of childbearing potential must use 2 reliable contraceptive methods during and for 1 month following cessation of therapy.

Other Warnings and Precautions

Fluid Retention

Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported. Peripheral edema is 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.

Pulmonary Veno-Occlusive Disease

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

Decreased Sperm Counts

Reduced sperm counts observed in men with PAH receiving usual dosages of bosentan; cannot exclude possibility of adverse effects on spermatogenesis. May impair fertility in males of reproductive potential; unknown whether such effects would be reversible.

Decreases in Hemoglobin and Hematocrit

Possible dose-related decreases in hemoglobin and hematocrit. Anemia requiring transfusion reported in the postmarketing setting.

Monitor hemoglobin 1 and 3 months after initiation of therapy and every 3 months thereafter.

Specific Populations

Pregnancy

Based on data from animal reproduction studies, bosentan may cause fetal harm, including birth defects and fetal death. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Contraindicated during pregnancy; exclude pregnancy before treatment is initiated. Females of reproductive potential must use 2 acceptable methods of contraception during treatment and for 1 month after treatment discontinuation. Pregnancy testing should occur monthly during therapy with the drug and one month after stopping treatment.

If bosentan is used during pregnancy or if patient becomes pregnant during therapy, apprise patient of potential hazard to the fetus.

Lactation

No data on the presence of bosentan in human milk, effects on the breastfed infant, or effect on milk production.

Because of the potential for serious adverse reactions to bosentan in breastfed infants (e.g., fluid retention, hepatotoxicity), advise patients not to breastfeed during treatment with bosentan.

Females and Males of Reproductive Potential

Exclude pregnancy before treatment is initiated in females of reproductive potential. Such females should use 2 reliable contraceptive methods during and for 1 month following treatment, unless patient has undergone tubal sterilization or chooses to use an IUD, in which case no additional contraceptive is needed. Hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients receiving bosentan, and they should not be used as the only contraceptive method. If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must also be used.

Advise patients on pregnancy planning and prevention, including emergency contraception.

Perform pregnancy testing monthly during therapy and 1 month after stopping treatment. Advise females of reproductive potential to contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected.

Decreased sperm counts observed. Bosentan may impair fertility in males of reproductive potential; unknown whether effects on fertility are reversible.

Pediatric Use

Efficacy in patients <18 years of age supported by an uncontrolled trial in 19 pediatric patients. In this study, hemodynamic improvements were similar to those seen in adults. Safety of bosentan in pediatric patients is supported by data from 100 pediatric patients treated with bosentan for a median of 17 months.

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 Cl_cr 15–30 mL/minute) on bosentan pharmacokinetics.

Common Adverse Effects

Common adverse effects with conventional tablets (≥3%): respiratory tract infection, anemia.

Common adverse effects with dispersible tablets (≥15%): upper respiratory tract infection, pyrexia.

Drug Interactions

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

Bosentan Pharmacokinetics

Absorption

Bioavailability

Healthy individuals: Following oral administration, peak plasma concentrations attained within approximately 3–5 hours. Absolute bioavailability about 50%.

Food

Food does not affect bioavailability.

Special Populations

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

Exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses higher than 2 mg/kg twice daily do not increase exposure to bosentan in pediatric patients.

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

Film-coated Tablets

20–25°C (may be exposed to 15–30°C).

Dispersible Tablets for Oral Suspension

Intact tablets: 20–25°C (excursions permitted to 15–30°C).

Divided tablets: 20–25°C in the opened blister for up to 7 days.

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 advising females of reproductive potential to avoid pregnancy and to use 2 reliable methods of contraception simultaneously during and for 1 month following bosentan therapy unless the patient has undergone tubal sterilization or chooses to use an intrauterine device (IUD), in which case no additional contraceptive is needed. If the partner has had a vasectomy, an additional hormonal or barrier method must be used. Advise patients to contact their clinician if they want to change the form of birth control which is used, to ensure that another acceptable form of birth control is selected. Discuss the use of emergency contraception in the event of unprotected sex or contraceptive failure. Advise prepubertal females to immediately report any changes to their reproductive status to their clinician. Advise female patients to inform their clinician immediately if a menstrual period is missed or pregnancy is suspected. Apprise patient of potential risk to fetus if pregnancy occurs.

• Importance of avoiding breastfeeding while on bosentan.

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

• Importance of advising males of reproductive potential that bosentan may impair fertility and decrease sperm counts.

• Importance of advising patients that bosentan dispersible tablets contain phenylalanine (1.87 mg per tablet).

• Risk of decreases in hemoglobin and hematocrit. Advise patients on the importance of hemoglobin testing.

• Risk of fluid retention; advise patients to report swelling of the ankles (with or without weight gain) or trouble breathing.

• Importance of patients taking bosentan as prescribed and of not interrupting or discontinuing therapy without consulting a clinician.

• 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.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

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

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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 REMS under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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