Class: Vasodilating Agents, Miscellaneous
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
- Hepatotoxicity
Risk of developing serious hepatic injury.1 b With close monitoring, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged bosentan therapy (>12 months) during postmarketing surveillance.a c
Serum aminotransferase (AST/ALT) concentrations must be measured prior to initiation of therapy and monthly thereafter.1 b c (See Hepatic Effects under Cautions.)
In patients with adverse hepatic effects, dosage reduction or discontinuance of the drug may be necessary.1 c (See Patients with Adverse Hepatic Effects under Dosage and Administration.)
Bosentan generally should be avoided in patients with elevated aminotransferases (>3 × ULN) at baseline (because monitoring for liver injury may be more difficult) and in those with preexisting moderate to severe hepatic impairment.1 b
- Fetotoxicity
May cause fetal harm; contraindicated in pregnant women.1 b Pregnancy must be excluded before start of treatment and prevented thereafter by use of reliable contraception.1 b (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Oral, injectable, transdermal, and implantable hormonal contraceptives may not be reliable when used concomitantly with bosentan and should not be used as the sole contraceptive method; additional forms of nonhormonal contraception should be used.1 b (See Specific Drugs under Interactions.)
REMS:
FDA approved a REMS for bosentan to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of bosentan and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Vasodilator; an endothelin receptor antagonist.1
Uses for Bosentan
Pulmonary Arterial Hypertension
Adjunctive therapy for the treatment of pulmonary arterial hypertension (PAH) (WHO group I), in patients with WHO class III or IV symptoms to improve exercise capacity and to slow clinical worsening.1 2 3 6
Additional studies needed to clarify the role of oral bosentan with or without concomitant IV epoprostenol in the treatment of PAH, particularly in patients with WHO class IV symptoms.4 7
CHF
Not effective in treatment of CHF with left ventricular dysfunction†.a
Bosentan Dosage and Administration
General
Restricted distribution program (see Boxed Warning); not available through community pharmacies.1 5 6 9 b c Contact manufacturer at 866-228-3546 for specific information.1 5
Medication guide must be distributed each time bosentan is dispensed.6 b
Avoid abrupt discontinuance.1 9 b To minimize the risk for clinical deterioration, consider gradual dosage reduction (e.g., 62.5 mg twice daily for 3–7 days).1 9
Administration
Oral Administration
Administer orally twice daily (morning and evening) without regard to meals.1 b
Dosage
Adults
Pulmonary Arterial Hypertension
Oral
Initially, 62.5 mg twice daily for 4 weeks, followed by maintenance dosage of 125 mg twice daily.1
Special Populations
Patients with Adverse Hepatic Effects
If elevations in AST and ALT concentrations are accompanied by manifestations of hepatic disease (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) or bilirubin concentrations are ≥2 × ULN, discontinue bosentan by gradually reducing dosage (e.g., 62.5 mg twice daily for 3–7 days).1 9
If confirmed (i.e., upon a repeat test) AST or ALT elevations of >3 but ≤5 × ULN develop during bosentan therapy, reduce dosage or interrupt therapy.1 9 c
If confirmed AST or ALT concentrations of >5 but ≤8 × ULN, discontinue bosentan by gradually reducing dosage.1 9 c
Monitor serum AST/ALT concentrations at least every 2 weeks following dosage reduction or discontinuance.1 c
May consider reinitiation of bosentan therapy at starting dosage of 62.5 mg twice daily following return of AST/ALT concentrations to pretreatment levels if AST/ALT elevations did not exceed 8 × ULN; check serum AST/ALT concentrations within 3 days of reinitiating therapy and every 2 weeks thereafter.1 9 c
Manufacturer states that reinitiation of bosentan therapy should not be considered if AST/ALT concentrations exceeded 8 × ULN.1 c 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 × ULN.1 c
Patients with Low Body Weight
In patients >12 years of age who weigh <40 kg, recommended dosage for both initial and maintenance therapy is 62.5 mg twice daily.1
Cautions for Bosentan
Contraindications
Known or suspected pregnancy.1 b
Concomitant therapy with cyclosporine or glyburide.1 b
Known hypersensitivity to bosentan or any ingredient in the formulation.1 b
Warnings/Precautions
Warnings
Hepatic Effects
With close monitoring, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged bosentan therapy (i.e., >12 months) during postmarketing surveillance.a c (See Boxed Warning.)
In at least 1 patient, marked elevations in liver function test results developed (after >20 months of bosentan therapy) accompanied by nonspecific symptoms.a c Following discontinuance, AST/ALT concentrations remained elevated and bilirubin concentrations continued to increase; liver failure and biopsy-confirmed cirrhosis developed.a c Causality to the drug could not be excluded.a c Liver failure later abated and liver function tests slowly resolved (7 months after discontinuance).c (See Boxed Warning.)
The manufacturer reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of bosentan therapy and to dosage adjustment and monitoring guidelines.a c (See Patients with Adverse Hepatic Effects under Dosage and Administration.)
Dose-dependent elevations in AST or ALT concentrations of >3 × ULN were observed in 11% of patients receiving bosentan (up to 2 g daily) in clinical trials; occasionally accompanied by elevations in bilirubin concentrations,1 9 indicating potential serious hepatic injury.1 (See Boxed Warning.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 b
Prior to initiating therapy in women of childbearing potential, ascertain that patient is not sexually active or is not pregnant (i.e., by obtaining negative results from 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).1 5 6 b
Must prevent pregnancy by means of reliable contraceptive methods.1 b (See Specific Drugs under Interactions.) Perform serum pregnancy tests monthly.1 9 b c
Sensitivity Reactions
Hypersensitivity Reactions
Angioedema (occurring 8 hours to 21 days after initiating therapy) reported during postmarketing surveillance.a
General Precautions
Hematologic Effects
Possible dose-related decreases in hemoglobin and hematocrit.1 9 b Monitor hemoglobin 1 and 3 months after initiation of therapy and every 3 months thereafter.1
Cardiovascular Effects
Increased hospitalization for CHF associated with weight gain and increased leg edema reported in patients with severe CHF during first 4–8 weeks of therapy.a
Fluid retention requiring diuretics, fluid management, or hospitalization for decompensating heart failure within weeks of initiating therapy reported in patients with PAH during postmarketing surveillance.a
Pulmonary Effects
Consider possibility of associated pulmonary veno-occlusive disease (PVOD) and discontinue bosentan if manifestations of pulmonary edema occur during therapy.a
Specific Populations
Pregnancy
Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)
Lactation
Not known whether bosentan is distributed into milk.1 b Use is not recommended.1 b
Pediatric Use
Safety and efficacy not established in children <12 years of age.5
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1
Hepatic Impairment
Use not recommended in patients with preexisting moderate to severe hepatic impairment or AST/ALT concentrations of >3 × ULN.1 9 Use with caution in patients with mild hepatic impairment.1
Common Adverse Effects
Headache,1 b nasopharyngitis,1 b flushing,1 b abnormal hepatic function,1 lower limb edema,1 b hypotension,1 b palpitations,1 b dyspepsia,1 b edema,1 fatigue,1 b pruritus,1 b rash,b anemia.1 b
Interactions for Bosentan
Induces and is metabolized by CYP2C9 and CYP3A4; may possibly induce CYP2C19.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP2C9 and CYP3A4: potential pharmacokinetic interaction (increased plasma bosentan concentrations).1 Concomitant administration of both a potent inhibitor of CYP2C9 and an inhibitor of CYP3A4 with bosentan is not recommended.a
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2C9 and CYP3A4 and possibly CYP2C19: potential pharmacokinetic interaction (decreased plasma substrate concentrations).1 9
Specific Drugs
Drug
|
Interaction
|
Comments
|
|---|
Antidiabetic agents, oral
|
Decreased plasma concentrations of antidiabetic agents metabolized by CYP2C9 or CYP3A41 9
|
|
Amiodarone
|
Increased plasma bosentan concentrations, particularly if combined with an inhibitor of CYP3A4a
|
Do not use concomitantly with both an inhibitor of CYP3A4 and bosentana
|
Atorvastatin
|
Decreased plasma atorvastatin concentrations1 9
|
|
Cyclosporine
|
Increased plasma bosentan concentrations, decreased plasma cyclosporine concentrations1
|
Concomitant use contraindicated1
|
Digoxin
|
Pharmacokinetic interaction unlikely1
|
|
Fluconazole
|
Increased plasma bosentan concentrations, particularly if combined with an inhibitor of CYP3A4a
|
Do not use concomitantly with both an inhibitor of CYP3A4 and bosentana
|
Glyburide
|
Increased risk of elevated serum aminotransferase concentrations; decreased plasma glyburide concentrations; decreased plasma bosentan concentrations1
|
Concomitant use contraindicated1
|
Hormonal contraceptives
|
Decreased plasma norethindrone and ethinyl estradiol concentrations;a possible contraceptive failure secondary to induction of contraceptive hormone metabolism1
|
Use concomitant nonhormonal contraceptive method;1 do not use hormonal contraceptives as the sole contraceptive methoda
|
Itraconazole
|
Increased plasma bosentan concentrations, particularly if combined with an inhibitor of CYP2C9a
|
Do not use concomitantly with both a potent inhibitor of CYP2C9 and bosentana
|
Ketoconazole
|
Increased plasma bosentan concentrations, especially if combined with an inhibitor of CYP2C91
|
Bosentan dosage adjustment not necessary, but consider potential for increased effects1
Do not use concomitantly with both a potent inhibitor of CYP2C9 and bosentana
|
Losartan
|
Pharmacokinetic interaction unlikely1
|
|
Lovastatin
|
Decreased plasma lovastatin concentrations1 9
|
|
Nimodipine
|
Pharmacokinetic interaction unlikely1
|
|
Ritonavir
|
Increased plasma bosentan concentrations, particularly if combined with an inhibitor of CYP2C9a
|
Do not use concomitantly with both a potent inhibitor of CYP2C9 and bosentana
|
Sildenafil
|
Decreased plasma sildenafil concentrationsa
Increased plasma bosentan concentrationsa
|
Bosentan or sildenafil dosage adjustment not necessary, whether sildenafil is being used in the treatment of PAH or erectile dysfunctiona
|
Simvastatin
|
Decreased plasma simvastatin concentrations1 9
|
|
Tacrolimus
|
Increased plasma bosentan concentrations in animalsa
|
Use concomitantly with cautiona
|
Warfarin
|
Decreased plasma warfarin concentrations1 9
|
|
Bosentan Pharmacokinetics
Absorption
Bioavailability
Absolute bioavailability in healthy individuals is about 50%.1
Food
Food does not affect bioavailability.1
Plasma Concentrations
Maximum plasma concentrations attained within 3–5 hours; steady state reached within 3–5 days.1
Special Populations
Increased exposure (twofold) to bosentan following oral or IV administration in patients with PAH compared with healthy individuals.1
Distribution
Extent
Does not penetrate into erythrocytes.1
Plasma Protein Binding
>98% (mainly albumin).1
Elimination
Metabolism
Metabolized by CYP2C9 and CYP3A4; appears to induce its own metabolism following multiple-dose administration.1
Elimination Route
Biliary excretion following metabolism in the liver.1
Half-life
Terminal elimination half-life is about 5 hours.1
Special Populations
Because of extensive hepatic metabolism, hepatic impairment may increase exposure to the drug.1
Pharmacokinetics of the drug not affected in patients with mild hepatic impairment; not evaluated in those with moderate or severe hepatic impairment.a
Stability
Storage
Oral
Tablets
20–25°C (may be exposed to 15–30°C).1
Actions
Exhibits specific and competitive antagonism of endothelin type A and type B receptors in the endothelium and vascular smooth muscle.1
Improves exercise capacity and hemodynamics in patients with PAH by inhibiting vasoconstricting effects of endothelin-1.1
Advice to Patients
Importance of patients taking medication as prescribed.b Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.b
Risk of liver injury.1 b Importance of patients promptly informing clinicians of any nausea, vomiting, fever, unusual tiredness, abdominal pain, or yellowing of the skin or white of the eyes.a b
Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 b
Importance of avoidance of pregnancy; importance of using reliable nonhormonal methods of contraception.1 b
Importance of monthly monitoring of serum aminotransferases and monthly pregnancy testing.1 b c
Importance of carefully reading the patient information (medication guide) provided by the manufacturer before initiating therapy and each time the prescription is refilled.1 b
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as concomitant illnesses.1 b
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Distribution of bosentan is restricted.1 5 6 b c (See General under Dosage and Administration.)
Bosentan
Routes
|
Dosage Forms
|
Strengths
|
Brand Names
|
Manufacturer
|
|---|
Oral
|
Tablets, film-coated
|
62.5 mg (of anhydrous bosentan)
|
Tracleer (with povidone)
|
Actelion
|
|
|
125 mg (of anhydrous bosentan)
|
Tracleer (with povidone)
|
Actelion
|
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
1. Actelion Pharmaceuticals US. Tracleer (bosentan) tablets prescribing information. South San Francisco, CA: 2001 Nov.
2. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002; 346:896-903. [IDIS 478525] [PubMed 11907289]
3. Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001; 358:1119-23. [IDIS 471290] [PubMed 11597664]
4. Dupuis J. Endothelin-receptor antagonists in pulmonary hypertension. Lancet. 2001; 358:1113-4. [IDIS 471289] [PubMed 11597660]
5. Giaid A, Yanagisawa M, Langleben D et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypersion. N Engl J Med. 1993; 328:1732-9 [PubMed 8497283]
6. FDA approves first oral medication for pulmonary arterial hypertension. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2001 Nov 20.
7. Newman JH. Treatment of primary pulmonary hypertension—the next generation. N Engl J Med. 2002; 346:933-5. [IDIS 478527] [PubMed 11907295]
8. Stewart DJ, Levy RD, Cernacek P et al. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease. Ann Intern Med. 1991; 114:464-9. [PubMed 1994793]
9. Actelion, South San Francisco, CA: Personal communication.
a. Actelion Pharmaceuticals US. Tracleer (bosentan) tablets prescribing information. South San Francisco, CA: 2006 Jan.
b. Actelion Pharmaceuticals US. Tracleer (bosentan) tablets medication guide. South San Francisco, CA: 2005 Nov 14.
c. Segal ES. Dear healthcare professional letter regarding important prescribing information for Tracleer (bosentan). South San Francisco, CA: Actelion Pharmaceuticals US; 2006 Mar 1.
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