Risk of developing serious hepatic injury. With close monitoring, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged bosentan therapy (>12 months) during postmarketing surveillance.
Serum aminotransferase (AST/ALT) concentrations must be measured prior to initiation of therapy and monthly thereafter. (See Hepatic Effects under Cautions.)
In patients with adverse hepatic effects, dosage reduction or discontinuance of the drug may be necessary. (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.
Fetotoxicity
May cause fetal harm; contraindicated in pregnant women. Pregnancy must be excluded before start of treatment and prevented thereafter by use of reliable contraception. (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. (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 ([Web]) or the ASHP REMS Resource Center ([Web]).
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.
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.
CHF
Not effective in treatment of CHF with left ventricular dysfunction†.
Dosage and Administration
General
Restricted distribution program (see Boxed Warning); not available through community pharmacies. Contact manufacturer at 866-228-3546 for specific information.
Medication guide must be distributed each time bosentan is dispensed.
Avoid abrupt discontinuance. To minimize the risk for clinical deterioration, consider gradual dosage reduction (e.g., 62.5 mg twice daily for 3–7 days).
Administration
Oral Administration
Administer orally twice daily (morning and evening) without regard to meals.
Dosage
Adults
Pulmonary Arterial Hypertension
Oral
Initially, 62.5 mg twice daily for 4 weeks, followed by maintenance dosage of 125 mg twice daily.
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).
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.
If confirmed AST or ALT concentrations of >5 but ≤8 × ULN, discontinue bosentan by gradually reducing dosage.
Monitor serum AST/ALT concentrations at least every 2 weeks following dosage reduction or discontinuance.
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.
Manufacturer states that reinitiation of bosentan therapy should not be considered if AST/ALT concentrations exceeded 8 × 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 × ULN.
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.
With close monitoring, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged bosentan therapy (i.e., >12 months) during postmarketing surveillance. (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. Following discontinuance, AST/ALT concentrations remained elevated and bilirubin concentrations continued to increase; liver failure and biopsy-confirmed cirrhosis developed. Causality to the drug could not be excluded. Liver failure later abated and liver function tests slowly resolved (7 months after discontinuance). (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. (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, indicating potential serious hepatic injury. (See Boxed Warning.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.
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).
Must prevent pregnancy by means of reliable contraceptive methods. (See Specific Drugs under Interactions.) Perform serum pregnancy tests monthly.
Sensitivity Reactions
Hypersensitivity Reactions
Angioedema (occurring 8 hours to 21 days after initiating therapy) reported during postmarketing surveillance.
General Precautions
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.
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.
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.
Pulmonary Effects
Consider possibility of associated pulmonary veno-occlusive disease (PVOD) and discontinue bosentan if manifestations of pulmonary edema occur during therapy.
Specific Populations
Pregnancy
Category X. (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)
Lactation
Not known whether bosentan is distributed into milk. Use is not recommended.
Pediatric Use
Safety and efficacy not established in children <12 years of age.
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.
Hepatic Impairment
Use not recommended in patients with preexisting moderate to severe hepatic impairment or AST/ALT concentrations of >3 × ULN. Use with caution in patients with mild hepatic impairment.
Induces and is metabolized by CYP2C9 and CYP3A4; may possibly induce CYP2C19.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP2C9 and CYP3A4: potential pharmacokinetic interaction (increased plasma bosentan concentrations). Concomitant administration of both a potent inhibitor of CYP2C9 and an inhibitor of CYP3A4 with bosentan is not recommended.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2C9 and CYP3A4 and possibly CYP2C19: potential pharmacokinetic interaction (decreased plasma substrate concentrations).
Decreased plasma norethindrone and ethinyl estradiol concentrations; possible contraceptive failure secondary to induction of contraceptive hormone metabolism
Use concomitant nonhormonal contraceptive method; do not use hormonal contraceptives as the sole contraceptive method
Absolute bioavailability in healthy individuals is about 50%.
Food
Food does not affect bioavailability.
Plasma Concentrations
Maximum plasma concentrations attained within 3–5 hours; steady state reached within 3–5 days.
Special Populations
Increased exposure (twofold) 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.
Half-life
Terminal elimination half-life is about 5 hours.
Special Populations
Because of extensive hepatic metabolism, hepatic impairment may increase exposure to the drug.
Pharmacokinetics of the drug not affected in patients with mild hepatic impairment; not evaluated in those with moderate or severe hepatic impairment.
Stability
Storage
Oral
Tablets
20–25°C (may be exposed to 15–30°C).
Actions
Exhibits specific and competitive antagonism of 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
Importance of patients taking medication as prescribed. Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.
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 white of the eyes.
Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of avoidance of pregnancy; importance of using reliable nonhormonal methods of contraception.
Importance of monthly monitoring of serum aminotransferases and monthly pregnancy testing.
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 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.
Distribution of bosentan is restricted. (See General under Dosage and Administration.)
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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