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Treatment of pulmonary artery hypertension (PAH) in patients with World Health Organization (WHO) Class III or IV symptoms to improve exercise capacity and decrease the rate of clinical deterioration
Investigational: Congestive heart failure
Bosentan (Tracleer®) is available only through a limited distribution program directly from the manufacturer (Actelion Pharmaceuticals 1-866-228-3546). It will not be available through wholesalers or individual pharmacies.
Based on animal studies, bosentan is likely to produce major birth defects if used by pregnant women. Pregnancy must be excluded prior to initiation of therapy, and effective contraception must be maintained throughout treatment. Hormonal contraception is not recommended as the sole contraceptive therapy due to a potential lack of efficacy in patients receiving bosentan.
Excretion in breast milk unknown/not recommended
Hypersensitivity to bosentan or any component of the formulation; concurrent use of cyclosporine or glyburide; pregnancy
Avoid use in moderate to severe hepatic impairment. Associated with a high incidence (11%) of significant transaminase elevations, indicating a potential for serious hepatic injury. Avoid use in patients with elevated serum transaminases (>3 times upper limit of normal) at baseline; dosage adjustment recommended if elevations occur during therapy. Monitor hepatic function closely (at least monthly). Treatment should be stopped in patients who develop elevated transaminases (ALT or AST) in combination with symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting, abdominal pain, and/or fever) or elevated serum bilirubin 2 times upper limit of normal.
Use in pregnancy is contraindicated; exclude pregnancy prior to initiation of therapy; patients must be instructed to use effective, nonhormonal contraception throughout treatment. Efficacy of hormonal contraceptive may be decreased, and should not be the sole contraceptive method in patients receiving bosentan. Use caution in patients with low hemoglobin levels or ischemic cardiovascular disease. May cause dose-related decreases in hemoglobin and hematocrit (monitoring of hemoglobin is recommended). May cause fluid retention evidenced by signs and symptoms of CHF, weight gain, and leg edema. Safety and efficacy in pediatric patients have not been established.
Central nervous system: Headache (16% to 22%)
Hematologic: Hemoglobin decreased (
Hepatic: Transaminases increased (>3 times upper limit of normal; up to 11%)
Respiratory: Nasopharyngitis (11%)
1% to 10%:
Cardiovascular: Flushing (7% to 9%), edema (lower limb, 8%; generalized 4%), hypotension (7%), palpitation (5%)
Central nervous system: Fatigue (4%)
Dermatologic: Pruritus (4%)
Gastrointestinal: Dyspepsia (4%)
Hematologic: Anemia (3%)
Hepatic: Abnormal hepatic function (6% to 8%)
<1%: Angioneurotic edema
Postmarketing and/or case reports: CHF (exacerbation), hypersensitivity, peripheral edema, rash, weight gain
No specific experience in overdose. Symptoms may include headache, nausea, vomiting, and hypotension. Treatment is supportive.
(major) of CYP2C8/9, 3A4; CYP2C8/9 (weak), 3A4 (weak)SubstrateInduces
Cyclosporine: Bosentan may enhance the metabolism of cyclosporine, decreasing its serum concentrations by ~50%; effect on sirolimus and/or tacrolimus has not been specifically evaluated, but may be similar. Cyclosporine increases serum concentrations of bosentan (approximately 3-4 times baseline). Concurrent use of cyclosporine is contraindicated.
CYP2C8/9 inducers: May decrease the levels/effects of bosentan. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.
CYP2C8/9 inhibitors: May increase the levels/effects of bosentan. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of bosentan. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of bosentan. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.
Glyburide: An increased risk of serum transaminase elevations was observed during concurrent therapy with bosentan. Concurrent use is contraindicated.
HMG-CoA reductase inhibitors: Agents metabolized via CYP3A4 may be decreased by bosentan; includes atorvastatin, lovastatin, and simvastatin.
Ketoconazole: May increase the serum concentrations of bosentan; concentrations are increased approximately twofold; monitor for increased effects.
Warfarin: Bosentan may increase the metabolism of oral anticoagulants; monitor for changes in INR.
Food: Bioavailability of bosentan is not affected by food.
Herb/Nutraceutical: Avoid St John's wort (may decrease serum concentrations of bosentan).
Store at 20°C to 25°C (68°F to 77°F).
Blocks endothelin receptors on vascular endothelium and smooth muscle. Stimulation of these receptors is associated with vasoconstriction. Although bosentan blocks both ETA and ETB receptors, the affinity is higher for the A subtype. Improvement in symptoms of pulmonary artery hypertension and a decrease in the rate of clinical deterioration have been demonstrated in clinical trials.
Distribution: Vd: 18 L
Protein binding, plasma: >98% to albumin
Metabolism: Hepatic via CYP2C9 and 3A4 to three primary metabolites (one having pharmacologic activity)
Half-life elimination: 5 hours; prolonged with heart failure, possibly in PAH
Excretion: Feces (as metabolites); urine (<3% as unchanged drug)
Oral: Adults: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily; adults <40 kg should be maintained at 62.5 mg twice daily
Note: When discontinuing treatment, consider a reduction in dosage to 62.5 mg twice daily for 3-7 days (to avoid clinical deterioration).
Dosage adjustment in renal impairment: No dosage adjustment required.
Dosage adjustment in hepatic impairment: Avoid use in patients with pretreatment moderate to severe hepatic insufficiency.
Modification based on transaminase elevation:
If any elevation, regardless of degree, is accompanied by clinical symptoms of hepatic injury (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin
AST/ALT >3 times but
AST/ALT >5 times but
AST/ALT >8 times upper limit of normal: Stop treatment.
May be administered with or without food, once in the morning and once in the evening.
Serum transaminase (AST and ALT) should be determined prior to the initiation of therapy and at monthly intervals thereafter. A woman of childbearing potential must have a negative pregnancy test prior to the initiation of therapy and monthly thereafter. Hemoglobin and hematocrit should be measured at baseline, at 1 month and 3 months of treatment, and every 3 months thereafter. Monitor for clinical signs and symptoms of liver injury.
May be taken with or without food.
Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed, with or without food. You will need frequent laboratory tests to determine effectiveness of this medication. You may experience headache (consult prescriber for approved analgesic); or GI upset (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report persistent headache or GI problems, swelling of extremities, or unusual weight gain (>5 lb/week); runny nose or persistent signs of a cold; chest pain or palpitations; unusual fatigue or weakness; yellowing of skin or eyes; change in color of stool or urine; or other persistent reactions. Approved only for postmenopausal women. Female patients must have a negative pregnancy test prior to beginning therapy. This drug may cause severe fetal abnormalities. Breast-feeding is not recommended.Pregnancy/breast-feeding precautions:
No significant effects or complications reported
No information available to require special precautions
May cause sedation
Carbamazepine, other anticonvulsants, and St John's wort may decrease the effects of bosentan. Conversely, nefazodone may increase the effects of bosentan.
Tablet: 62.5 mg, 125 mg
Tracleer® (AT, CA, CH, DE, ES, FR, GB, IE, IL, IT, NO, SE)