Trade Names:Tracleer- Tablets 62.5 mg- Tablets 125 mg
Antagonizes endothelin (ET) receptor by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle.
T max is 3 to 5 h. Absolute bioavailability is approximately 50%. Steady state is reached in 3 to 5 days.
Vd is approximately 18 L. More than 98% protein bound (mainly albumin).
Metabolized in the liver. There are 3 metabolites, one of which contributes 10% to 20% of bosentan's effects. Bosentan induces CYP2C9, CYP3A4, and possibly CYP2C19; it may induce its own metabolism.
Half-life is approximately 5 h. Eliminated by biliary excretion; less than 3% is recovered in urine. Cl is 4 L/h.
In those with severe renal impairment (CrCl 15 to 30 mL/min), concentrations of the 3 metabolites may increase 2-fold, although it is not clinically significant.Hepatic Function Impairment
Exposure to bosentan would be significantly increased; avoid use in those with moderate or severe liver impairment or elevated aminotransferases more than 3 times the ULN.Elderly
It is not known whether bosentan pharmacokinetics are influenced by age.Children
It is not known whether bosentan pharmacokinetics are influenced by age.Gender
It is not known whether bosentan pharmacokinetics are influenced by gender.Body weight
It is not known whether bosentan pharmacokinetics are influenced by body weight.
Treatment of pulmonary arterial hypertension (PAH) in patients with WHO Class III and IV symptoms, to improve exercise ability and decrease the rate of clinical worsening.
Coadministration of cyclosporine or glyburide; hypersensitivity to bosentan or any component of the product; pregnancy.
PO 62.5 mg twice daily for 4 wk; then increase to maintenance dosage of 125 mg twice daily.Dosage Adjustment
If ALT/AST is more than 3 and less than or equal to 5 times the ULN, confirm by another aminotransferase test. If confirmed, reduce the daily dosage to 62.5 mg twice daily or interrupt treatment and monitor aminotransferase levels at least every 2 wk. If the aminotransferase levels return to pretreatment values, continue or reintroduce the treatment as appropriate. If ALT/AST is more than 5 and less than or equal to 8 times the ULN, confirm by another aminotransferase test. If confirmed, stop treatment and monitor aminotransferase levels at least every 2 wk. Once the aminotransferase levels return to pretreatment values, consider reintroduction of the treatment. If ALT/AST is more than 8 times the ULN, treatments should be stopped and reintroduction of bosentan should not be considered.Discontinuation of therapy
Consider gradual dose reduction (62.5 mg twice daily for 3 to 7 days).Patients under 40 kg but older than 12 yr of age Initial and maintenance dose
PO 62.5 mg twice daily.
Store at 59° to 86°F.
Bosentan trough concentrations may be increased, while cyclosporine plasma levels may be decreased; coadministration is contraindicated.Glyburide
Plasma concentrations of both glyburide and bosentan may be decreased; coadministration is contraindicated.HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, simvastatin)
Plasma concentrations of simvastatin and its metabolite may be decreased when coadministered with bosentan. Bosentan is also expected to reduce plasma concentrations of other HMG-CoA reductase inhibitors metabolized by CYP3A4 (ie, atorvastatin, lovastatin). Monitor cholesterol levels and adjust the HMG-CoA reductase inhibitor dose accordingly.Hormonal contraceptives (ie, oral, injectable, implantable, transdermal)
Plasma concentrations may be reduced by bosentan, decreasing the effectiveness. Women should not rely on hormonal contraception alone when taking bosentan.Ketoconazole
Plasma concentrations of bosentan may be increased. No dosage adjustment is necessary, but consider increased effects of bosentan. Addition monitoring is warranted.Phosphodiesterase type 5 inhibitors (eg, sildenafil)
Coadministration may elevate bosentan plasma concentrations, increasing the pharmacologic effects and risk of toxicity. Phosphodiesterase type 5 inhibitor concentrations may be reduced, decreasing the pharmacologic effects. Coadminister these agents with caution. Closely monitor the clinical response and for adverse reactions. Adjust therapy as needed.Rifampin
Coadministration may increase bosentan trough concentrations after the first concomitant dose and decrease bosentan trough concentrations at steady-state. Measure liver function weekly for the first 4 wk of concurrent use before reverting to normal monitoring.Ritonavir-containing regimens
Coadministration may increase bosentan trough concentrations. In patients receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on tolerability. In patients receiving bosentan, stop bosentan at least 36 hours before starting ritonavir. At least 10 days after starting ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon tolerability.Tacrolimus
Although not studied in humans, coadministration resulted in markedly increased plasma concentrations of bosentan in animals. Use with caution.Warfarin
Warfarin plasma concentrations may be decreased by bosentan. Clinically important changes in INR or warfarin dose were not seen in patients with PAH during clinical trials. Because warfarin has a narrow therapeutic index, monitor coagulation parameters and adjust the warfarin dose as needed.
None well documented.
Syncope (5%); hypotension, palpitations (4%).
Anemia (3%); anemia requiring transfusion, leukopenia, neutropenia, thrombocytopenia (postmarketing).
Abnormal hepatic function test (4%); hepatic cirrhosis, jaundice, liver failure (postmarketing).
Respiratory tract infection (22%); sinusitis (4%).
Edema (11%); chest pain (5%); arthralgia, flushing (4%); angioneurotic edema, hypersensitivity (postmarketing).
WarningsPotential liver injury
At least 3-fold increase in ALT or AST occurs in approximately 11% of patients, accompanied by elevated bilirubin in a small number of cases. Serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid use in patients with aminotransferases elevations (greater than 3 times ULN) at baseline. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting) or increases in bilirubin greater than or equal to 2 times ULN, stop treatment.Pregnancy
Bosentan is very likely to produce major birth defects if used by pregnant women; this effect has been seen consistently when it is administered to animals. Therefore, pregnancy must be excluded before the start of treatment with bosentan and prevented thereafter by the use of a reliable method of contraception. Do not use hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, as the sole means of contraception because these may not be effective in patients receiving bosentan. Therefore, effective contraception through additional forms of contraception must be practiced. Obtain monthly pregnancy tests.Distribution program
Because of potential liver injury and in an effort to make the chance of fetal exposure to bosentan as small as possible, bosentan may be prescribed only through the Tracleer Access Program by calling 1-866-228-3546. Only prescribers and pharmacies registered may prescribe and distribute bosentan. In addition, bosentan may be dispensed only to patients who are enrolled in and meet all the conditions of the program.
Ensure that liver enzymes are measured before starting therapy and monthly during treatment. Ensure that Hgb is measured after 1 and 3 mo of therapy and then every 3 mo for duration of treatment. Document baseline disease state activity (eg, exercise capacity, walking distance). Reassess periodically to document response to therapy. Monitor for signs of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting). Discontinue medication if noted.
Category X . Pregnancy must be excluded before starting bosentan.
Safety and efficacy not established.
Select dose with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and comorbidity.
Avoid use in patients with moderate or severe hepatic impairment or elevated aminotransferases (more than 3 times the ULN).
There was a decline in sperm count of at least 50% in 25% of patients after 3 or 6 mo of treatment with bosentan.
Dose-related decreases in hemoglobin and hematocrit may occur.
Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and discontinue bosentan.
Blurred vision, decreased blood pressure, dizziness, headache, increased heart rate, nausea, sweating, vomiting.
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