Bosentan
Mechanism :
It is competitive antagonist of endothelin-1; blocks endothelin receptors on vascular endothelium and smooth muscle resulting in inhibition of vasoconstriction.
Indication :
- Pulmonary arterial hypertension in patients with WHO class III or IV symptoms.
Contraindications :
Hypersensitivity to bosentan or any of the components, concurrent use of cyclosporine or glyburide.
Dosing :
Persistent pulmonary hypertension of the newborn (PPHN):
≥34 weeks gestational age: Oral: Initial 1 mg/kg/dose twice daily; may increase to 2 mg/kg/dose twice daily.
Children 3 years-12 years:
4 to 8 kg: Oral: 16 mg twice daily
>8 to 16 kg: Oral: 32 mg twice daily
>16 to 24 kg: Oral: 48 mg twice daily
>24 to 40 kg: Oral: 64 mg twice daily
Children ≥12 years and Adolescents:
>20 to 40 kg: Initial: 31.25 mg twice daily; increase to a target dose of 62.5 mg twice daily.
>40 kg: Initial: 62.5 mg twice daily; increase to a target dose of 125 mg twice daily.
Adverse Effect :
Elevations in aminotransferases, elevated bilirubin, decrease in hematocrit and hemoglobin, thrombocytopenia. (Monitor hemoglobin initially after a month and then every 3 monthly). Other adverse effects: Flushing, edema, fatigue, hypotension, palpitations, diarrhea, dyspepsia, rash, angioneurotic edema, pruritus, headache, dizziness.
Interaction :
Cyclosporine: Significantly increases serum levels of bosentan.
Glyburide: Concurrent use is contraindicated since it results in an increased risk of serum transaminase elevations.
CYP3A4 Inhibitors (clarithromycin and erythromycin): May increase serum concentrations or effects of bosentan.
CYP2C8/9 inducers (Carbamazepine, Phenytoin, Rifampin) and isoenzyme CYP3A4 inducers (Carbamazepine, Nevirapine): May decrease bosentan serum concentrations or effects.
St. John Wort: The herbal medicine may potentially decrease serum concentrations of bosentan and is not recommended for concurrent use.
Oral Contraceptives: Bosentan significantly decreases the serum concentrations of oral contraceptives.
Renal Dose :
Dose in Renal Impairment GFR (mL/min)
| 20-50 | Dose as in normal renal function |
| 10-20 | Dose as in normal renal function |
| <10 | Dose as in normal renal function |
Dose in Patients undergoing Renal Replacement Therapies
| CAPD | Not dialysed. Dose as in normal renal function |
| HD | Not dialysed. Dose as in normal renal function |
| HDF/High flux | Not dialysed. Dose as in normal renal function |
| CAV/VVHD | Not dialysed. Dose as in normal renal function |
Hepatic Dose :
Baseline:
Baseline AST/ALT > 3 times the upper limit of normal (ULN): Use is contraindicated.
On treatment:
AST/ALT > 3 to 5 times ULN: Reconfirm the results by repeating the test. Adults and Adolescents weighing > 40 kg: Reduce the dose to 62.5 mg twice daily or withhold treatment and monitor LFT once every 2 weeks. When levels return to baseline, restart treatment at 62.5 mg twice daily; reassess LFT within 3 days. In children: Withhold treatment. When levels return to baseline, reintroduce bosentan at the dose used prior to treatment interruption; reassess LFT within 3 days.
AST/ALT > 5 to 8 times ULN: Reconfirm the results by repeating the test. Discontinue treatment if confirmed. Monitor LFT once every 2 weeks. When levels return to baseline, restart treatment at 62.5 mg twice daily in adults and adolescents. In children, restart at the dose used prior to treatment interruption. Reassess LFTs within 3 days.
AST/ALT > 8 times ULN or clinical symptoms of hepatotoxicity or bilirubin increases > 2 times ULN: Discontinue treatment permanently.