Bosentan

Indications

Bosentan is used for: Pulmonary Arterial Hypertension (PAH)

Adult Dose

Oral Pulmonary hypertension Adult: >12 yr <40 kg: Initial and maintenance dose is 62.5 mg bid; >40 kg: Initially, 62.5 mg bid for 4 wk, then increased to a maintenance dose of 125 mg bid. Elderly: No dosage adjustment needed. Hepatic impairment: Mild: No dosage adjustment needed. Moderate and severe: Contraindicated.

Child Dose

Renal Dose

Renal impairment: No dosage adjustment needed in renal impairment or dialysis patients.

Administration

Bosentan should be administered in the morning and evening with or without food.

Contra Indications

Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of hepatotoxicity in WHO Class II patients, which may preclude future use as their disease progresses.

Precautions

Hepatotoxicity and teratogenicity. Elevations of AST or ALT associated with Bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with Tracleer. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly .Discontinue Bosentan if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin > 2 Lactation: Not known if excreted in breast milk; not recommended

Pregnancy-Lactation

Pregnancy Based on animal data, bosentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy; see Contraindications and Black Box Warnings In animal reproduction studies, oral administration of bosentan to pregnant rats at 2 times the maximum recommended human dose (MRHD) on a mg/m2 basis caused teratogenic effects in rats (eg, malformations of the head, mouth, face, and large blood vessels) Advise pregnant women of the potential risk to a fetus Patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus Based on findings in animals, bosentan may impair fertility in males of reproductive potential; It is unknown whether effects on fertility would be reversible Lactation There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan, advise women not to breastfeed during treatment with bosentan

Interactions

Increased bosentan levels w/ CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, diltiazem), CYP2C9 inhibitors (e.g. amiodarone, fluconazole), tacrolimus. Rifampicin initially increases but subsequently decreases bosentan concentration. May decrease plasma levels of warfarin, statins (e.g. simvastatin, lovastatin), hormonal contraceptives, sildenafil, tadalafil. Potentially Fatal: Increased risk of hepatotoxicity may occur w/ glibenclamide. Ciclosporin markedly increases bosentan concentration.

Adverse Effects

Side effects of Bosentan : >10% Hgb decreased; >1 g/dL (57%), Inhibition of spermatogenesis (25%), Headache (16-22%), Nasopharyngitis (11%), Transaminses increased (12%), Respiratory tract infection (22%), Increased transaminases (12%) 1-10% Edema, lower limb (5-8%), Flushing (7-9%), Hypotension (7%), Hepatic abnormalities (4%), Palpitations (4%), Anemia (3%), Dyspepsia (4%), Edema, general (4%), Fatigue (2%), Pruritus (4%) <1% Hyperbilirubinemia, Vasculitis, Jaundice, Leukopenia, Thrombocytopenia, Leukocytoplastic

Mechanism of Action

Competitive antagonist of endothelin-1; blocks endothelin receptors on vascular endothelium and smooth muscle resulting in inhibition of vasoconstriction