Bosentanum

Uses

Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III

Bosentanum is also used to associated treatment for these conditions: NYHA Functional Class II-IV Pulmonary arterial hypertension, Ocular Inflammation, Ocular bacterial infections

How Bosentanum works

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET_A and ET_B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET_A receptors than ET_B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentanumis a specific and competitive antagonist at endothelin receptor types ET_A and ET_B.

Dosage

Bosentanum dosage

Adult/Geriatric:

• <40 kg: Initial and maintenance: 62.5 mg twice daily
• ≥40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily. Doses more than 125 mg twice daily do not appear to confer additional clinical benefit but may increase risk of liver toxicity.

Pediatric:

• Infants ≥7 months and Children: Limited data available (Barst 2003; Ivy 2004; Maiya 2006; Rosenzweig 2005):
• 5 to <10 kg: Initial: 15.6 mg daily for 4 weeks; increase to maintenance dose of 15.6 mg twice daily.
• 10 to 20 kg: Initial: 31.25 mg daily for 4 weeks; increase to maintenance dose of 31.25 mg twice daily.
• >20 to 40 kg: Initial: 31.25 mg twice daily for 4 weeks; increase to maintenance dose of 62.5 mg twice daily.
• >40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily.
• Children >12 years and Adolescents: Refer to adult dosing.

Side Effects

Headache, nasopharyngitis, flushing, fluid retention (e.g. peripheral oedema), hypotension, palpitations, dyspepsia, fatigue, pruritus, rash, anaemia (dose-related), reduced sperm count (reversible).

Toxicity

Bosentanumhas been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

Precaution

Consider discontinuation of therapy if pulmonary oedema occurs. Avoid abrupt withdrawal and consider dose reduction (e.g. half the dose for 3-7 days) to minimise risk of clinical deterioration. Lactation.

Interaction

Increased bosentan levels with 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.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Volume of Distribution

• 18 L

Elimination Route

Absolute bioavailability is approximately 50% and food does not affect absorption.

Half Life

Terminal elimination half-life is about 5 hours in healthy adult subjects.

Clearance

• 4 L/h [patients with pulmonary arterial hypertension]

Elimination Route

Bosentanumis eliminated by biliary excretion following metabolism in the liver.

Pregnancy & Breastfeeding use

Pregnancy Category X. Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Contraindication

Acute porphyria; moderate and severe hepatic impairment. Coadministration with ciclosporin or glibenclamide. Pregnancy (use 2 forms of contraception during treatment and 1 mth after stopping).

Special Warning

Renal Impairment: No dosage adjustment necessary. Bosentanumis unlikely to be removed by dialysis (due to high molecular weight and extensive plasma protein binding).

Hepatic Impairment: Hepatic impairment at treatment initiation:

• Mild impairment: No dosage adjustment necessary.
• Moderate to severe impairment: Use should be avoided; systemic exposure is significantly increased in patients with moderate impairment (not studied in patients with severe impairment).

Acute Overdose

Symptoms: Nausea, vomiting, hypotension, dizziness, sweating and blurred vision.

Management: Symptomatic and supportive treatment.

Storage Condition

Store between 20-25° C.

Innovators Monograph

You find simplified version here Bosentanum