Ambrisentan

SOURCE: UK SPC for Ambrisentan 10 mg film-coated Tablets (https://www.medicines.org.uk/emc/product/11697/smpc), indicated in pulmonary arterial hypertension. PRESCRIBING RESTRICTION: treatment must be initiated by a physician experienced in the treatment of PAH. IN COMBINATION WITH TADALAFIL: when used in combination with tadalafil, ambrisentan should be titrated to 10 mg once daily. In the AMBITION study, patients received 5 mg ambrisentan daily for the first 8 weeks before up-titrating to 10 mg dependent on tolerability; patients were initiated with 5 mg ambrisentan and 20 mg tadalafil, the tadalafil dose was increased to 40 mg after 4 weeks and the ambrisentan dose to 10 mg after 8 weeks, and more than 90% of patients achieved this. Doses could also be decreased depending on tolerability. DISCONTINUATION: limited data suggest that abrupt discontinuation of ambrisentan is not associated with rebound worsening of PAH. MONITORING: hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation and treatment should not be initiated if baseline ALT and/or AST are >3 x ULN; monthly monitoring of ALT and AST is recommended, and therapy should be discontinued if there is sustained, unexplained, clinically significant elevation or if elevation is accompanied by signs or symptoms of hepatic injury such as jaundice. Haemoglobin and/or haematocrit should be measured during treatment, for example at 1 month, 3 months and periodically thereafter; initiation is not recommended in patients with clinically significant anaemia, and if a clinically significant decrease occurs with other causes excluded, dose reduction or discontinuation should be considered. HEPATIC IMPAIRMENT: ambrisentan has not been studied in individuals with hepatic impairment (with or without cirrhosis) and must not be initiated in severe hepatic impairment or with clinically significant elevated hepatic aminotransferases (>3 x ULN). ELDERLY: no dose adjustment required over the age of 65. PAEDIATRIC (weight-band, not per-kg — so not expressed as a mg/kg dose): patients aged 8 to less than 18 years weighing 50 kg or more, as monotherapy or in combination with other PAH therapies — initial dose 5 mg once daily, with subsequent once-daily titration to 10 mg dependent on clinical response and tolerability; when co-administered with cyclosporine A the dose for paediatric patients 50 kg or over should be limited to 5 mg once daily with careful monitoring. Safety and efficacy in children below 8 years of age have not been established and no clinical data are available. Verify any under-18 use against a children's formulary. EFFICACY LIMITS: ambrisentan has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I PAH, and the efficacy of monotherapy has not been established in WHO functional class IV PAH.