5 mg film-coated tablets
Volibris® 5 mg film-coated tablets
10 mg film-coated tablets
Volibris® 10 mg film-coated tablets
5 mg film-coated tablets
Each tablet contains 5 mg of ambrisentan.
10 mg film-coated tablets
Each tablet contains 10 mg of ambrisentan.
Excipient(s) with known effect:
5 mg film-coated tablets
Each tablet contains approximately 95 mg of lactose (as monohydrate), approximately 0.25 mg of lecithin (soya) (E322) and approximately 0.11 mg of Allura red AC Aluminium Lake (E129).
10 mg film-coated tablets
Each tablet contains approximately 90 mg of lactose (as monohydrate), approximately 0.25 mg of lecithin (soya) (E322) and approximately 0.45 mg of Allura red AC Aluminium Lake (E129).
For the full list of excipients, see section 6.1.
Film-coated tablet (tablet).
5 mg film-coated tablets
Pale-pink, square, convex, film-coated tablet with “GS” debossed on one side and “K2C” on the other side.
10 mg film-coated tablets
Deep-pink, oval, convex, film-coated tablet with “GS” debossed on one side and “KE3” on the other side.
Volibris is indicated for treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III, including use in combination treatment (see section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.
Treatment must be initiated by a physician experienced in the treatment of PAH.
Posology
Ambrisentan monotherapy
Volibris is to be taken orally to begin at a dose of 5 mg once daily and may be increased to 10 mg daily depending upon clinical response and tolerability.
Ambrisentan in combination with tadalafil
When used in combination with tadalafil, Volibris 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 (see section 5.1). When used in combination with tadalafil, patients were initiated with 5 mg ambrisentan and 20 mg tadalafil. Dependent on tolerability the dose of tadalafil was increased to 40 mg after 4 weeks and the dose of ambrisentan was increased to 10 mg after 8 weeks. More than 90% of patients achieved this. Doses could also be decreased depending on tolerability.
Limited data suggest that the abrupt discontinuation of ambrisentan is not associated with rebound worsening of PAH.
When co-administered with cyclosporine A, the dose of ambrisentan should be limited to 5 mg once daily and the patient should be carefully monitored (see sections 4.5 and 5.2).
Special populations
Elderly patients
No dose adjustment is required in patients over the age of 65 (see section 5.2).
Patients with renal impairment
No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited experience with ambrisentan in individuals with severe renal impairment (creatinine clearance <30 ml/min); therapy should be initiated cautiously in this subgroup and particular care taken if the dose is increased to 10 mg ambrisentan.
Patients with hepatic impairment
Ambrisentan has not been studied in individuals with hepatic impairment (with or without cirrhosis). Since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile, hepatic impairment might be expected to increase exposure (Cmax and AUC) to ambrisentan. Therefore ambrisentan must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal (>3xULN); see sections 4.3 and 4.4).
Paediatric population
The safety and efficacy of ambrisentan in children and adolescents aged below 18 years has not been established. No data are available.
Method of administration
It is recommended that the tablet is swallowed whole and it can be taken with or without food. It is recommended that the tablet should not be split, crushed or chewed.
Hypersensitivity to the active substance, to soya, or to any of the excipients listed in section 6.1.
Pregnancy (see section 4.6).
Women of child-bearing potential who are not using reliable contraception (see sections 4.4 and 4.6).
Breast-feeding (see section 4.6).
Severe hepatic impairment (with or without cirrhosis) (see section 4.2).
Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT))>3xULN (see sections 4.2 and 4.4).
Idiopathic pulmonary fibrosis (IPF), with or without secondary pulmonary hypertension (see section 5.1).
Ambrisentan has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I PAH.
The efficacy of ambrisentan as monotherapy has not been established in patients with WHO functional class IV PAH. Therapy that is recommended at the severe stage of the disease (e.g. epoprostenol) should be considered if the clinical condition deteriorates.
Liver function
Liver function abnormalities have been associated with PAH. Cases consistent with autoimmune hepatitis, including possible exacerbation of underlying autoimmune hepatitis, hepatic injury and hepatic enzyme elevations potentially related to therapy have been observed with ambrisentan (see sections 4.8 and 5.1). Therefore hepatic aminotransferases (ALT and AST) should be eva luated prior to initiation of ambrisentan and treatment should not be initiated in patients with baseline values of ALT and/or AST >3xULN (see section 4.3).
Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended. If patients develop sustained, unexplained, clinically significant ALT and/or AST elevation, or if ALT and/or AST elevation is accompanied by signs or symptoms of hepatic injury (e.g. jaundice), ambrisentan therapy should be discontinued.
In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of ambrisentan may be considered following resolution of hepatic enzyme abnormalities. The advice of a hepatologist is recommended.
Haemoglobin concentration
Reductions in haemoglobin concentrations and haematocrit have been associated with endothelin receptor antagonists (ERAs) including ambrisentan. Most of these decreases were detected during the first 4 weeks of treatment and haemoglobin generally stabilised thereafter. Mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment with ambrisentan in the long-term open-label extension of the pivotal Phase 3 clinical studies. In the post-marketing period, cases of anaemia requiring blood cell transfusion have been reported (see section 4.8).
Initiation of ambrisentan is not recommended for patients with clinically significant anaemia. It is recommended that haemoglobin and/or haematocrit levels are measured during treatment with ambrisentan, for example at 1 month, 3 months and periodically thereafter in line with clinical practice. If a clinically significant decrease in haemoglobin or haematocrit is observed, and other causes have been excluded, dose reduction or discontinuation of treatment should be considered. The incidence of anaemia was increa
