Volibris

Ambrisentan in combination with cyclosporine A

In paediatric patients, when co-administered with cyclosporine A, the dose of ambrisentan for patients ≥50 kg should be limited to 5 mg once daily, or for patients ≥20 to <50 kg should be limited to 2.5 mg once daily. The patient should be carefully monitored.

Special populations Elderly patients

No dose adjustment is required in patients over the age of 65.
Patients with renal impairment
No dose adjustment is required in patients with renal impairment. 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). 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).
Paediatric population
The safety and efficacy of ambrisentan in children below 8 years of age have not been established.

Method of administration
Volibris is for oral use. 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.

Contraindications
Hypersensitivity to the active substance, to soya, or to any of the excipients.
Pregnancy.
Women of child-bearing potential who are not using reliable contraception.
Breast-feeding.
Severe hepatic impairment (with or without cirrhosis).

Baseline values of hepatic aminotransferases (aspartate aminotransferases and/or alanine aminotransferases >3xULN.
Idiopathic pulmonary fibrosis, with or without secondary pulmonary hypertension,

Adverse Events

Adverse events associated with the use of Volibris include: Very common (≥ 1/10): Anaemia (decreased haemoglobin, decreased haematocrit), headache, dizziness, palpitation, flushing, dyspnoea, upper respiratory congestion, nasopharyngitis, nausea, diarrhea, vomiting, peripheral edema, fluid retention, chest pain/discomfort, fatigue. Common (≥ 1/100 to <1/10: Hypersensitivity reactions, blurred vision, visual impairment, tinnitus, cardiac failure, hypotension, syncope, epistaxis, rhinitis, sinusitis, abdominal pain, constipation, hepatic transaminases increased, rash, asthenia. Uncommon (≥1/1 000 to <1/100): Sudden hearing loss, hepatic injury, autoimmune hepatitis.

Special warnings and precautions for use

Ambrisentan has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I 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
Hhepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of ambrisentan and treatment should not be initiated in patients with baseline values of ALT and/or AST >3xULN.
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', 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 haemoglobin 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. 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 increased when ambrisentan was dosed in combination with tadalafil (15% adverse event frequency), compared to the incidence of anaemia when ambrisentan and tadalafil were given as monotherapy (7% and 11%, respectively).
Fluid retention
Peripheral oedema has been observed with ERAs including ambrisentan. Most cases of peripheral oedema in clinical studies with ambrisentan were mild to moderate in severity, although it may occur with greater frequency and severity in patients ≥65 years. Post-marketing reports of fluid retention occurring within weeks after starting ambrisentan have been received and, in some cases, have required intervention with a diuretic or hospitalisation for fluid management or decompensated heart failure. If patients have pre-existing fluid overload, this should be managed as clinically appropriate prior to starting ambrisentan. If clinically significant fluid retention develops during therapy with ambrisentan, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy. The occurrence of peripheral oedema was highest within the first month of treatment initiation.
Women of child-bearing potential
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre- treatment pregnancy test is negative and reliable contraception is practiced. If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynaecologist should be considered. Monthly pregnancy tests during treatment with ambrisentan are recommended.

Pulmonary veno-occlusive disease
If PAH patients develop acute pulmonary oedema when treated with ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered.
Concomitant use with other medicinal products
Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin,
Excipients
Lactose and Lecithin (soya)
Volibris tablets contain lactose and lecithin. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take these products. If a patient is hypersensitive to soya, ambrisentan must not be used.
Volibris 5 mg and 10 mg tablets contain the azo colouring agent allura red AC aluminium lake (E129) which may cause allergic reactions.