Volibris

Treatment must be initiated by a physician experienced in the treatment of PAH. Posology Adults 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. 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. 2). 5 mg once daily. 2). 2). 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.

4). Paediatric population The safety and efficacy of ambrisentan in children below 8 years of age have not been established. 3 regarding data available in juvenile animals). 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.

Summary of the safety profile Peripheral oedema (37%) and headache (28%) were the most common adverse reactions observed with ambrisentan. 4). Serious adverse reactions associated with ambrisentan use include anaemia (decreased haemoglobin, decreased haematocrit) and hepatotoxicity.

Reductions in haemoglobin concentrations and haematocrit (10%) have been associated with ERAs including ambrisentan. 4). 1). Tabulated list of adverse reactions Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (cannot be estimated from available data).

For dose-related adverse reactions the frequency category reflects the higher dose of ambrisentan. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. g. g. 4) Skin and subcutaneous tissue disorders Common Rash8 General disorders and administration site conditions Very common Peripheral oedema, fluid retention, chest pain/discomfort5, fatigue Common Asthenia 1 See section ‘Description of selected adverse reactions’.

2 The frequency of headache appeared higher with 10 mg ambrisentan. 3 Cases were only observed in a placebo-controlled clinical study of ambrisentan in combination with tadalafil. 4 Most of the reported cases of cardiac failure were associated with fluid retention.

5 Frequencies were observed in a placebo-controlled clinical study of ambrisentan in combination with tadalafil. Lower incidence was observed with ambrisentan monotherapy. 6 Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting ambrisentan therapy.

7 The incidence of nasal congestion was dose related during ambrisentan therapy. 8 Rash includes rash erythematous, rash generalised, rash papular and rash pruritic. 4). The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan.

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.

g. epoprostenol) should be considered if the clinical condition deteriorates. 5 Liver function Liver function abnormalities have been associated with PAH. 1). 3). Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended.

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.

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. 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 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).

1. 6). 6). 6). 2). 4). 1).