4.1. Therapeutic indications

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.

Volibris is indicated for treatment of PAH in adolescents and children (aged 8 to less than 18 years) of WHO Functional Class (FC) II to III including use in combination treatment. Efficacy has been shown in IPAH, familial, corrected congenital and in PAH associated with connective tissue disease (see section 5.1).

4.2. Posology and method of administration

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.

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.

Ambrisentan in combination with cyclosporine A

In adults, 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).

Paediatric patients aged 8 to less than 18 years

Ambrisentan monotherapy or in combination with other PAH therapies

Volibris is to be taken orally based on the dose regimen described below:

Body weight (kg)

Initial once daily dose (mg)

Subsequent once daily dose titration (mg)a

≥50

5

10

≥35 to <50

5

7.5

≥20 to <35

2.5

5

a =dependent on clinical response and tolerability (see section 5.1)

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 (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 below 8 years of age have not been established. No clinical data are available.

In addition, animal studies indicated a risk of a decrease in brain weight (compared to controls); the clinical relevance of this finding is unknown but may be considered a higher potential risk for children under 4 years of age (see section 5.3 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.

4.3. Contraindications

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).

4.4. 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.

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 evaluated 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 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 (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 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. Peripheral oedema was reported more frequently with 10 mg ambrisentan in short-term clinical studies (see section 4.8).

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, with or without associated weight gain, 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 incidence of peripheral oedema was increased when ambrisentan was dosed in combination with tadalafil (45% adverse event frequency), compared to the incidence of peripheral oedema when ambrisentan and tadalafil were given as monotherapy (38% and 28%, respectively). 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 (see sections 4.3 and 4.6).

Pulmonary veno-occlusive disease

Cases of pulmonary oedema have been reported with vasodilating medicinal products, such as ERAs, when used in patients with pulmonary veno-occlusive disease. Consequently, 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 (see sections 4.5 and 5.2).

Excipients

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Lecithin (soya)

This medicinal product contains lecithin derived from soya. If a patient is hypersensitive to soya, ambrisentan must not be used (see section 4.3).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Allura red AC aluminium lake

Volibris 5 mg and 10 mg tablets contain the azo colouring agent allura red AC aluminium lake (E129), which may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

Ambrisentan does not inhibit or induce phase I or II drug metabolising enzymes at clinically relevant concentrations in in vitro and in vivo non-clinical studies, suggesting a low potential for ambrisentan to alter the profile of medicinal products metabolised by these pathways.

The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers with results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.

Cyclosporine A

Steady-state co-administration of ambrisentan and cyclosporine A resulted in a 2-fold increase in ambrisentan exposure in healthy volunteers. This may be due to the inhibition by cyclosporine A of transporters and metabolic enzymes involved in the pharmacokinetics of ambrisentan. Therefore, when co-administered with cyclosporine A, the dose of ambrisentan in adult patients or paediatric patients weighing ≥50 kg should be limited to 5 mg once daily; for paediatric patients ≥20 to <50 kg the dose should be limited to 2.5 mg once daily (see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no dose adjustment of cyclosporine A is warranted.

Rifampicin

Co-administration of rifampicin (an inhibitor of Organic Anion Transporting Polypeptide [OATP], a strong inducer of CYP3A and 2C19, and inducer of P-gp and uridine-diphospho-glucuronosyltransferases [UGTs]) was associated with a transient (approximately 2-fold) increase in ambrisentan exposure following initial doses in healthy volunteers. However, by day 8, steady state administration of rifampicin had no clinically relevant effect on ambrisentan exposure. Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin (see sections 4.4 and 5.2).

Phosphodiesterase inhibitors

Co-administration of ambrisentan with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan (see section 5.2).

Other targeted PAH treatments

The efficacy and safety of ambrisentan when co-administered with other treatments for PAH (e.g. prostanoids and soluble guanylate cyclase stimulators) has not been specifically studied in controlled clinical trials in PAH patients (see section 5.1). No specific interactions between ambrisentan and soluble guanylate cyclase stimulators or prostanoids are anticipated based on the known biotransformation data (see section 5.2). However, no specific interactions studies have been conducted with these medicinal products. Therefore, caution is recommended in the case of co-administration.

Oral contraceptives

In a clinical study in healthy volunteers, steady-state dosing with ambrisentan 10 mg once daily did not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone components of a combined oral contraceptive (see section 5.2). Based on this pharmacokinetic study, ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen- based contraceptives.

Warfarin

Ambrisentan had no effects on the steady-state pharmacokinetics and anti-coagulant activity of warfarin in a healthy volunteer study (see section 5.2). Warfarin also had no clinically significant effects on the pharmacokinetics of ambrisentan. In addition, in patients, ambrisentan had no overall effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international normalised ratio (INR).

Ketoconazole

Steady-state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a clinically significant increase in exposure to ambrisentan (see section 5.2).

Effect of ambrisentan on xenobiotic transporters

In vitro, ambrisentan has no inhibitory effect on human transporters at clinically relevant concentrations, including the P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), multi-drug resistance related protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporting polypeptides (OATP1B1 and OATP1B3) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).

Ambrisentan is a substrate for Pgp-mediated efflux.

In vitro studies in rat hepatocytes also showed that ambrisentan did not induce Pgp, BSEP or MRP2 protein expression.

Steady-state administration of ambrisentan in healthy volunteers had no clinically relevant effects on the single-dose pharmacokinetics of digoxin, a substrate for Pgp (see section 5.2).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Ambrisentan 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. Monthly pregnancy tests during treatment with ambrisentan are recommended.

Pregnancy

Ambrisentan is contraindicated in pregnancy (see section 4.3). Animal studies have shown that ambrisentan is teratogenic. There is no experience in humans.

Women receiving ambrisentan must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs (see sections 4.3, 4.4 and 5.3).

Breast-feeding

It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in milk has not been studied in animals. Therefore, breast-feeding is contraindicated in patients taking ambrisentan (see section 4.3).

Male fertility

The development of testicular tubular atrophy in male animals has been linked to the chronic administration of ERAs, including ambrisentan (see section 5.3). Although no clear evidence of a detrimental effect of ambrisentan long-term exposure on sperm count was found in ARIES-E study, chronic administration of ambrisentan was associated with changes in markers of spermatogenesis. A decrease in plasma inhibin-B concentration and an increase in plasma FSH concentration were observed. The effect on male human fertility is not known but a deterioration of spermatogenesis cannot be excluded. Chronic administration of ambrisentan was not associated with a change in plasma testosterone in clinical studies.

4.7. Effects on ability to drive and use machines

Ambrisentan has minor or moderate influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of ambrisentan (such as hypotension, dizziness, asthenia, fatigue) should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills (see section 4.8). Patients should be aware of how they might be affected by ambrisentan before driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

Peripheral oedema (37%) and headache (28%) were the most common adverse reactions observed with ambrisentan. The higher dose (10 mg) was associated with a higher incidence of these adverse reactions, and peripheral oedema tended to be more severe in patients ≥65 years in short-term clinical studies (see section 4.4).

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. Most of these decreases were detected during the first 4 weeks of treatment and haemoglobin generally stabilised thereafter (see section 4.4).

Hepatic enzyme elevations (2%), hepatic injury and autoimmune hepatitis (including exacerbation of underlying disease) have been observed with ambrisentan (see sections 4.4 and 5.1).

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.

System organ class

Frequency

Adverse reaction(s)

Blood and lymphatic system disorders

Very common

Anaemia (decreased haemoglobin, decreased haematocrit)1

Immune system disorders

Common

Hypersensitivity reactions (e.g. angioedema, rash, pruritus)

Nervous system disorders

Very common

Headache (including sinus headache, migraine)2, dizziness

Eye disorders

Common

Blurred vision, visual impairment

Ear and labyrinth disorders

Common

Tinnitus3

Uncommon

Sudden hearing loss3

Cardiac disorders

Very common

Palpitation

Common

Cardiac failure4

Vascular disorders

Very common

Flushing5

Common

Hypotension, syncope

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoea6, upper respiratory (e.g. nasal, sinus) congestion7, nasopharyngitis7

Common

Epistaxis, rhinitis7, sinusitis7

Gastrointestinal disorders

Very common

Nausea, diarrhoea, vomiting5

Common

Abdominal pain, constipation

Hepatobiliary disorders

Common

Hepatic transaminases increased

Uncommon

Hepatic injury (see section 4.4), autoimmune hepatitis (see section 4.4)

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.

Description of selected adverse reactions

Decreased haemoglobin

In the post-marketing period, cases of anaemia requiring blood cell transfusion have been reported (see section 4.4). The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan. Across the 12-week placebo controlled Phase 3 clinical studies, mean haemoglobin concentrations decreased for patients in the ambrisentan groups and were detected as early as week 4 (decrease by 0.83 g/dL); mean changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 17 patients (6.5%) in the ambrisentan treatment groups had decreases in haemoglobin of ≥15% from baseline and which fell below the lower limit of normal.

Paediatric population

The safety of ambrisentan in paediatric patients with PAH aged 8 to less than 18 years was evaluated in 41 patients who were treated with once daily ambrisentan 2.5 mg or 5 mg (low dose group) or once daily ambrisentan 2.5 mg or 5 mg titrated to 5 mg, 7.5 mg, or 10 mg based on body weight (high dose group) alone or in combination with other PAH medicinal products for 24 weeks in a Phase 2b open label trial. Safety was further evaluated in a long-term extension study in 38 of the 41 subjects. The adverse reactions observed, which were assessed as related to ambrisentan, were consistent with those observed in controlled studies in adult patients, with headache (15%, 6/41 subjects during the 24 weeks of the Phase 2b open label trial and 8%, 3/38 subjects during the long-term extension study) and nasal congestion (7%, 3/41 subjects during the 24 weeks of the Phase 2b open label trial) occurring most commonly.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In healthy volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea and nasal congestion.

Due to the mechanism of action, an overdose of ambrisentan could potentially result in hypotension (see section 5.3). In the case of pronounced hypotension, active cardiovascular support may be required. No specific antidote is available.