Ambrisentan

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.

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 (C_max 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).

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. Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no dose adjustment of cyclosporine A is warranted.

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.

Initiation of ambrisentan is not recommended for patients with clinically significant anaemia.

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.

Male fertility

The development of testicular tubular atrophy in male animals has been linked to the chronic administration of ERAs, including ambrisentan. 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

Ambrisentan is contraindicated in pregnancy. 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.

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.

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.

Male fertility

The development of testicular tubular atrophy in male animals has been linked to the chronic administration of ERAs, including ambrisentan. 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

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. Patients should be aware of how they might be affected by ambrisentan before driving or using machines.

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.

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.

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

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.

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. 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.