Volibris · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-094896 · has-adverse-reaction-information · PDF-Seite 9

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 Very common Anaemia (decreased haemoglobin, disorders 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

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HOS-094892 · has-contraindication-information · PDF-Seite 4

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).

HOS-094891 · has-indication-information · PDF-Seite 3

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).

HOS-094894 · has-interaction-information · PDF-Seite 6

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, 6 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 pros

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HOS-094895 · has-pregnancy-information · PDF-Seite 8

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.

HOS-094893 · has-warning-information · PDF-Seite 4

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. 4 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 cli

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