Leitlinien & Arzneimittelsicherheit

HOS-097044 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most commonly reported adverse reactions are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia, and flushing. These reactions are more frequent during the up-titration phase. The majority of these reactions are of mild to moderate intensity. The safety of selexipag has been evaluated in a long-term, phase 3 placebo-controlled study enrolling 1 156 adult patients with symptomatic PAH (GRIPHON study). The mean treatment duration was 76.4 weeks (median 70.7 weeks) for patients receiving selexipag versus 71.2 weeks (median 63.7 weeks) for patients on placebo. The exposure to selexipag was up to 4.2 years. Tabulated list of adverse reactions Adverse reactions obtained from the pivotal clinical GRIPHON study and post-marketing surveillance are tabulated below. The adverse reactions are ranked by frequency within each system organ class (SOC) and presented in order of decreasing seriousness. 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). System organ class Very common Common Uncommon Blood and lymphatic Anaemia* disorders Haemoglobin decreased* Endocrine disorders Hyperthyroidism* Thyroid-stimulating Hormone decreased Metabolism and Decreased appetite nutrition disorders Weight decrease Nervous system Headache* disorders Cardiac disorders Sinus tachycardia* Vascular disorders Flushing* Hypotension* Respiratory, thoracic Nasopharyngitis (of Nasal congestion and mediastinal non-infectious disorders origin) Gastro-intestinal Diarrhoea* Abdominal pain disorders Vomiting* Dyspepsia* Nausea* Skin and subcutaneous Rash tissue disorders

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HOS-097040 · has-contraindication-information · PDF-Seite 5

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Severe coronary heart disease or unstable angina.  Myocardial infarction within the last 6 months.  Decompensated cardiac failure if not under close medical supervision.  Severe arrhythmias.  Cerebrovascular events (e.g., transient ischaemic attack, stroke) within the last 3 months.  Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension.  Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil; see section 4.5). 5

HOS-097039 · has-indication-information · PDF-Seite 3

Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II–III, either as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy in patients who are not candidates for these therapies. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease (see section 5.1).

HOS-097042 · has-interaction-information · PDF-Seite 6

Effect of other medicinal products on selexipag Selexipag is hydrolysed to its active metabolite by carboxylesterases (see section 5.2). Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4. The glucuronidation of the active metabolite is catalysed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a weak substrate of the P-gp efflux pump. The active metabolite is a weak substrate of the breast cancer resistance protein (BCRP). 6 The pharmacokinetics of selexipag and its active metabolite are not affected by warfarin. Inhibitors of CYP2C8 In the presence of 600 mg gemfibrozil, twice a day, a strong inhibitor of CYP2C8, exposure to selexipag increased approximately 2-fold, whereas exposure to the active metabolite, the major contributor to efficacy, increased approximately 11-fold. Concomitant administration of Uptravi with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated (see section 4.3). Concomitant administration of Uptravi with clopidogrel (loading dose of 300 mg or maintenance dose of 75 mg once a day), a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag but increased the exposure to the active metabolite approximately 2.2 and 2.7-fold following loading dose and maintenance dose, respectively. The total daily dose of Uptravi should be decreased by reducing each dose to half when co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox, teriflunomide). Alternatively, a once daily dosing frequency to achieve half of the daily dose of Uptravi may be continued in patients already well controlled on a once daily dosing regimen or may be applied in patients for whom the appropriate dose strength(s) supporting twice daily dosing with half the dose is not available. When co-administration of a moderate CYP2C8 inhibitor is stopped increase the total daily dose of Uptravi, as applicable. The maximum dose of 1 600 micrograms twice daily should not be exceeded (see section 4.2). Inducers of CYP2C8 In the presence of 600 mg rifampicin, once a day, an inducer of CYP2C8 (and UGT enzymes), the exposure to selexipag did not change, whereas exposure to the active metabolite was reduced by half. Dose adjustment of selexipag may be required with concomitant administration of inducers of CYP2C8 (e.g., rifampicin, carb

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HOS-097043 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Women of childbearing potential should practise effective contraception while taking selexipag (see section 4.4). Pregnancy There are no data from the use of selexipag in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Selexipag and its main metabolite showed 20- to 80-times lower prostacyclin (IP) receptor potency in vitro for animal species used in reproductive toxicity testing compared to humans. Therefore, safety margins for potential IP receptor-mediated effects on reproduction are accordingly lower than for non-IP-related effects (see section 5.3). Uptravi is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether selexipag or its metabolites are excreted in human milk. In rats, selexipag or its metabolites are excreted in milk (see section 5.3). A risk to the suckling child cannot be excluded. Uptravi should not be used during breast-feeding. Fertility There are no clinical data available. In rat studies, selexipag at high doses caused transient disturbances in oestrus cycles that did not affect fertility (see section 5.3). The relevance for humans is not known.

HOS-097041 · has-warning-information · PDF-Seite 6

Hypotension Selexipag has vasodilatory properties that may result in lowering of blood pressure. Before prescribing Uptravi, physicians should carefully consider whether patients with certain underlying conditions could be adversely affected by vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension, hypovolaemia, severe left ventricular outflow obstruction or autonomic dysfunction) (see section 4.8). Hyperthyroidism Hyperthyroidism has been observed with Uptravi. Thyroid function tests are recommended as clinically indicated in the presence of signs or symptoms of hyperthyroidism (see section 4.8). Pulmonary veno-occlusive disease Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in patients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occur when Uptravi is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered. If confirmed, treatment is to be discontinued. Elderly (≥ 65 years) There is limited clinical experience with selexipag in patients over the age of 75 years, therefore, Uptravi should be used with caution in this population (see section 4.2). Hepatic impairment There is no clinical experience with selexipag in patients with severe liver impairment (Child-Pugh class C), therefore treatment should not be administered in these patients. The exposure to selexipag and its active metabolite is increased in subjects with moderate hepatic impairment (Child-Pugh class B; see section 5.2). In patients with moderate hepatic impairment, the total daily dose of Uptravi should be reduced (see section 4.2). Renal impairment In patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2), caution should be exercised during dose titration. There is no experience with Uptravi in patients undergoing dialysis (see section 5.2), therefore Uptravi should not be used in these patients. Women of childbearing potential Women of childbearing potential should practise effective contraception while taking selexipag (see section 4.6).