Yuvanci · 4.4 Special warnings and precautions for use · 1

HOS-099083 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most common adverse reactions (occurring in the Yuvanci treated patients) from the combined double-blind / open-label A DUE study data were anaemia/haemoglobin decrease (24.9%), oedema/fluid retention (18.4%), and headache (15.1%). Based on the identified adverse reaction terms for Yuvanci, macitentan, and tadalafil, the most common treatment-emergent serious adverse events in the combined double-blind and open-label period were bronchitis reported in 3 (1.6%) patients, anaemia and palpitations each reported in 2 patients (1.1%), migraine, hypotension, intermenstrual bleeding, oedema/fluid retention and influenza, each reported in 1 patient (0.5%). Tabulated list of adverse reactions 9 The safety profile presented below is based on data for Yuvanci and the known safety profile of the individual components macitentan and tadalafil. The safety data for Yuvanci was obtained from a double-blind, active controlled, Phase 3 clinical study (A DUE) and an open-label extension in patients with PAH. The total number of patients receiving Yuvanci was 185 patients with a median exposure to Yuvanci of 105.1 weeks. Known adverse reactions for macitentan and tadalafil which have not been observed in the A DUE study, are included in table 1 based on the prescribing information for the individual components macitentan and tadalafil. Adverse reactions are listed by MedDRA system organ class and by frequency. Frequency categories are defined as follows: 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 (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions in patients with PAH treated with Yuvanci, macitentan and/or tadalafil System organ class Adverse reaction(s) Frequencya b Infections and infestations Bronchitis Very common Influenza Common Urinary tract infection Common Upper respiratory tract Common infection Pharyngitisb Common

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HOS-099079 · has-contraindication-information · PDF-Seite 3

 Hypersensitivity to any of the active substances, or to any of the excipients listed in section 6.1.  Acute myocardial infarction within the last 90 days.  Pregnancy (see sections 4.4 and 4.6).  Women of childbearing potential who are not using reliable contraception (see sections 4.4 and 4.6).  Breastfeeding (see section 4.6).  Patients with severe hepatic impairment, with or without cirrhosis (Child-Pugh Class C) (see sections 4.2 and 4.4). 3  Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) > 3 × ULN) (see sections 4.2 and 4.4).  Severe hypotension (<90/50 mm Hg).  Co-administration with nitrates or guanylate cyclase stimulators (such as riociguat, see section 4.5).  Patients with a history of non-arteritic anterior ischaemic optic neuropathy (NAION).

HOS-099078 · has-indication-information · PDF-Seite 2

Yuvanci is indicated as substitution therapy for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III, who are already treated with the combination of macitentan and tadalafil given concurrently as separate tablets.

HOS-099081 · has-interaction-information · PDF-Seite 6

Pharmacokinetic interactions Effects of other medicinal products on Yuvanci Strong CYP3A4 inducers Potent inducers of CYP3A4 including rifampicin, St. John’s wort, carbamazepine, and phenytoin may reduce the efficacy of Yuvanci. The concomitant use of Yuvanci should be avoided. Rifampicin (600 mg daily) reduced the steady-state exposure to macitentan by 79% but did not affect the exposure to the active metabolite aprocitentan. Rifampicin (600 mg daily), reduced tadalafil AUC by 88% and Cmax by 46%, relative to the AUC and Cmax values for tadalafil alone (10 mg). Strong CYP3A4 inhibitors The combination of Yuvanci with strong CYP3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir and saquinavir is not recommended. Ketoconazole (400 mg once daily) increased exposure to macitentan approximately 2-fold. Exposure to the active metabolite of macitentan was reduced by 26%. Ketoconazole (200 mg daily), increased tadalafil (10 mg) single dose exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) single dose exposure (AUC) 4-fold and Cmax by 22%. Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) single dose exposure (AUC) 2-fold with no change in Cmax. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32% and decreased Cmax by 30%. Dual moderate CYP3A4 and CYP2C9 inhibitors Caution should be exercised when Yuvanci is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone). 6 Fluconazole 400 mg daily, a moderate dual inhibitor of CYP3A4 and CYP2C9, may increase exposure to macitentan approximately 3.8-fold, based on physiologically-based pharmacokinetic (PBPK) modelling. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. The uncertainties of such modelling should be considered. Co-administration of moderate CYP3A4 inhibitors with moderate CYP2C9 inhibitors Moderate CYP3A4 inhibitor (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitor (e.g., miconazole and piperine) should be administered with caution if administered concomitantly with Yuvanci. Co-administration of mode

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HOS-099082 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential / Contraception in males and females Yuvanci treatment should only be initiated in women of childbearing potential when the absence of pregnancy has been verified, appropriate advice on contraception provided, and reliable contraception is practised (see sections 4.3 and 4.4). Women should not become pregnant for 1 month after 8 discontinuation of Yuvanci. Monthly pregnancy tests during treatment with Yuvanci are recommended to allow the early detection of pregnancy. Yuvanci is contraindicated in women of childbearing potential who are not using reliable contraception (see section 4.3). Pregnancy There are no data from the use of Yuvanci in pregnant women. There are no data from the use of macitentan in pregnant women. Studies with macitentan in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is still unknown. There are limited data from the use of tadalafil in pregnant women. Yuvanci is contraindicated during pregnancy (see section 4.3). Breastfeeding It is unknown whether active substances of Yuvanci are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of macitentan in milk. A risk to the breastfed child cannot be excluded. Yuvanci is contraindicated during breastfeeding (see section 4.3). Male fertility The development of testicular tubular atrophy in male animals was observed after treatment with macitentan (see section 5.3). Decreases in sperm count have been observed in patients taking ERAs. Macitentan, like other ERAs, may have an adverse impact on spermatogenesis in men. Two clinical studies with tadalafil suggested no impairment of fertility in humans, although a decrease in sperm concentration was seen in some men.

HOS-099080 · has-warning-information · PDF-Seite 4

Liver function Elevations of liver aminotransferases (AST and ALT) have been associated with PAH and with endothelin receptor antagonists (ERAs) (see section 4.8). Yuvanci is contraindicated in patients with severe hepatic impairment, with or without cirrhosis (Child-Pugh Class C) or elevated hepatic aminotransferases greater than 3 times the upper limit of normal (> 3 × ULN). Liver enzyme tests should be obtained prior to initiation of Yuvanci (see sections 4.2 and 4.3). Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended. If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin > 2 × ULN, or by clinical symptoms of liver injury (e.g., jaundice), Yuvanci treatment should be discontinued. Reinitiation of Yuvanci may be considered following the return of hepatic enzyme levels to within the normal range in patients who have not experienced clinical symptoms of liver injury. The advice of a hepatologist is recommended. Use in women of childbearing potential Yuvanci treatment should only be initiated in women of childbearing potential when the absence of pregnancy has been verified, appropriate advice on contraception provided, and reliable contraception is practised (see sections 4.3 and 4.6). Women should not become pregnant for 1 month after discontinuation of Yuvanci. Monthly pregnancy tests during treatment with Yuvanci are recommended to allow the early detection of pregnancy. Haemoglobin concentration Decrease in haemoglobin concentrations has been associated with endothelin receptor antagonists (ERAs) including macitentan (see section 4.8). In placebo-controlled studies, macitentan-related decreases in haemoglobin concentration were not progressive, stabilised after the first 4-12 weeks of treatment and remained stable during chronic treatment. Cases of anaemia requiring blood cell transfusion have been reported with macitentan and other ERAs. Initiation of Yuvanci is not recommended in patients with severe anaemia. It is recommended that haemoglobin concentrations be measured prior to initiation of treatment with Yuvanci, and tests repeated during treatment as clinically indicated. 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

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