Rezdiffra · 4.4 Special warnings and precautions for use · 1

HOS-100700 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most frequently reported adverse reactions are diarrhoea, nausea, and pruritus. Diarrhoea typically occurred at treatment initiation, was mild to moderate and self-limiting, resolving on average in 2 to 3 weeks. The median time to complete resolution of diarrhoea was 3 to 4 weeks. Nausea occurred at treatment initiation and was mild to moderate, occurring more commonly in female patients. Other rare events included cholecystitis and urticaria. The most common reason for discontinuation in all age groups was withdrawal by subject. Tabulated list of adverse reactions Unless otherwise stated, the frequencies of adverse reactions in Table 1 are based on all-cause adverse event frequencies identified in patients randomised to the double-blind treatment arms of the Phase 3 clinical studies (MAESTRO-NASH and MAESTRO-NAFLD-1). Adverse reactions are listed by MedDRA system organ class and frequency: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 1: List of adverse reactions in MAESTRO-NASH and MAESTRO-NAFLD-1 System Organ Class Frequency: Adverse reactions Nervous system disorders Uncommon: Dizziness Gastrointestinal disorders Very Common: Diarrhoea, nausea Uncommon: Abdominal pain, constipation, vomiting Rare: Obstructive pancreatitis2 Hepatobiliary disorders Rare: Cholecystitis1,2, cholelithiasis Not known: Hepatotoxicity Skin and subcutaneous tissue Common: Pruritus disorders Uncommon: Rash Rare: Urticaria 1 The term “cholecystitis” includes Preferred Terms of bile duct stone, biliary colic, biliary dilatation, cholecystitis, cholecystitis acute, cholecystitis chronic and cholangitis. 2 A higher incidence of cholecystitis and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the Exposure Adjusted Incidence Rates (EAIRs) for these events were less than 1 per 100 patient years (PY) for all treatment arms. Description of selected adverse reactions Liver enzyme elevations

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HOS-100696 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-100695 · has-indication-information · PDF-Seite 3

Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (fibrosis stages F2 to F3).

HOS-100698 · has-interaction-information · PDF-Seite 4

Resmetirom is partially metabolised by CYP2C8. Effects of other medicinal products on resmetirom CYP2C8 inhibitors Clopidogrel, a moderate CYP2C8 inhibitor, increased resmetirom exposure (1.3-fold in Cmax and 1.7- fold in AUC) in healthy adult subjects. Dose adjustment of resmetirom is recommended when used concomitantly with moderate CYP2C8 inhibitors. As greater increases are expected with strong inhibitors (e.g. gemfibrozil), their use is not recommended (see section 4.2). OATP1B1, OATP1B3 and BCRP inhibitors No clinically significant differences in the pharmacokinetics of resmetirom were observed when used concomitantly with ciclosporin (an OATP1B1/1B3 and BCRP inhibitor). 4 Effects of resmetirom on other medicinal products HMG-CoA reductase inhibitors (statins) The effect of resmetirom on the pharmacokinetics of statins (i.e., simvastatin, rosuvastatin, pravastatin and atorvastatin) was evaluated in studies in healthy subjects: • Simvastatin: AUC increased by 1.7-fold and Cmax by 1.4-fold following a single dose of simvastatin 20 mg with resmetirom (100 mg/day). • Rosuvastatin: AUC increased by 1.4-fold and Cmax by 1.8-fold following a single dose of rosuvastatin 20 mg with resmetirom (100 mg/day). • Pravastatin: AUC increased by 1.4-fold and Cmax by 1.3-fold following a single dose of pravastatin 40 mg with resmetirom (100 mg/day). • Atorvastatin: AUC increased by 1.4-fold with no change in Cmax following a single dose of atorvastatin 20 mg with resmetirom (100 mg/day). The dose of rosuvastatin and simvastatin should be limited to a daily dose of 20 mg and the dose of pravastatin and atorvastatin should be limited to a daily dose of 40 mg. CYP2C8 substrates Resmetirom is a substrate and mild inhibitor of CYP2C8. In a clinical study in healthy subjects, co- administration of a single oral dose of pioglitazone (15 mg), a moderately sensitive CYP2C8 substrate, with resmetirom (100 mg/day) resulted in a 1.5-fold increase in the AUC of pioglitazone, with no change in Cmax. Although no dose adjustment is required, clinical monitoring is recommended when resmetirom is used with certain CYP2C8 substrates for which small increases in exposure may lead to serious or dose-related adverse reactions. Warfarin In healthy subjects with stable INR, administration of resmetirom (100 mg/day) for multiple days had minimal effect on the AUC and Cmax of R- and S-warfarin

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HOS-100699 · has-pregnancy-information · PDF-Seite 5

Pregnancy There are no data from the use of resmetirom in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of resmetirom during pregnancy. Breast-feeding It is unknown whether resmetirom and/or its metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from resmetirom therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. 5 Fertility No fertility data are available in humans. Animal studies do not indicate any direct or indirect effects on fertility (see section 5.3).

HOS-100697 · has-warning-information · PDF-Seite 4

Gallbladder events In clinical studies, cholecystitis was observed more often in resmetirom-treated patients than in placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. Use in other liver diseases Resmetirom has not been studied in patients with other underlying liver diseases. Resmetirom should be used with caution in MASH patients with other underlying liver diseases such as autoimmune liver diseases or active viral hepatitis. Resmetirom should be used with caution in patients with alcohol- related liver disease. Liver enzymes Conduct liver enzyme monitoring periodically during treatment. If hepatotoxicity is suspected, discontinue resmetirom treatment and continue to monitor liver chemistry. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.