Beyonttra · 4.6 Fertility, pregnancy, and lactation · 1

HOS-100812 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile Based on the clinical study, the most frequently reported adverse reactions were diarrhoea (11.6%) and gout (11.2%). Tabulated list of adverse reactions The safety data reflect exposure of 421 participants with ATTR-CM to acoramidis 712 mg (as two tablets of 356 mg) administered orally twice daily in a pivotal Phase 3 randomised, double-blind, placebo-controlled study of 30 months fixed treatment duration in patients diagnosed with ATTR-CM. Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categories using the standard convention: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), and Uncommon (≥ 1/1 000 to < 1/100). Adverse reactions listed in the table below are from cumulative clinical data in ATTR-CM participants. Table 1: List of adverse reactions System Organ Class Very common Gastrointestinal disorders Diarrhoea Metabolism and nutrition disorders Gout Description of selected adverse reactions The majority of events of diarrhoea and gout were non-serious and resolved. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-100808 · has-contraindication-information · PDF-Seite 3

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

HOS-100807 · has-indication-information · PDF-Seite 2

BEYONTTRA is indicated for the treatment of wild-type or variant transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM).

HOS-100810 · has-interaction-information · PDF-Seite 4

Effect of acoramidis on other medicinal products Transporter systems Based on a clinical study in healthy adult volunteers, inhibition of organic anion transporter (OAT)-1 and -3 is not expected to result in clinically relevant drug-drug interactions with OAT-1 and OAT-3 substrates (e.g., non-steroidal anti-inflammatory medicines, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir, cidofovir, zidovudine, zalcitabine). Based on an in vitro study, no drug-drug interaction with co-administered breast cancer resistance protein (BCRP) substrates is anticipated at clinically relevant concentrations. Based on in vitro studies, acoramidis is unlikely to cause any clinically relevant uridine 5'-diphospho (UDP)-glucuronosyl transferase-dependent or Cytochrome P450-dependent interactions. However, acoramidis was shown to be an inhibitor of CYP2C8 and CYP2C9 in vitro. No in vivo study has been performed. Therefore, concomitant CYP2C8 and CYP2C9 substrates with narrow therapeutic index should be used with caution. Effect of other medicinal products on acoramidis Diuretics Based on population pharmacokinetic (PK) analysis, concomitant diuretic use in patients does not affect steady-state plasma acoramidis concentrations. Breast Cancer Resistance Protein inhibitors Acoramidis is a substrate for BCRP. Based on an in vitro study, a clinically relevant interaction with BCRP inhibitors is not expected. Gastric acid reducing agents No dedicated in vivo drug-drug interaction study with gastric acid reducing agents was performed. Thus, the effect of gastric acid reducing agents on the pharmacokinetics of acoramidis is unknown. Despite the marked pH dependent solubility of acoramidis in the physiological pH range, no differences were observed in the systemic exposure to acoramidis or in the pharmacodynamic marker (TTR stabilisation) between patients taking acid reducing agents and patients not taking acid reducing agents, in the phase 3 study. Effect on laboratory test Acoramidis may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone (TSH). No corresponding clinical findings consistent with thyroid dysfunction have been observed.

HOS-100811 · has-pregnancy-information · PDF-Seite 4

Pregnancy There are no data on the use of acoramidis in pregnant women. Studies in animals have shown developmental toxicity at a dose which also caused maternal toxicity (see section 5.3). Acoramidis is not recommended during pregnancy and in women of childbearing potential not using contraception. 4 Breast-feeding It is unknown whether acoramidis or its metabolites are excreted in human milk. Available data in animals have shown excretion of acoramidis in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. Acoramidis should not be used during breast-feeding. Fertility No human data on fertility is available. Impairment of fertility has not been observed in non-clinical studies in supratherapeutic exposures.

HOS-100809 · has-warning-information · PDF-Seite 3

Hepatic impairment Acoramidis has not been studied in patients with hepatic impairment and therefore is not recommended for use in this population (see sections 4.2 and 5.2). Renal impairment Data in patients with severe renal impairment (creatinine clearance < 30 mL/min) are limited (see sections 4.2 and 5.2) and there are no data for patients on dialysis. Hence acoramidis should be used with caution in this population. Renal haemodynamic parameters Patients treated with acoramidis experienced an initial decrease in estimated glomerular filtration rate (eGFR) in the first month of treatment and a corresponding increase in measured serum creatinine (see section 5.1). This change in eGFR and serum creatinine was non-progressive, reversible in those patients whose treatment was interrupted, and not associated with kidney injury, consistent with a renal haemodynamic effect. Information about excipients Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free’. 3