Bylvay · 4.8 Undesirable effects · 1

HOS-287267 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most commonly reported adverse reaction was diarrhoea (30.6%). Other reported adverse reactions were mild to moderate increases in blood bilirubin (24.8%), ALT (14%) and AST (9.1%), vomiting (16.5%), stomach pain (11.6%), and decreases in Vitamin D (11%) and E levels (5%). Tabulated list of adverse reactions The table lists adverse reactions identified in clinical trials in patients with PFIC aged between 4 months to 25 years of age (median 3 years 7 months). Adverse reactions are ranked according to system organ class, using the following convention: 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 the available data). Table 3: Frequency of adverse reactions in PFIC patients MedDRA system organ class Frequency Adverse drug reaction Gastrointestinal disorders Very common diarrhoeaa, vomiting abdominal painb Hepatobiliary disorders Very common blood bilirubin increased, ALT increased Common hepatomegaly, AST increased Metabolism and nutrition site Very common vitamin D deficiency disorders Common vitamin E deficiency a Based on the combined frequency of diarrhoea, diarrhoea haemorrhagic and faeces soft b Includes abdominal pain upper and abdominal pain lower ALT = alanine aminotransferase AST = aspartate aminotransferase Description of selected adverse reactions Gastrointestinal adverse reactions In clinical trials, diarrhoea was the most common gastrointestinal adverse drug reaction. Adverse reactions of diarrhoea, diarrhoea haemorrhagic and soft faeces were of short duration with most events ≤ 5 days in duration. Most cases of diarrhoea were mild to moderate in intensity and non-serious. Dose reduction, treatment interruption and discontinuation due to diarrhoea was reported with few patients requiring intravenous or oral hydration due to diarr

Auszug; vollständigen Abschnitt im Original lesen.

HOS-287263 · has-contraindication-information · PDF-Seite 5

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

HOS-287262 · has-indication-information · PDF-Seite 3

Bylvay is indicated for the treatment of progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older (see sections 4.4 and 5.1).

HOS-287265 · has-interaction-information · PDF-Seite 6

Transporter-mediated interactions Odevixibat is a substrate for the efflux transporter P-glycoprotein (P-gp). In adult healthy subjects, co- administration of the strong P-gp inhibitor itraconazole increased the plasma exposure of a single dose of odevixibat 7 200 mcg by approximately 50-60%. This increase is not considered clinically relevant. No other potentially relevant transporter-mediated interactions were identified in vitro (see section 5.2). Cytochrome P450-mediated interactions In vitro, odevixibat did not induce CYP enzymes (see section 5.2). In in vitro studies, odevixibat was shown to be an inhibitor of CYP3A4/5 (see section 5.2). In adult healthy subjects, concomitant use of odevixibat decreased the area under the curve (AUC) of oral midazolam (a CYP3A4 substrate) by 30% and 1-OH-midazolam exposure by less than 20%, which is not considered clinically relevant. No interaction studies have been conducted with UDCA and rifampicin. In an interaction study with a lipophilic combination oral contraceptive containing ethinyl estradiol (EE) (0.03 mg) and levonorgestrel (LVN) (0.15 mg) conducted in adult healthy females, concomitant use of odevixibat had no impact on the AUC of LVN and decreased the AUC of EE by 17%, which is not considered clinically relevant. Interaction studies with other lipophilic medicinal products have not been performed, therefore, an effect on the absorption of other fat-soluble medicinal products cannot be excluded. In clinical trials, decreased levels of fat-soluble vitamins were observed in some patients receiving odevixibat. Levels of fat-soluble vitamins should be monitored (see section 4.4). Paediatric population No interaction studies have been performed in paediatric patients. No differences are expected between the adult and paediatric populations.

HOS-287266 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential Women of childbearing potential should use an effective method of contraception when treated with odevixibat. Pregnancy There are no or limited data from the use of odevixibat in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Odevixibat is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether odevixibat or its metabolites are excreted in human milk. There is insufficient information on the excretion of odevixibat in animal milk (see section 5.3). 6 A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from odevixibat therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother. Fertility No fertility data are available in humans. Animal studies do not indicate any direct or indirect effects on fertility or reproduction (see section 5.3).

HOS-287264 · has-warning-information · PDF-Seite 5

Enterohepatic circulation The mechanism of action of odevixibat requires that the enterohepatic circulation of bile acids and bile salt transport into biliary canaliculi is preserved. Conditions, medicinal products or surgical procedures that impair either gastrointestinal motility, or enterohepatic circulation of bile acids, including bile salt transport to biliary canaliculi have the potential to reduce the efficacy of odevixibat. For this reason, e.g. patients with PFIC2 who have a complete absence or lack of function of Bile Salt Export Pump (BSEP) protein (i.e. patients with BSEP3 subtype of PFIC2) will not respond to odevixibat. There are limited clinical data with odevixibat in PFIC subtypes other than 1 and 2. Diarrhoea Diarrhoea has been reported as a common adverse reaction when taking odevixibat. Diarrhoea may lead to dehydration. Patients should be monitored regularly to ensure adequate hydration during episodes of diarrhoea (see section 4.8). Treatment interruption or discontinuation may be required for persistent diarrhoea. Liver monitoring Elevations in liver enzymes and bilirubin levels have been observed in patients treated with odevixibat. Assessment of liver function tests is recommended for all patients prior to initiating odevixibat, with monitoring per standard clinical practice. For patients with liver function test elevations and severe hepatic impairment (Child-Pugh C), more frequent monitoring is to be considered. Fat-soluble vitamin absorption Assessment of fat-soluble vitamin (FSV) levels (Vitamins A, D, E) and international normalised ratio (INR) are recommended for all patients prior to initiating odevixibat, with monitoring per standard clinical practice. If FSV deficiency is diagnosed, supplemental therapy should be prescribed. 5