Voranigo · 4.1 Therapeutic indications · 1

HOS-100756 · has-adverse-reaction-information · PDF-Seite 8

Summary of safety profile The most common adverse reactions, including laboratory abnormalities, were ALT increased (59.3%), AST increased (45.5%), GGT increased (37.7%), fatigue (36.5%) and diarrhoea (24.6%). The most common grade ≥ 3 adverse reactions were ALT increased (9.6%), AST increased (4.2%) and GGT increased (3.0%). Serious adverse reactions of hepatic failure, autoimmune hepatitis and ALT increased each occurred in 0.6% of patients who received Voranigo. Permanent discontinuation of vorasidenib due to grade ≥ 3 ALT increased or autoimmune hepatitis was reported in 3.0% and 0.6% of patients, respectively. Dose interruptions due to an adverse reaction occurred in 18.6% of patients treated with vorasidenib. The most common adverse reactions requiring dose interruption were ALT increased (14.4%) and AST increased (6.0%). Dose reductions of vorasidenib due to an adverse reaction occurred in 9.6% of patients. The most common adverse reaction requiring dose reduction was ALT increased (7.8%). Tabulated list of adverse reactions The adverse reactions described in this section are derived from study data (INDIGO study [N=167]) and post-marketing experience with Voranigo. 8 The adverse reactions reported in patients treated with vorasidenib are listed below in Table 3 by MedDRA system organ class and by frequency. 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), not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3: Adverse drug reactions reported in patients treated with vorasidenib System organ class Frequency Adverse reactions Blood and lymphatic system Very common Platelet count decreaseda disorders Hyperglycaemia Metabolism and nutrition Common Decreased appetite disorders Hypophosphataemia Nervous system disorders Very common Dizziness Respiratory, thoracic and Common Dyspnoea mediastinal disorders

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HOS-100752 · has-contraindication-information · PDF-Seite 5

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

HOS-100751 · has-indication-information · PDF-Seite 2

Voranigo as monotherapy is indicated for the treatment of predominantly non-enhancing Grade 2 astrocytoma or oligodendroglioma with an IDH1 R132 or IDH2 R172 mutation in adult and adolescent patients aged 12 years and older and weighing at least 40 kg who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy (see section 5.1). 2

HOS-100754 · has-interaction-information · PDF-Seite 6

Based on in vitro experiments vorasidenib is a strong inducer by means of pregnane X receptor (PXR) activation and may affect the plasma exposure of co-administered medicines that are metabolised or transported by enzymes or transporters whose expression is mediated by PXR. Effect of other medicinal products on vorasidenib Strong CYP1A2 inhibitors Co-administration of vorasidenib with strong CYP1A2 inhibitors (fluvoxamine and ciprofloxacin) may increase vorasidenib plasma concentration. Concomitant use of strong CYP1A2 inhibitors should be avoided and consider alternative therapies that are not strong inhibitors of CYP1A2 during treatment with vorasidenib. 6 In an in vivo drug-drug interaction study, co-administration of 20 mg vorasidenib with a strong CYP1A2 inhibitor (500 mg ciprofloxacin twice daily for 14 days) increased vorasidenib maximum plasma concentration (Cmax) by 29% and area under the plasma time-concentration curve (AUC) by 153%. Moderate CYP1A2 inducers Co-administration of vorasidenib with moderate CYP1A2 inducers (phenytoin and rifampicin) may decrease vorasidenib plasma concentration. Consider alternative therapies that are not moderate CYP1A2 inducers during treatment with vorasidenib. Gastric acid reducing agents No clinically significant differences in vorasidenib pharmacokinetics were observed following co-administration of vorasidenib with the gastric acid reducing agent omeprazole. Effect of vorasidenib on other medicinal products Cytochrome P450 (CYP) substrates with narrow therapeutic index Co-administration of vorasidenib with CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 substrates with narrow therapeutic index (including, but not limited to, amitriptyline, alfentanil, carbamazepine, ciclosporin, dosulepin, everolimus, fentanyl, fosphenytoin, ifosfamide, imipramine, phenobarbital, phenytoin, pimozide, quinidine, sirolimus, tacrolimus, tamoxifen, trimipramine, valproic acid, and warfarin) may decrease the plasma concentrations of these medicinal products. Concomitant use of substrates of these enzymes with narrow therapeutic index should be avoided in patients taking vorasidenib. Sensitive substrates of CYP enzymes without narrow therapeutic index Co-administration of vorasidenib with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 without narrow therapeutic index (including, but not limited to, bupropion, buspirone, celecoxib, darunavir, ibrutinib

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HOS-100755 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential / Contraception Pregnancy testing is recommended in women of childbearing potential prior to starting treatment with vorasidenib (see section 4.4). Women of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment and for at least 2 months after the last dose. Since the effect 7 of vorasidenib on the metabolism and efficacy of systemically acting hormonal contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy (see sections 4.4 and 4.5). Pregnancy There are no or limited amount of data from the use of vorasidenib in pregnant women. Studies in animals have shown embryo-foetal development toxicity (see section 5.3). Vorasidenib should not be used during pregnancy and in women of childbearing potential not using contraception. Women of childbearing potential or male patients with female partners of childbearing potential should be advised on the potential risk to a foetus. Breast-feeding It is unknown whether vorasidenib and its metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment and for at least 2 months after the last dose. Fertility There are no human data on the effect of vorasidenib on fertility. Findings on reproductive organs were observed during repeat-dose toxicity studies in female and male animals (see section 5.3). The clinical relevance of these effects is unknown. Male and female patients who are planning to conceive a child should be advised to seek reproductive counselling, and men should seek advice on cryo-preservation of sperm prior to treatment (see section 4.4).

HOS-100753 · has-warning-information · PDF-Seite 5

Hepatotoxicity Drug-induced hepatotoxicity, including serious cases of hepatic failure, hepatic necrosis and hepatitis acute have been reported in patients treated with vorasidenib in the pivotal clinical study or in post- marketing experience (see section 4.8). Liver enzymes (including ALT, AST and gamma-glutamyl transferase (GGT)) and total bilirubin must be monitored prior to starting treatment, every 2 weeks during the first 2 months of treatment and then once monthly for the first 2 years of treatment, and as clinically indicated thereafter. Consider weekly monitoring for ALT or AST elevations ≤ 3 times the ULN. Withhold, reduce dose or permanently discontinue treatment based on the severity of the liver enzyme abnormalities (see section 4.2). Carcinogenicity risk Animal findings may be suggestive of potential carcinogenic risk (notably in liver, see section 5.3). Carcinogenicity studies have not been conducted yet and long-term clinical safety data are insufficient. Therefore, a carcinogenicity risk in humans could not be excluded. 5 Women of childbearing potential / Contraception Vorasidenib could cause foetal harm when administered to a pregnant woman. Pregnancy testing is recommended in women of childbearing potential prior to starting treatment. Women of childbearing potential should use effective contraception during treatment and for at least 2 months after the last dose. Women who are planning to conceive a child should be advised to seek reproductive counselling. Vorasidenib may decrease concentrations of hormonal contraceptives and, therefore, concomitant use of a barrier method of contraception is recommended during treatment and for at least 2 months after the last dose (see sections 4.5 and 4.6). Male patients Males with female partners of childbearing potential should use effective contraception during treatment and for at least 2 months after the last dose. Men should seek advice on cryo-preservation of sperm prior to treatment (see section 4.6). Hepatic impairment The safety and efficacy of vorasidenib have not been established in patients with severe hepatic impairment (Child-Pugh class C). Vorasidenib should be used with caution in patients with pre-existing severe hepatic impairment (Child-Pugh class C) and this patient population should be closely monitored (see sections 4.2 and 5.2). Renal impairment The pharmacokinetics and safety of vorasidenib have not been stu

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