Ztalmy · 4.1 Therapeutic indications · 1

HOS-100142 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most commonly reported adverse reactions in clinical trials in patients with CDD include somnolence (29.4%) and pyrexia (23.5%). Tabulated list of adverse reactions Adverse reactions reported with ganaxolone in a clinical trials in patients with CDD with an average exposure duration of 411.5 days (N = 102) are listed in the table below by System Organ Class and frequency. The frequencies 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 7 System organ class Very common Common Nervous system disorders Somnolence Sedation Hypersomnia Lethargy Drooling Gastrointestinal disorders Salivary hypersecretion General disorders and Pyrexia administration site conditions Description of selected adverse reactions Somnolence and sedation ZTALMY can cause somnolence and sedation. In a placebo-controlled study for CDD, the incidence of somnolence and sedation was 31.4%, and 3.9% respectively in patients treated with ZTALMY, compared with 15.7%, and 3.9% respectively in patients treated with placebo. These adverse reactions appear early in treatment and are dose-related; symptoms may decrease with continued treatment. 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-100138 · has-contraindication-information · PDF-Seite 5

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

HOS-100137 · has-indication-information · PDF-Seite 2

ZTALMY is indicated for the adjunctive treatment of epileptic seizures associated with cyclin- dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 to 17 years of age. ZTALMY may be continued in patients 18 years of age and older.

HOS-100140 · has-interaction-information · PDF-Seite 6

CYP3A4 inducers Coadministration with a strong CYP3A4 inducer will decrease ganaxolone exposure. Concomitant use of rifampicin decreased the AUC0-inf of ganaxolone by approximately 57-68%. Enzyme inducing antiepileptics (e.g., carbamazepine, phenytoin, phenobarbital, and primidone) and St. John’s Wort may result in similarly lower plasma exposures of ganaxolone. In patients on a stable dose of ganaxolone or in patients initiating or increasing the dose of concomitant enzyme-inducing antiepileptic medicinal products or St. John’s Wort a dose increase may be necessary; however, do not exceed the maximum daily dose (see section 4.4). CYP3A4 inhibitors Coadministration of ganaxolone with itraconazole, a strong CYP3A4 inhibitor, increased the ganaxolone AUC by 17% in healthy subjects (the Cmax was unchanged). The changes in ganaxolone exposures when coadministered with strong, moderate, or weak CYP3A4 inhibitors are not expected to be clinically significant. UGT inhibitors Ganaxolone is a substrate for UGT1A3, UGT1A6, UGT1A9, and UGT2B15. No formal drug-drug interaction studies have been conducted with ganaxolone in combination with UGT inhibitors such as valproate. Dose reduction of ganaxolone and/or the UGT inhibitor may be necessary when given in combination. Oral contraceptives The potential interaction of ganaxolone with oral contraceptives has not been investigated. 6 Ethanol interaction Concomitant use with CNS depressants (including alcohol) may increase the risk of sedation and somnolence (see section 4.4). Patients should be prohibited from drinking alcohol during treatment.

HOS-100141 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are limited data on the use of ganaxolone in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). ZTALMY is not recommended during pregnancy and in woman of childbearing potential not using contraception. Breast-feeding Ganaxolone and its metabolites are excreted in human milk. Based on an average milk intake, the calculated maximum relative infant dose of ganaxolone is approximately 1% of the maternal dose. The effect of ganaxolone on breastfed newborns/infants is unknown. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue ZTALMY taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility There are no human data on the effect of ganaxolone on fertility. Animal studies are insufficient with respect to fertility (see section 5.3).

HOS-100139 · has-warning-information · PDF-Seite 5

Somnolence and sedation ZTALMY causes somnolence and sedation (see sections 4.5 and 4.8). Other Central Nervous System (CNS) depressants, including concomitantly used anti-seizure medicinal products, opioids, antidepressants, and alcohol, could potentiate the somnolence and sedation effect. Suicidal behaviour and ideation Suicidal behaviour and ideation have been reported in patients treated with anti-epileptic drugs (AEDs) in several indications. A meta-analysis of randomised placebo-controlled trials with AEDs has shown a small increased risk of suicidal behaviour and ideation. The mechanism of this risk is not known. The available data do not exclude the possibility of an increased risk with ganaxolone. Patient’s caregivers should be advised to monitor for signs of suicidal behaviour and ideation, or self-harm behaviour during treatment and when changes in the treatment regimen become necessary. Caregivers should be advised to seek medical advice should any signs of suicidal behaviour and ideation, or self-harm emerge. Alcohol use In animal models, ganaxolone has been shown to potentiate the effects of alcohol. Patients should not use alcohol during treatment (see section 4.5). CYP3A4 inducers Concomitant use with strong cytochrome P450 (CYP) 3A4 inducers e.g. carbamazepine, phenobarbital, phenytoin, primidone, rifampicin and St John’s Wort should be avoided as they can reduce ganaxolone exposure (see section 4.5). Hepatic impairment An increase in ganaxolone exposure was seen in patients with severe hepatic impairment (Child-Pugh C) (see section 5.2). A dosage adjustment is recommended in these patients (see section 4.2). Abuse ZTALMY has potential for abuse (see section 5.3). 5 Dependence It was not possible to assess physical dependence during clinical trials with ganaxolone; animal studies suggest that abrupt discontinuation of ganaxolone may cause withdrawal symptoms (see sections 5.1 and 5.3). It is therefore recommended that ganaxolone be tapered according to the dosage recommendations unless symptoms warrant immediate discontinuation (see section 4.2). Excipients with known effect This medicinal product contains less than 1 mmol sodium (23 mg) per each daily dose, that is to say essentially ‘sodium-free’. This medicinal product contains 0.00068 mg benzoic acid in each mL. Benzoic acid may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks o

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