ZTALMY Oral suspension Ref.[51076] Active ingredients: Ganaxolone

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).

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 0.92 mg sodium benzoate and 0.00068 mg benzoic acid in each mL. Benzoate salt and benzoic acid may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

This medicinal product contains 0.00023 mg benzyl alcohol in each mL. Benzyl alcohol may cause allergic reactions. Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called “gasping syndrome”) in young children. Do not give to your newborn baby (up to 4 weeks old), unless recommended by your doctor. Do not use for more than a week in young children (less than 3 years old), unless advised by your doctor or pharmacist. Increased risk due to accumulation in young children. Ask your doctor or pharmacist for advice if you are pregnant or breast‑feeding, or if you have a liver or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”).

This medicinal product contains 1.02 mg methyl parahydroxybenzoate and 0.2 mg propyl parahydroxybenzoate in each mL. Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

CYP3A4 inducers

Coadministration with a strong CYP3A4 inducer will decrease ganaxolone exposure.

Concomitant use of rifampicin decreased the AUC_0-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 drugs 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 C_max 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.

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.

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).

ZTALMY has a moderate to major influence on the ability to drive and use machines because it may cause somnolence, sedation and sedation-related adverse reactions, such as fatigue and ataxia, and other CNS-related events such as dizziness (see section 4.4). Patients should be advised not to drive or use machines (see section 4.8).

Summary of the safety profile

The most commonly reported adverse drug 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.

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.

Not applicable.