Ganaxolone

Ganaxolone causes somnolence and sedation. Other Central Nervous System (CNS) depressants, including concomitantly used anti-seizure medicinal products, opioids, antidepressants, and alcohol, could potentiate the somnolence and sedation effect.

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.

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.

For patients with severe hepatic impairment (Child-Pugh C) the initial target dose should be one-half the recommended target dose. The dose titration should be performed as detailed in the table(s) below.

The dose in patients with severe hepatic impairment weighing 28 kg or less is shown below:

The dose in patients with severe hepatic impairment weighing more than 28 kg is shown below:

Higher or lower doses may be considered in patients with severe hepatic impairment based on individual clinical response and tolerability.

There are limited data on the use of ganaxolone in pregnant women. Animal studies are insufficient with respect to reproductive toxicity.

Ganaxolone is not recommended during pregnancy and in woman of childbearing potential not using contraception.

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 ganaxolone 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.

Ganaxolone 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. Patients should be advised not to drive or use machines.

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

Ganaxolone 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 ganaxolone, 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.