Zuranolone

Co-administration of repeated 50 mg daily doses of zuranolone with alcohol or alprazolam led to increased impairment in psychomotor performance. If use with another CNS depressant medicinal product (such as opioids, benzodiazepines, non-benzodiazepine hypnotics, gabapentinoids and sedating antidepressants) is unavoidable, dose reduction should be considered.

Systemic exposure (area under the curve to infinity [AUC_inf]) to zuranolone is reduced by 85% in the presence of rifampin (strong CYP3A inducer). Concomitant use of zuranolone with a CYP3A inducer decreases the exposure of zuranolone which may reduce the efficacy of zuranolone. Concomitant use of zuranolone with CYP3A inducers (e.g. carbamazepine, phenobarbitol, phenytoin, primidone, rifampicin, St John's Wort, and efavirenz) should be avoided.

The recommended dose is 30 mg taken orally once daily during the 14 day treatment period when used with strong CYP3A inhibitors.

Concomitant use of zuranolone with a strong CYP3A inhibitor increases the exposure of zuranolone. Systemic exposure (AUC_inf) to zuranolone is increased 62% when administered in combination with itraconazole. The dose of zuranolone should be reduced to 30 mg when used with a strong CYP3A inhibitor (e.g. protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).

Grapefruit products are inhibitors of CYP3A and should be avoided while taking zuranolone.

The recommended dose in patients with moderate (estimated glomerular filtration rate [eGFR] 30 to 59 mL/min) or severe renal impairment (eGFR <30 mL/min not requiring dialysis) is 30 mg taken orally once daily during the 14 day treatment period.

The recommended dose in patients with severe hepatic impairment (Child-Pugh class C) is 30 mg taken orally once daily during the 14 day treatment period.

Zuranolone has potential for abuse. In a human abuse potential study in recreational CNS depressant users (N=60), zuranolone (30, 60 and 90 mg) had dose dependent abuse potential when compared to alprazolam (1.5 mg and 3 mg) on positive subjective measures of "drug liking", "overall drug liking", "take drug again", "high", and "good drug effects".

Based on data from clinical trials, zuranolone has low physical dependence potential.

Caution should be used in individuals with a history of abuse or addiction to alcohol or other substances.

Zuranolone is contraindicated during pregnancy. There are no or limited data from the use of zuranolone in pregnant women. Studies in animals have shown reproductive toxicity.

Women of childbearing potential have to use effective contraception during treatment and for 7 days following discontinuation of treatment. Patients should be advised on the use of effective contraception.

Data from a clinical lactation study indicate that zuranolone is present in low levels in human breast milk. The calculated maximum relative infant dose (RID) was <1%. In most subjects, concentrations of zuranolone in breast milk were below the level of quantification limit by 6 days after the last dose. The effect of zuranolone on breastfed newborns/infants is unknown and there are limited data on the effect on milk production.

Breast-feeding should be discontinued during treatment with zuranolone, unless in the judgement of the healthcare professional, the benefits of breast-feeding outweigh the possible risks for the child.

Fertility

There are no human data on the effects of zuranolone on human fertility. Data from male and female animal studies showed no zuranolone-related effects on fertility or reproduction function at clinically relevant doses.

Zuranolone has a major influence on the ability to drive and use machines. Zuranolone has been reported to cause somnolence, dizziness, sedation and confusional state.

Two computer-based driving simulation studies evaluated the effects of bedtime zuranolone 30 mg and 50 mg administration on next-morning driving performance, 9 hours after dosing. The driving ability of healthy adults was impaired in a dose-dependent manner following single and repeat nightly administration. Exposure-response modelling of the standard deviation of lateral position (SDLP) data from the two driving simulation studies found that median placebo corrected SDLP falls below the threshold associated with a blood alcohol concentration (BAC) of 0.05% by 12 hours after a single dose and after 7 evening doses of zuranolone.

Patients should be counselled not to engage in potentially hazardous activities, such as driving a vehicle or operating machinery, for at least 12 hours after each zuranolone dose. Patients should be advised that they may not be able to assess their own ability to perform these activities.

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) were somnolence (27.6%), dizziness (13.3%), and sedation (11.2%). The serious adverse reaction was confusional state (1.3%).

The frequency of zuranolone-treated subjects who discontinued treatment due to ADRs was 2%. These ADRs were somnolence (2%) and sedation (1%). The frequency of zuranolone-treated subjects who had a dose reduction or interruption due to ADRs was 14.3%. The most frequently reported ADRs leading to dose reduction or interruption were somnolence (8.2%), dizziness (6.1%) and sedation (3.1%).

Tabulated list of adverse reactions

ADRs are presented in the following table. The ADRs are listed by system organ class (SOC) and frequency. Frequency categories were defined according to 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).

Adverse drug reactions occurring in patients with PPD treated with zuranolone:

Description of selected adverse reactions

Somnolence and sedation

Among subjects treated with zuranolone 50 mg, somnolence occurred in 26.5% of subjects and sedation in 11.2% of subjects. All events were assessed as mild or moderate in severity, with 69.7% of somnolence events and 58.3% of sedation events occurring within the first 2 days of treatment.

Confusional state

Confusional state was reported in 1 subject who received zuranolone 50 mg and resulted in dose reduction. Serious confusional state occurred in 1 subject who received 30 mg and resolved the same day following interruption of treatment, with treatment resuming at a reduced dose.