zuranolone: prescribing information – dosing, contraindications, interactions, side effects

Zurzuvae is indicated for the treatment of postpartum depression (PPD) in adults following childbirth (see section 5.1).

Posology

The recommended dose is 50 mg zuranolone (two 25 mg capsules) taken orally once daily for 14 days as a single course of treatment. No data on additional treatment in case of a relapse or an insufficient response to zuranolone are available.

The dose may be reduced to 40 mg (two 20 mg capsules) taken orally once daily for 14 days if the patient does not tolerate 50 mg (see section 4.4). If required, dosing may be stopped without down- titration.

Zuranolone may be used alone or with stable background oral antidepressant therapy (see sections 4.4, 4.5 and 5.1).

Zuranolone should be taken in the evening. If an evening dose is missed, the patient should be instructed to take the next dose at their regular time in the evening of the next day. The patient should not take additional capsules on the same day to make up for the missed dose. The patient should continue taking zuranolone once daily until the full treatment course (14 days) is completed.

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

Special populations

Renal impairment
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. No dose adjustment is necessary in patients with mild renal impairment (eGFR 60 to 89 mL/min) (see section 5.2).

Hepatic impairment
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. No dose adjustment is necessary in patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B) (see section 5.2).

Paediatric population
The safety and efficacy of Zurzuvae in postpubertal females less than 18 years old have not been established. No data are available.

There is no relevant use of Zurzuvae in prepubertal females.

Method of administration

Zurzuvae should be taken orally once daily in the evening with fat-containing food as either a meal or snack (e.g. fat-containing dairy products, meats and oily fish, avocado, hummus, soy-based products, nuts, peanut butter, chocolate, or fat-containing nutritional bars or drinks) (see section 5.2).

Zurzuvae capsules are swallowed whole.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Pregnancy (see section 4.6).

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 Table 1. 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).

Table 1. Adverse drug reactions occurring in patients with PPD treated with zuranolone

System organ class (SOC)
Adverse drug reaction
Frequency
Psychiatric disorders
Memory impairment
Common
Confusional state
Common
Nervous system disorders
Somnolence
Very common
Dizziness
Very common
Sedation
Very common
Tremor
Common
Gastrointestinal disorders
Diarrhoea
Common
General disorders and administration site conditions
Fatigue
Common

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.

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.

Impaired ability to drive or engage in potentially hazardous activities

Zuranolone impairs the ability to drive due to central nervous system (CNS) depressant effects.
Patients should be counselled not to drive or engage in other potentially hazardous activities until at least 12 hours after taking each dose of zuranolone. Patients should be advised that they may not be able to assess their own ability to perform these activities (see section 4.7).

Central nervous system depressant effects

Zuranolone can cause CNS depressant effects such as somnolence and sedation (see section 4.8).
Alcohol and other CNS depressants may increase CNS depressant effects or impairment of psychomotor performance (see section 4.5).

The zuranolone dose should be reduced or permanently discontinued based on the severity of the adverse reaction and the individual sensitivity of the patient to these effects (see section 4.2 or 4.5).

Drug interactions

Concomitant use of zuranolone with CYP3A inducers should be avoided (see section 4.5).

Abuse potential and dependence

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.

Excipients

Sodium content
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium free'.

CNS depressant medicinal products and alcohol

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 (see section 4.4).

Effect of other medicinal products on the pharmacokinetics of zuranolone

In vitro studies showed that zuranolone is metabolised primarily by CYP3A.

CYP3A inducers
Systemic exposure (area under the curve to infinity [AUCinf]) to zuranolone is reduced by 85% in the presence of rifampin (strong CYP3A inducer) (see section 5.2). 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.

Strong CYP3A inhibitors
Concomitant use of zuranolone with a strong CYP3A inhibitor increases the exposure of zuranolone.
Systemic exposure (AUCinf) 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) (see section 4.2).

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

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

Zuranolone is contraindicated during pregnancy (see section 4.3). There are no or limited data from the use of zuranolone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

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.

Breast-feeding

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 (see section 5.2). The effect of zuranolone on breastfed newborns/infants is unknown and there are limited data on the effect on milk production (see section 5.3).

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 (see section 5.3).

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 (see section 4.8).

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 (see section 4.4).

One case of intentional overdose with zuranolone was reported during premarketing clinical trials. The patient took 330 mg (6.5 times the MRHD) of zuranolone and was reported to be in an altered state of consciousness. The event resolved the next day following treatment with intravenous fluids.

Overdose with zuranolone may result in excessive CNS depressant effects (see sections 4.4 and 4.8).

There is no specific antidote for zuranolone overdose. Appropriate supportive measures should be provided as dictated by the patient’s clinical status.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Psychoanaleptics, other antidepressants, ATC code: N06AX31

Mechanism of action

Zuranolone is a synthetic neuroactive steroid (NAS) that exhibits potent positive allosteric modulation of the gamma-aminobutyric acid-A (GABAA) receptor. Zuranolone enhances GABAergic activity at synaptic and extrasynaptic GABAA receptors and has also been shown to increase cell surface expression of GABAA receptors in in vitro studies. Zuranolone may exert antidepressant effects by enhancing GABAergic inhibition.

Pharmacodynamic effects

Cardiac electrophysiology
At a dose up to 2 times the MRHD, zuranolone does not cause clinically significant QTc interval prolongation nor any other clinically significant effect on other electrocardiography (ECG) parameters.

Clinical efficacy and safety

The efficacy of zuranolone for the treatment of women with PPD was studied in a randomised, double-blind, parallel-group, placebo-controlled, multi‑centre study (217‑PPD‑301 [NCT04442503]).
Female subjects aged 18 to 45 were randomized 1:1 to receive either zuranolone 50 mg or placebo, orally once daily. Subjects enrolled were to have a total score ≥ 26 at baseline in the 17-item Hamilton Depression Rating (HAMD-17) scale. Subjects also met criteria for MDE per DSM-5 (Diagnostic and Statistical Manual of Mental Disorders – 5th edition) criteria. The criteria were limited to onset of symptoms in the third trimester or within 4 weeks of delivery. Subjects started treatment up to 12 months following childbirth. Subjects were followed for 4 weeks after the 14 day treatment course.

Table 2. Population characteristics

Parameter
217-PPD-301†
(SKYLARK)
Age (years) – mean (min, max)
30 (19, 44)
Taking a stable dose of oral antidepressants* for at least 30 days before baseline 15% Race White 70% Black or African American 22% Asian 1% Other/Mixed 7% Ethnicity Hispanic or Latino 39% Body mass index (kg/m2) - mean (min, max) 30 (19, 45) Subjects with PPD onset following, and within the first 4 weeks of, childbirth 67% HAMD-17 total score at baseline – mean (min, max)

Absorption

Once-daily administration of zuranolone 50 mg resulted in accumulation of approximately 1.5-fold in systemic exposures and steady state was achieved in 3 to 5 days.

Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours post-dose.

Effect of food
Following administration of zuranolone 30 mg to healthy volunteers, the maximum serum concentration (Cmax) increased 228% and the AUC increased 55% with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The Cmax increased 334% and the AUC increased 90% with a high-fat meal (800 to 1000 calories, 50% fat) compared to fasted conditions. The time at maximum concentration (tmax) was not impacted by food. Exposure at doses up to 90 mg remained approximately dose linear with consumption of a moderate-fat meal (700 calories; 30% fat).

Distribution

The volume of distribution of zuranolone following oral administration is high (> 500 L) and was independent of dose. Zuranolone did not distribute preferentially into red blood cells.

Zuranolone is highly protein bound (> 99.5%) to plasma proteins.

Distribution into breast milk
The distribution of zuranolone into human breast milk was studied in a group of 14 healthy lactating women treated with daily oral administration of zuranolone 30 mg for 5 days. At steady state (Day 5), the calculated daily infant dose was low (approximately 0.00135 mg/kg/day), reflecting a mean RID of 0.357% compared to the maternal dose. From a simulation, the expected mean RID associated with a 50 mg maternal dose was 0.738% for an infant with a milk intake of 150 mL/kg/day and 0.984% for an infant with a milk intake of 200 mL/kg/day.

Biotransformation

Zuranolone undergoes extensive metabolism, with CYP3A identified as a primary enzyme involved.
There were no human metabolites circulating at > 10% of total drug-related material and none are considered to contribute to the therapeutic effects of zuranolone.