4.1. Therapeutic indications

Zurzuvae is indicated for the treatment of moderate or severe postnatal depression (PND) in adults following childbirth (see section 5.1).

4.2. Posology and method of administration

Posology

Treatment should be initiated under the supervision of a specialist prescriber.

The recommended dose of zuranolone is 50 mg (two 25 mg capsules) for 14 days as a single course of treatment.

The dose of zuranolone may be reduced to 40 mg (two 20 mg capsules) if the patient does not tolerate 50 mg (see section 4.4).

Treatment duration beyond 14 days has not been evaluated.

If a patient forgets to take zuranolone, the patient should be instructed to skip the missed dose and take the next dose at their regular time the next day. The patient should not take additional capsules on the same day to make up for the missed dose.

Zuranolone may be used alone or as an adjunct to oral antidepressant therapy.

If dose discontinuation is required, treatment may be stopped without down-titration.

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. 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. 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).

Concomitant use with CYP3A inhibitors

The recommended dose is 30 mg when used with strong CYP3A inhibitors (see section 4.5). No dose adjustment is recommended when zuranolone is concomitantly used with a moderate or weak CYP3A inhibitor e.g. fluoxetine.

Concomitant use with CYP3A inducers

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

Paediatric population

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

There is no relevant use of zuranolone in prepubertal females.

Method of administration

Zuranolone should be taken orally once daily, in the evening with fat-containing food (e.g., nuts, peanut butter, avocado, eggs, and cheese) (see section 5.2).

Zuranolone capsules are swallowed whole.

4.3. Contraindications

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

• During pregnancy.

4.4. Special warnings and precautions for use

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 to 40 mg or permanently discontinued based on the severity of the adverse reaction and the individual sensitivity of the patient to these effects.

A dose reduction of zuranolone should be considered if use with a CNS depressant medicinal product is unavoidable (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, 90 mg) had dose dependent abuse potential when compared to alprazolam (1.5 mg, 3 mg) on positive subjective measures of “drug liking”, “overall drug liking”, “take drug again”, “high” and “good drug effects”.

Zuranolone may produce physical dependence. In a driving simulation study (N=67), healthy subjects who received 50 mg of zuranolone for up to 7 days (on the 7th day subjects received 50 mg or 100 mg) experienced mild or moderate symptoms of possible withdrawal syndrome.

The risk for developing physical dependence and a subsequent withdrawal syndrome upon abrupt zuranolone discontinuation for individuals who take a higher than recommended dosage and/or use zuranolone for a longer duration than recommended (see section 4.2), has not been evaluated in clinical studies.

In a nonclinical study, convulsions were observed in a dog upon abrupt zuranolone discontinuation following administration daily for 14 days at doses that produced exposures higher than the maximum recommended human dose (see section 5.3).

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

Suicide/suicidal thoughts or clinical worsening:

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs therefore, patients should be closely monitored. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.

Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

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 products such as opioids, benzodiazepines, nonbenzodiazepine hypnotics, gabapentinoids and sedating antidepressants is unavoidable, dose reduction of zuranolone should be considered (see section 4.4).

Effect of other medicinal products on the pharmacokinetics of zuranolone

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 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 (see section 4.2).

Grapefruit juice products are known to inhibit CYP3A and should be avoided.

Non-significant drug interactions

Oral contraceptives

In a clinical study in healthy volunteers, repeated administration of zuranolone did not alter the exposure of simvastatin, a sensitive CYP3A4 substrate, indicating an absence of induction potential with substrates of CYP3A4. Based on in vitro studies, zuranolone is not an inhibitor of CYP3A4 at clinically relevant concentrations. Cumulatively these results suggest that zuranolone is unlikely to alter the exposure of oral contraceptives.

Effect of zuranolone on the pharmacokinetics of other medicinal products

Clinical studies

Clinical DDI studies indicate that repeated administration of zuranolone prior to administration of simvastatin (CYP3A substrate) or bupropion (CYP2B6 substrate) did not alter the exposure of simvastatin or bupropion. Zuranolone is not expected to cause a drug interaction through CYP450 enzyme induction.

In vitro studies

Enzyme systems

Zuranolone is not an inhibitor of CYP1A2, CYP2B6, or CYP2C19 and had very low inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4. Zuranolone was a direct inhibitor of CYP2C8 with an IC50 of 14 μM. A risk-based analysis that considered factors such as Cmax and unbound fraction indicated zuranolone is unlikely to cause a clinically significant medicinal product interaction due to inhibition of CYPs.

Efflux and uptake transporters

The interaction of zuranolone with the human BSEP, BCRP, and MDR1 efflux transporters, and human MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2 uptake transporters was evaluated. Although zuranolone exhibited mild inhibition of some transporters, further evaluation supports that at clinically relevant concentrations, zuranolone is not expected to inhibit any of the transporters evaluated. Zuranolone is not a substrate of P-glycoprotein.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data on the use of zuranolone in pregnant women. Studies in animals have shown reproductive toxicity. Based on findings from animal studies, zuranolone may cause foetal harm (see section 5.3).

Zuranolone is contraindicated during pregnancy and not recommended in women of childbearing potential not using contraception. Patients should use effective contraception during treatment and for 7 days following discontinuation of treatment. Women of childbearing potential 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.

The developmental and health benefits of breast‑feeding should be considered along with the mother's clinical need for zuranolone and any potential adverse effects on the breastfed child from zuranolone or from the underlying maternal condition.

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).

4.7. Effects on ability to drive and use machines

Zuranolone has a major influence on the ability to drive and use machines. Two studies evaluated the effects of bedtime zuranolone 30 mg and 50 mg administration on next‑morning driving performance, 9 hours after dosing, using a computer-based driving simulation. The driving ability of healthy adults was impaired in a dose-dependent manner following single and repeat nightly administration. A single dose of zuranolone 30 mg or 50 mg caused a statistically significant impairment in next morning‑driving performance compared to placebo. The mean effect on driving performance was not statistically significantly different following nightly administration of zuranolone 30 mg compared to placebo on Day 6; however, driving ability was impaired in some subjects taking zuranolone. Statistically significant effects on driving were observed on Day 8 following daily administration of zuranolone 50 mg.

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).

4.8. Undesirable effects

Summary of the safety profile

Zuranolone was evaluated in two placebo-controlled clinical studies in adults with PND (see section 5.1). Adverse drug reactions (ADRs) with onset up to 3 days after treatment discontinuation are reported at the highest frequency from either study. Serious adverse reaction (SAR) in 1 subject was confusional state.

Treatment discontinuation was reported at 2.0% and dose reductions or interruption was 14.3% in zuranolone-treated subjects. The most reported adverse reaction leading to treatment discontinuation is somnolence (2.0%).

Most ADRs in subjects receiving zuranolone were mild to moderate in intensity. The most frequently reported (≥ 10% in zuranolone 50 mg and greater than placebo) adverse reactions were somnolence, dizziness, and sedation.

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 PND treated with zuranolone

System organ class (SOC)

Adverse drug reaction

Frequency

Psychiatric disorders

Memory impairment

Common

Confusional state

Common

Nervous system disorders

Somnolence1

Very Common

Dizziness2

Very Common

Sedation

Very Common

Tremor

Common

Gastrointestinal disorders

Diarrhoea

Common

General disorders and administration site conditions

Fatigue3

Common

1 Include the following preferred terms (PTs): somnolence and hypersomnia.

2 Include the following PTs: dizziness and vertigo.

3 Include the following PTs: fatigue and asthenia.

Description of selected adverse reactions

Somnolence and sedation

These ADRs were generally mild to moderate in severity; most appeared within the first two days of treatment, were limited to the on-treatment period, and improved during the treatment course. Most somnolence and sedation ADRs resolved without intervention. In cases where dose reduction due to these ADRs was needed, most subjects completed the treatment course at the reduced dose.

Confusional state

Across the two clinical studies, two subjects experienced confusional state. One subject who received zuranolone 50 mg experienced a non-serious ADR which led to dose reduction to 40 mg. One subject who received zuranolone 30 mg had a SAR at Day 3. The SAR resolved on the same day and treatment was withheld for one day. The subject completed the treatment period on a reduced dose of zuranolone 20 mg without any further symptoms during the study.

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:

United Kingdom

Yellow Card Scheme

Website: at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 following morning.

Overdose with zuranolone may result in excessive CNS depressant effects (see section 4.4).

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