Zuranolone (Monograph)

Brand name: Zurzuvae
Drug class: Antidepressants, Miscellaneous

Medically reviewed by Drugs.com on Feb 10, 2025. Written by ASHP.

[Web]

Introduction

Neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator; antidepressant.¹

Uses for Zuranolone

Postpartum Depression

Treatment of postpartum depression in adults.^{1 2 3}

American College of Obstetricians and Gynecologists (ACOG) recommends psychotherapy as first-line treatment for mild-to-moderate perinatal depression.⁴ When drug therapy is needed, ACOG recommends selective serotonin-reuptake inhibitors (SSRIs) as first-line, with serotonin- and norepinephrine-reuptake inhibitors (SNRIs) recommended as alternative.⁴ Pharmacotherapy should be individualized based on prior response to therapy.⁴ If there is no pharmacotherapy history, ACOG states that sertraline or escitalopram are reasonable first-line medications.⁴

ACOG recommends consideration for either zuranolone or brexanolone in postpartum period for moderate-to-severe perinatal depression with onset in third trimester or within 4 weeks postpartum; the decision to use these drugs should be based on consideration of benefits, risks, and challenges of therapy.^{4 5}

Zuranolone Dosage and Administration

General

Patient Monitoring

• Monitor patients for CNS depression while taking zuranolone; dosage adjustments may be necessary.¹

Administration

Administer orally.¹

Should be taken with fat-containing food (e.g., 400—1000 calories, 25% to 50% fat).¹

Can be used alone or as adjunct to oral antidepressant therapy.¹

Safety and efficacy beyond 14 days in single treatment course not established.¹

If evening dose is missed, take next dose at regular time the following evening; do not take extra capsules on same day to make up for missed dose; then continue taking once daily until remainder of 14-day treatment course complete.¹

Dosage

Adults

Postpartum Depression

Oral

50 mg orally once daily in the evening with fat-containing food for 14 days.¹

Dosage Modification for Toxicity

If CNS depressant effects reported within 14-day treatment period, consider reducing dosage to 40 mg once daily in the evening.¹

Dosage Modification for Drug Interactions

When used concomitantly with strong CYP3A4 inhibitor, reduce dosage to 30 mg once daily in the evening for 14 days.¹

No dosage modification recommended when used concomitantly with a moderate CYP3A4 inhibitor.¹

Avoid concomitant use with CYP3A4 inducers.¹

Special Populations

Hepatic Impairment

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: no dosage adjustment.¹

Severe hepatic impairment (Child-Pugh class C): 30 mg orally once daily in the evening for 14 days.¹

Renal Impairment

Mild renal impairment (eGFR 60—89 mL/minute per 1.73 m²): no dosage adjustment.¹

Moderate or severe renal impairment (eGFR <60 mL/minute per 1.73 m²): 30 mg orally once daily in the evening for 14 days.¹

Geriatric Patients

No specific population dosage recommendations at this time.¹

Cautions for Zuranolone

Contraindications

• None.¹

Warnings/Precautions

Warnings

Impaired Ability to Drive or Engage in Physically Hazardous Activities

Risk of CNS depressant effects and resulting driving impairment (see Boxed Warning).¹

Advise patients not to drive motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness, such as operating machinery, until at least 12 hours after zuranolone administration for duration of 14-day treatment course.¹ Inform patients that they may not be able to assess their own driving competence or degree of driving impairment caused by zuranolone.¹

Other Warnings/Precautions

CNS Depressant Effects

Can cause CNS depressant effects such as somnolence, confusion, and higher risk of falls.¹ Other CNS depressants such as alcohol, benzodiazepines, opioids, tricyclic antidepressants, or drugs that increase zuranolone concentration, may increase impairment of psychomotor performance or CNS depressant effects such as somnolence, cognitive impairment, and risk of respiratory depression.¹

If patient develops CNS depressant effects, consider dosage reduction or discontinuation.¹ If use with another CNS depressant is unavoidable, consider dosage reduction.¹ Reduction in dosage is recommended in patients taking strong CYP3A4 inhibitors.¹

Suicidal Thoughts and Behaviors

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes), incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged ≤24 years was greater than in placebo-treated patients.¹ There is considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.¹ There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with highest incidence in patients with major depressive disorder.¹ Zuranolone does not directly affect monoaminergic systems.¹ Consider changing therapeutic regimen, including discontinuing zuranolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.¹

Embyro-fetal Toxicity

Based on animal studies, may cause fetal harm when administered to a pregnant woman.¹

Advise pregnant women of potential risk to an infant exposed to zuranolone in utero.¹ Advise females of reproductive potential to use effective contraception during treatment and for one week after final dose.¹

Abuse Potential and Dependence

Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction.¹ Dose-dependent, abuse-related adverse reactions, including euphoric mood, feeling drunk, and somnolence, reported.¹

May produce physical dependence.¹ Adverse reactions reported upon discontinuation include insomnia, palpitations, decreased appetite, nightmare, hyperhidrosis, and paranoia that were mild-to-moderate in severity.¹ These adverse reactions indicate a potential for physical dependence with zuranolone.¹

Risk for developing physical dependence and subsequent withdrawal syndrome upon abrupt discontinuation for individuals who take higher than recommended dosage and/or use for a longer duration than recommended has not been evaluated.¹

Specific Populations

Pregnancy

Insufficient evidence in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.¹ Based on animal studies, may cause fetal harm.¹ Advise pregnant women of potential risk to fetus.¹

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including zuranolone, during pregnancy.¹ Healthcare providers are encouraged to register patients by calling National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at [Web].¹

Lactation

Available data indicate that zuranolone is present in low levels in human milk.¹ No data on effects on the breast-fed infant and limited data on effects on milk production.¹ Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for zuranolone and any potential adverse effects on breast-fed child from zuranolone or from underlying maternal condition.¹

Females and Males of Reproductive Potential

Based on animal studies, zuranolone may cause embryo-fetal harm when administered to a pregnant woman.¹ Advise females of reproductive potential to use effective contraception during treatment with zuranolone and for 1 week after the final dose.¹

Pediatric Use

Safety and effectiveness not established.¹

Geriatric Use

No experience in geriatric patients with postpartum depression.¹

Hepatic Impairment

Exposure increased in severe hepatic impairment (Child-Pugh class C); recommended dosage in severe hepatic impairment is lower than in normal hepatic function.¹ Recommended dosage in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment is same as in normal hepatic function.¹

Renal Impairment

Increased exposure in patients with moderate (eGFR 30 to 59 mL/minute per 1.73 m²) and severe (eGFR 15 to 29 mL/minute per 1.73 m²) renal impairment.¹ Recommended dosage in moderate and severe renal impairment is lower than in normal renal function.¹ Recommended dosage in patients with mild renal impairment (eGFR 60—89 mL/minute per 1.73 m²) is same as in normal renal function.¹ Not studied in renal impairment with eGFR of <15 mL/minute per 1.73 m² or dialysis.¹

Common Adverse Effects

Most common adverse effects (≥5% of patients): somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, urinary tract infection.¹

Drug Interactions

CYP3A4 substrate.¹ Not an inhibitor of CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, or CYP3A4.¹ Not an inducer of CYP1A2, CYP2B6, or CYP3A4 at the therapeutic dose range.¹

Not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, or OATP1B3.¹ Does not inhibit P-gp, BCRP, bile salt export pump (BSEP), OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT2, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1 or MATE2.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use with a CYP3A4 inducer decreases exposure of zuranolone, which may reduce efficacy of zuranolone.¹ Avoid concomitant use of zuranolone with CYP3A4 inducers.¹

Concomitant use with a strong CYP3A4 inhibitor increases exposure of zuranolone, which may increase risk of zuranolone-associated adverse reactions.¹ Reduce zuranolone dosage when used with a strong CYP3A4 inhibitor.¹

CNS Depressants

Due to additive pharmacological effects, the concomitant use of CNS depressant drugs, including alcohol, may increase impairment of psychomotor performance or CNS depressant effects.¹ If use with another CNS depressant is unavoidable, consider dosage reduction.¹ Caution should be used when zuranolone is administered in combination with other CNS drugs or alcohol.¹

Specific Drugs

Zuranolone Pharmacokinetics

Absorption

Bioavailability

C_max and AUC increase approximately dose proportionally with doses ranging from 30 to 60 mg (with moderate-fat meal [700 calories, 30% fat]).¹

Once-daily administration results in accumulation of approximately 1.5-fold systemic exposure.¹

Onset

Time to peak concentration (T_max): 5 to 6 hours.¹

Steady State: 3 to 5 days.¹

Effect of Food

Low-fat meal (400—500 calories, 25% fat): increases C_max by approximately 3.5-fold, AUC_last by approximately 1.8-fold.¹

High-fat meal (800 to 1,000 calories, 50% fat): increases C_max by approximately 4.3-fold and AUC_lastby approximately 2-fold.¹

T_max not affected by food.¹

Distribution

Extent

Present in low levels in human milk.¹

Plasma Protein Binding

>99.5%.¹

Elimination

Metabolism

Extensive metabolism, primarily by CYP3A4.¹

No active metabolites.¹

Elimination Route

45% recovered in urine as metabolites, negligible unchanged drug; 41% recovered in feces as metabolites, <2% as unchanged drug.¹

Half-life

Approximately 19.7 to 24.6 hours.¹

Special Populations

Black or African American patients have 14% higher mean apparent clearance compared to patients of other races.¹

Stability

Storage

Oral

Capsules

Store at 20-25ºC; excursions permitted between 15-30ºC.¹

Actions

• Neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator.¹

• Mechanism of action in treatment of postpartum depression not fully understood; thought to be related to positive allosteric modulation of GABA_A receptors.¹

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).¹

• Advise patients that zuranolone should be taken in the evening with fat-containing food.¹ Advise patients that if an evening dose is missed, the next dose should be taken the next day as scheduled.¹ Advise patients not to take extra capsules to make up for the missed dose.¹ Patients should then continue taking zuranolone once daily until the remainder of the 14-day treatment course is complete.¹

• Advise patients that zuranolone causes driving impairment.¹ Advise patients not to drive a motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness, such as operating machinery, until at least 12 hours after zuranolone administration for the duration of the 14-day treatment course.¹ Inform patients that they may not be able to assess their own driving competence or the degree of driving impairment caused by zuranolone.¹

• Advise patients that zuranolone can cause somnolence, dizziness, sedation, and confusion.¹ Advise patients to use caution if taking zuranolone in combination with alcohol, other CNS depressants, or medications that increase the concentration of zuranolone.¹

• Advise patients to look for the emergence of suicidal thoughts and behaviors and instruct them to report such symptoms to their clinician immediately.¹

• Advise patients that zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction and that zuranolone is associated with the potential for physical dependence.¹

• Advise pregnant women and females of reproductive potential of the potential risk to an infant exposed to zuranolone.¹ Advise patients to notify their clinician if they become pregnant or intend to become pregnant during treatment with zuranolone.¹ Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to zuranolone during pregnancy.¹ Advise females of reproductive potential to use effective contraception during treatment with zuranolone and for one week after the final dose.¹

• Advise women to inform their clinician if they are or plan to breast-feed.¹ Advise patients that zuranolone passes into breast milk and it is not known whether there is harm to the breast-fed infant.¹

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.¹

• Inform patients of other important precautionary information.¹

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.¹

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