Zuranolone (Monograph)

Brand name: Zurzuvae
Drug class: Antidepressants, Miscellaneous

Introduction

Zuranolone, a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator, is an antidepressant.

Uses for Zuranolone

Zuranolone has the following uses:

Zuranolone is indicated for the treatment of postpartum depression (PPD) in adults.

Zuranolone Dosage and Administration

General

Zuranolone is available in the following dosage form(s) and strength(s):

Capsules: 20 mg, 25 mg, and 30 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

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

Recommended dosage is 50 mg orally once daily in the evening for 14 days. Administer with fat-containing food.

If CNS depressant effects occur, dosage may be reduced to 40 mg once daily.

In patients with severe hepatic impairment (Child-Pugh C), recommended dosage is 30 mg orally once daily in the evening for 14 days.

In patients with moderate or severe renal impairment (eGFR <60 mL/min/1.73 m²), recommended dosage is 30 mg orally once daily in the evening for 14 days.

The safety and effectiveness of zuranolone use beyond 14 days in a single treatment course have not been established.

Dosage modifications are necessary for concomitant use with CYP3A4 inducers or CYP3A4 inhibitors. See Full Prescribing Information.

Related/similar drugs

sertraline, fluoxetine, citalopram, Zoloft, Prozac, Celexa

Cautions for Zuranolone

Contraindications

None.

Warnings/Precautions

Impaired Ability to Drive or Engage in Other Potentially Hazardous Activities

Zuranolone causes driving impairment due to central nervous system (CNS) depressant effects. In two driving simulation studies, the driving ability of healthy adults was impaired in a dose-dependent manner following repeat nighttime administration of 30 mg of zuranolone (0.6 times the recommended dose) for five days as well as 50 mg of zuranolone (recommended dose) for seven days.

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. Inform patients that they may not be able to assess their own driving competence or the degree of driving impairment caused by zuranolone.

CNS Depressant Effects

Zuranolone can cause CNS depressant effects such as somnolence and confusion.

In Study 1, 36% of patients who received 50 mg of zuranolone and 6% of patients who received placebo daily developed somnolence. In Study 2, 19% of patients who received another zuranolone capsule formulation (approximately equivalent to 40 mg of zuranolone) and 11% of patients who received placebo daily developed somnolence. In each clinical study, some zuranolone-treated patients developed confusional state. One of these cases was severe, and was also associated with somnolence, dizziness, and gait disturbance. A higher percentage of zuranolone-treated patients, compared to placebo-treated patients, experienced somnolence, dizziness, or confusion that required dosage reduction, interruption, or discontinuation.

Because zuranolone can cause CNS depressant effects, patients may be at higher risk of falls.

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 the risk of respiratory depression in zuranolone-treated patients.

If patients develop CNS depressant effects, consider dosage reduction or discontinuation of zuranolone. If use with another CNS depressant is unavoidable, consider dosage reduction. Reduce the zuranolone dosage in patients taking strong CYP3A4 inhibitors.

Suicidal Thoughts and Behaviors

In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was 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. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Zuranolone is not approved in pediatric patients.

Zuranolone does not directly affect monoaminergic systems. Consider changing the therapeutic regimen, including discontinuing zuranolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.

Embryo-fetal Toxicity

Based on findings from animal studies, zuranolone may cause fetal harm when administered to a pregnant woman. In rat studies following exposure during gestation or throughout gestation and lactation, adverse effects on development (fetal malformations, embryofetal and offspring mortality, growth deficits) were observed. In addition, neuronal death was observed in rats exposed to zuranolone during a period of brain development that in humans begins during the third trimester of pregnancy and continues during the first few years after birth. Advise a pregnant woman of the potential risk to an infant exposed to zuranolone in utero. Advise females of reproductive potential to use effective contraception during treatment with zuranolone and for one week after the final dose.

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including zuranolone, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/.

Risk Summary: Based on findings from animal studies, zuranolone may cause fetal harm. Advise pregnant women of the potential risk to a fetus. Available data on zuranolone use in pregnant women from the clinical development program are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animals, oral administration of zuranolone to pregnant rats during organogenesis resulted in developmental toxicity, including embryofetal death and fetal malformations, with a no adverse effect level (NOAEL) associated with maternal plasma exposures 7 times greater than in humans at the maximum recommended human dose (MRHD) of 50 mg. Oral administration of zuranolone to rats during pregnancy and lactation resulted in developmental toxicity in the offspring, including, perinatal mortality, at maternal exposures similar to that in humans at the MRHD. Developmental toxicity was observed at doses that were also maternally toxic. Neuronal death was observed in rats exposed to zuranolone during a period of brain development that begins during the third trimester of pregnancy in humans and continues up to a few years after birth.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

Available data from a clinical lactation study in 14 women indicate that zuranolone is present in low levels in human milk. There are no data on the effects of zuranolone on breastfed infants and limited data on the effects on milk production.

The developmental and health benefits of breastfeeding 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.

Females and Males of Reproductive Potential

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

Pediatric Use

The safety and effectiveness of zuranolone in pediatric patients have not been established.

Geriatric Use

Postpartum depression is a condition associated with pregnancy; there is no geriatric experience with zuranolone.

Hepatic Impairment

Exposure to zuranolone was increased in patients with severe hepatic impairment. The recommended zuranolone dosage in patients with severe hepatic impairment (Child-Pugh C) is lower than in patients with normal hepatic function.

The recommended zuranolone dosage in patients with mild or moderate hepatic impairment (Child-Pugh A or Child-Pugh B) is the same as those with normal hepatic function.

Renal Impairment

Exposure to zuranolone was increased in patients with moderate (eGFR 30 to 59 mL/min/1.73 m²) and severe (eGFR 15 to 29 mL/min/1.73 m²) renal impairment.

The recommended zuranolone dosage in patients with moderate and severe renal impairment is lower than those with normal renal function. The recommended dosage in patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m²) is the same as those in patients with normal renal function. Zuranolone has not been studied in patients with eGFR of < 15 mL/min/1.73 m² or patients requiring dialysis.

Common Adverse Effects

Most common adverse reactions (incidence 5% and greater than placebo) were somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

CNS Depressants:Concomitant use may increase impairment of psychomotor performance or CNS depressant effects. If use with another CNS depressant is unavoidable, consider dosage reduction.

Strong CYP3A4 Inhibitors:Concomitant use may increase the risk of zuranolone-associated adverse reactions. Reduce the zuranolone dosage to 30 mg orally once daily in the evening for 14 days when used concomitantly with a strong CYP3A4 inhibitor.

CYP3A4 Inducers: Concomitant use may decrease the efficacy of zuranolone. Avoid concomitant use.

Actions

Mechanism of Action

The mechanism of action of zuranolone in the treatment of postpartum depression is not fully understood, but is thought to be related to its positive allosteric modulation of GABA_A receptors.

Advice to Patients

Patient Counseling Information

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

• Inform patients that zuranolone causes driving impairment. Advise patients to take zuranolone in the evening. 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. Warn patients that they may not be able to assess their own ability to drive or the degree of impairment caused by zuranolone.

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

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

• Inform patients to take zuranolone with fat-containing food.

• Instruct patients that if a daily dose is missed, the missed dose should be taken the next day as scheduled. Patients should be advised not to take extra capsules to make up for the missed dose.

• 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.

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with zuranolone. Advise female patients of reproductive potential to use effective contraception during treatment with zuranolone and for one week after the final dose.

• Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to zuranolone during pregnancy.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

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

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