Postpartum Depression 
Zuranolone is used for the treatment of postpartum depression in adults.1
Clinical Experience
The efficacy of zuranolone for the treatment of postpartum depression was demonstrated in 2 randomized, placebo-controlled, double-blind, multicenter studies in women with postpartum depression who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode with onset of symptoms in the third trimester or within 4 weeks of delivery.1,2,3 In these studies, concomitant use of existing oral antidepressants was allowed for patients taking a stable dose of oral antidepressant for at least 30 days before baseline.1 These studies included patients with 17-item Hamilton Depression Rating Scale (HAMD-17) scores ≥26 at baseline.1 The primary endpoint of both studies was the change from baseline in depressive symptoms as measured by the HAMD-17 total score at Day 15.1,2,3 Baseline demographics and disease characteristics of enrolled patients were similar between the zuranolone and placebo groups in both studies.1
In Study 1 (NCT04442503), 200 patients were randomized 1:1 to receive zuranolone 50 mg orally or placebo once daily in the evening with fat-containing food for 14 days, with the option to reduce the dosage based on tolerability to 40 mg once daily of zuranolone or placebo.1,2 Patients were followed for a minimum of 4 weeks after the 14-day treatment course.1 Of the initial 200 enrolled patients, 170 completed the 45-day study.2 The mean age was 30 years (range: 19 to 44 years) and patients were primarily (70%) white.1 Baseline use of stable antidepressants was reported in 15% of patients.1 Patients reported significantly greater improvement on the primary endpoint compared to patients in the placebo group, with a mean change in HAMD-17 score from baseline of -15.6 in the zuranolone group and -11.6 in the placebo group, at day 15.1 Secondary endpoints included a change from baseline in HAMD-17 score at days 3, 28, and 45 and a change from baseline in Clinical Global Impressions severity score at day 15; significant improvement was also reported at study days 3, 28, and 45.2 Subgroup analyses of the primary endpoint did not suggest differences in response to zuranolone 50 mg based on age, race, or body mass index.1
In Study 2 (NCT02978326), patients were randomized 1:1 to receive zuranolone 30 mg in another capsule formulation (approximately equivalent to 40 mg of zuranolone) or placebo once daily in the evening with food for 14 days, with the option to reduce the dosage to 20 mg based on tolerability.1,3 Patients were followed for a minimum of 4 weeks after the 14-day treatment course in both studies.1 A total of 153 patients were randomized; outcomes were assessed for 150 patients.3 The mean age was 28 years (range: 18 to 44 years); 56% of patients were white and 41% were Black or African American.1 Baseline use of stable oral antidepressants was reported in 19% of patients.1 Patients experienced statistically significantly greater improvement on the primary endpoint compared to patients in the placebo group, with a mean change in HAMD-17 score from baseline of -17.8 in the zuranolone group and -13.6 in the placebo group.1
Clinical Perspective
The American College of Obstetricians and Gynecologists (ACOG) recommends psychotherapy be considered first-line treatment for patients with mild-to-moderate perinatal depression.4 When drug therapy is indicated, ACOG recommends that selective serotonin-reuptake inhibitors (SSRIs) be used first-line, with serotonin- and norepinephrine-reuptake inhibitors (SNRIs) recommended as an 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 of either zuranolone or brexanolone in the postpartum period for moderate-to-severe perinatal depression with onset in the 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 Brexanolone treatment requires in-hospital IV infusion and may not be readily accessible; zuranolone provides another option for severe postpartum depression that is orally administered.5
General
Patient Monitoring
- Monitor patients for CNS depression while taking zuranolone; dosage adjustments may be necessary.1
Administration
Zuranolone is administered orally as capsules.1
Zuranolone should be taken with fat-containing food (e.g., 400—1000 calories, 25% to 50% fat).1
Zuranolone can be used alone or as an adjust to oral antidepressant therapy.1
The safety and efficacy of zuranolone use beyond 14 days in a single treatment course have not been established.1
If a zuranolone evening dose is missed, the patient should be advised to take the next dose at the regular time the following evening.1 The patient should be advised to not take extra capsules on the same day to make up for the missed dose.1 The patient should then continue taking zuranolone once daily until the remainder of the 14-day treatment course is complete.1
Store zuranolone capsules at 20-25°C; excursions permitted between 15-30°C.1
Dosage
Adult Dosage
Postpartum Depression
The recommended dosage of zuranolone is 50 mg orally once daily in the evening with fat-containing food for 14 days.1
Dosage Modification for Toxicity
If patients experience CNS depressant effects within the 14-day treatment period, consider reducing the dosage of zuranolone to 40 mg orally once daily in the evening.1
Dosage Modification for Drug Interactions
When used concomitantly with a strong cytochrome P-450 (CYP) 3A4 inhibitor, reduce the zuranolone dosage to 30 mg orally once daily in the evening for 14 days.1
No dosage modification is recommended when zuranolone is used concomitantly with a moderate CYP3A4 inhibitor.1
Avoid concomitant use of zuranolone with CYP3A4 inducers.1
Special Populations
Hepatic Impairment
The recommended dosage of zuranolone in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment is the same as those with normal hepatic function.1
The recommended dosage of zuranolone in patients with severe hepatic impairment (Child-Pugh class C) is 30 mg orally once daily in the evening for 14 days.1
Renal Impairment
The recommended dosage of zuranolone in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60—89 mL/minute per 1.73 m2) is the same as those with normal renal function.1
The recommended dosage of zuranolone in patients with moderate or severe renal impairment (eGFR <60 mL/minute per 1.73 m2) is 30 mg orally once daily in the evening for 14 days.1
Geriatric Patients
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Contraindications
Warnings/Precautions
Warnings
Impaired Ability to Drive or Engage in Potentially Hazardous Activities
A boxed warning regarding the risk of CNS depressant effects and resulting driving impairment is included in the prescribing information for zuranolone.1
Zuranolone causes driving impairment due to CNS depressant effects.1 In 2 randomized, controlled, 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 dosage) for 5 days as well as 50 mg of zuranolone (the recommended dosage) for 7 days.1
These studies evaluated the effects of nighttime zuranolone administration on next-morning driving performance (9 hours after dosing) using a computer-based driving simulation.1 In the first study, 50 mg of zuranolone was administered for 6 consecutive nights and on the seventh night, a single dose of 50 mg or 100 mg was administered.1 The primary driving performance outcome measure was the change in Standard Deviation of Lateral Position (a measure of driving impairment) in the zuranolone group compared to the placebo group on Days 2 and 8 (after single dose and repeat doses, respectively).1 A single 50 mg dose of zuranolone caused significant impairment in next-morning driving performance compared to placebo.1 Significant effects were also observed on Day 8 following daily administration of zuranolone 50 mg.1 Administration of 100 mg of zuranolone (twice the maximum recommended dose) on the final night increased impairment in driving ability.1
In the second study, 30 mg of zuranolone was administered for 4 consecutive nights and on the fifth night, a single dose of 30 mg or 60 mg of zuranolone was administered.1 The primary driving performance outcome measure was the change in Standard Deviation of Lateral Position in the zuranolone group compared to the placebo group on Days 2 and 6 (after a single dose and repeat doses, respectively).1 A single 30 mg dose of zuranolone caused significant impairment in next-morning driving performance compared to placebo.1 The mean effect on driving performance was not significantly different following 30 mg of zuranolone compared to placebo on Day 6; however, driving ability was impaired in some participants taking zuranolone.1 Administration of 60 mg of zuranolone (1.2 times the maximum recommended dose) on the final night caused significant impairment in next-morning driving performance compared to placebo.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
Other Warnings/Precautions
CNS Depressant Effects
Zuranolone can cause CNS depressant effects such as somnolence and confusion.1 Because zuranolone can cause CNS depressant effects, patients may be at 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 cause CNS depressant effects such as somnolence, cognitive impairment, and risk of respiratory depression in zuranolone-treated patients.1
In Study 1, 35% of patients who received 50 mg of zuranolone and 6% of patients who received placebo daily developed somnolence.1 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.1 In each clinical study, some zuranolone-treated patients developed confusional state.1 One of these cases was severe and was also associated with somnolence, dizziness, and gait disturbance.1 A higher percentage of zuranolone-treated patients, compared to placebo-treated patients, experienced somnolence, dizziness, or confusion that required dosage reduction, interruption, or discontinuation.1
The manufacturer provides recommendations to reduce the risk of CNS depressant effects and/or mitigate CNS depressant effects that occurs with zuranolone treatment.1 If the patient develops CNS depressant effects, consider dosage reduction or discontinuation of zuranolone.1 If use with another CNS depressant is unavoidable, consider dosage reduction.1 A reduction in the dosage of zuranolone is recommended in patients taking strong cytochrome P-450 3A4 inhibitors.1
Suicidal Thoughts and Behaviors
In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (selective serotonin-reuptake inhibitors 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 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 the highest incidence in patients with major depressive disorder.1 Consider changing the therapeutic regimen, including discontinuing zuranolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.1
Embryo-fetal Toxicity
Based on findings from animal studies, zuranolone may cause fetal harm when administered to a pregnant woman.1 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.1 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.1
Advise a pregnant woman of the potential risk to an infant exposed to zuranolone in utero.1 Advise females of reproductive potential to use effective contraception during treatment with zuranolone and for one week after the final dose.1
Abuse Potential and Dependence
Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction.1
In a human abuse potential study, single oral doses of 30 mg, 60 mg, and 90 mg of zuranolone (0.6 times, 1.2 times, and 1.8 times the recommended daily dose, respectively) were compared to single oral doses of alprazolam (1.5 mg and 3 mg) and placebo in healthy, nondependent individuals with a history of recreational CNS depressant use.1 The study demonstrated that zuranolone has dose-dependent abuse potential comparable to alprazolam and greater abuse potential than placebo on positive subjective measures.1 In the human abuse potential study, dose-dependent, abuse-related adverse reactions, including euphoric mood, feeling drunk, and somnolence, were reported with zuranolone use.1
Zuranolone may produce physical dependence.1 Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (with 50—100 mg given on the seventh day) included insomnia, palpitations, decreased appetite, nightmare, hyperhidrosis, and paranoia.1 These adverse reactions indicate a potential for physical dependence with zuranolone and were mild-to-moderate in severity.1
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 has not been evaluated in clinical studies.1 However, convulsions were observed in a dog upon abrupt zuranolone discontinuation after dogs were administered zuranolone for 14 days at doses that produced exposures higher than the maximum recommended human dose.1
Specific Populations
Pregnancy
There is insufficient evidence with zuranolone in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 Based on findings from animal studies, zuranolone may cause fetal harm.1 Advise pregnant women of the potential risk to a fetus.1
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.1 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.1 Development toxicity was observed at doses that were also maternally toxic.1 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.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 the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at [Web].1
Lactation
Available data from a clinical lactation study in 14 lactating women indicate that zuranolone is present in low levels in human milk.1 There are no data on the effects of zuranolone on the breast-fed infant and limited data on the effects on milk production.1 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 breast-fed child from zuranolone or from the underlying maternal condition.1
A steady-state milk study was conducted in 14 healthy lactating women treated with daily oral administration of 30 mg of zuranolone for 5 days.1 At steady state (Day 5), the calculated maximum relative infant dose for zuranolone was <1%.1 The daily infant dose was low (approximately 0.0013 mg/kg per day), reflecting a mean relative infant dose of 0.357% compared to the maternal dose.1 Concentrations of zuranolone in breast milk were below the level of quantification limit by 4—6 days after the last dose.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 one week after the final dose.1
Pediatric Use
Safety and effectiveness of zuranolone in pediatric patients have not been established.1
Geriatric Use
There is no experience with zuranolone in geriatric patients with postpartum depression.1
Hepatic Impairment
Exposure to zuranolone is increased in patients with severe hepatic impairment (Child-Pugh class C).1 The recommended zuranolone dosage in patients with severe hepatic impairment is lower than in patients with normal hepatic function.1 The recommended zuranolone dosage in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment is the same as in those with normal hepatic function.1
Renal Impairment
Exposure to zuranolone is increased in patients with moderate (estimated glomerular filtration rate [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 The recommended zuranolone dosage in patients with moderate and severe renal impairment is lower than in those with normal renal function.1 The recommended dosage of zuranolone in patients with mild renal impairment (eGFR 60—89 mL/minute per 1.73 m2) is the same as those in patients with normal renal function.1 Zuranolone has not been studied in patients with eGFR of <15 mL/minute per 1.73 m2 or patients requiring dialysis.1
Common Adverse Effects
The most common adverse effects of zuranolone (≥5% of patients) reported in clinical studies include somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.1
Zuranolone is a substrate of cytochrome P-450 (CYP) 3A4.1
Zuranolone is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, or CYP3A4.1 Zuranolone is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at the therapeutic dosage range.1
Zuranolone is not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, or OATP1B3.1 Zuranolone 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 of zuranolone with a CYP3A4 inducer decreases the exposure of zuranolone, which may reduce the efficacy of zuranolone.1 When zuranolone was co-administered with rifampin (a strong CYP3A4 inducer), the Cmax and AUC decreased by 69% and 85%, respectively.6 While not evaluated, a moderate CYP3A4 inducer is expected to decrease the AUC of zuranolone by approximately 50%.6 Avoid concomitant use of zuranolone with CYP3A4 inducers.1
Concomitant use of zuranolone with a strong CYP3A4 inhibitor increases the exposure of zuranolone, which may increase the risk of zuranolone-associated adverse reactions.1 When zuranolone was co-administered with itraconazole (a strong CYP3A4 inhibitor), the Cmax and AUCinfof zuranolone were increased 25% and 63%, respectively.6 Reduce the zuranolone dosage when used with a strong CYP3A4 inhibitor.1
Central Nervous System (CNS) Depressant Drugs
Zuranolone does not affect the pharmacokinetics of alprazolam or ethanol.1 Increased impairment of psychomotor performance was observed when zuranolone was coadministered with alprazolam or ethanol.1
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
Description
Zuranolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator.1 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 GABAA receptors.1
Zuranolone exposure (maximum serum concentration [Cmax] and AUC) increases approximately dose proportionally with doses ranging from 30 mg to 60 mg with a moderate-fat meal (700 calories, 30% fat).1 Once-daily administration of zuranolone results in accumulation of approximately 1.5-fold in systemic exposures, and steady state is achieved in 3 to 5 days.1 Following oral administration, peak zuranolone concentrations (Tmax) occur at 5 to 6 hours.1 The absolute bioavailability of zuranolone has not been evaluated.1 Following oral administration of zuranolone with a low-fat meal (400—500 calories, 25% fat), the Cmax increases by approximately 3.5-fold and the AUClast increases by approximately 1.8-fold compared to fasting conditions.1 Following oral administration of zuranolone with a high-fat meal (800 to 1,000 calories, 50% fat), Cmax increases by approximately 4.3-fold and the AUClast increases by approximately 2-fold compared to fasting conditions.1 The Tmax is not affected by food.1 Plasma protein binding of zuranolone is >99.5%.1 The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours.1 Zuranolone undergoes extensive metabolism, with cytochrome P-450 3A4 as a primary enzyme involved.1 There are no circulating metabolites greater than 10% of total drug-related materials, and none is considered to contribute to the therapeutic effects of zuranolone.1 Following oral administration of zuranolone, 45% of the dose is recovered in the urine as metabolites with negligible unchanged drug and 41% of the dose is recovered in the feces as metabolites with less than 2% as unchanged drug.1 Black or African American patients have a 14% higher mean apparent clearance compared to patients of other races.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.
Only references cited for selected revisions after 1984 are available electronically.
1. Sage Therapeutics and Biogen Inc. Zurzuvae® (zuranolone) capsules prescribing information. Cambridge, MA; 2023 Nov.
2. Deligiannidis KM, Meltzer-Brody S, Maximos B et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023; 180:668-675.
3. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H et al. Effect of zuranolone vs placebo in postpartum depression: a randomized clinical trial. JAMA Psychiatry . 2021; 78(9):951-959.
4. Committee on Clinical Practice Guidelines-Obstetrics. Treatment and management of mental health conditions during pregnancy and postpartum. Clinical Practice Guidelines 5. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2023; 141(6):1262-1288.
5. American College of Obstetricians and Gynecologists. Zuranolone for the treatment of postpartum depression: practice advisory. August 2023. From American College of Obstetricians and Gynecologists website. Accessed 2024 July 11.
6. US Food and Drug Administration. Center for DRug Evaluation and Research. Application number 217369Orig2s000: Integrated review. Accessed 2024 July 11. [Web]