zuranolone (Rx)

Brand and Other Names:Zurzuvae

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 20mg
  • 25mg
  • 30mg

Postpartum Depression

Indicated for treatment of postpartum depression (PPD)

50 mg PO qPM x 14 days; administer with fat-containing food

Consider reducing dose to 40 mg if CNS depressant effects occur within the 14-day treatment period

May use alone or as an adjunct to oral antidepressant therapy

Use beyond 14 days in a single treatment course has not been established

Dosage Modifications

Renal impairment

  • Mild (eGFR 60-89 mL/min/1.73 m2): No dosage modification recommended
  • Moderate-to-severe (eGRF <60 mL/min/1.73 m2): Reduce dose to 30 mg qPM

Hepatic impairment

  • Mild-to-moderate (Child-Pugh A or B): No dosage modification recommended
  • Severe (Child-Pugh C): Reduce dose to 30 mg qPM

Coadministration with CYP3A4 inducers

  • Avoid coadministration

Coadministration with CYP3A4 inhibitors

  • Strong CYP3A4 inhibitors: Reduce dose to 30 mg qPM
  • Moderate CYP3A4 inhibitors: No dosage modification recommended

Dosing Considerations

May cause embryo-fetal harm when administered to pregnant females; use effective contraception during treatment and for 1 week after final dose

Safety and efficacy not established

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Interactions

Interaction Checker

and zuranolone

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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                    Adverse Effects

                    >10%

                    Somnolence (36%)

                    Dizziness (13%)

                    1-10%

                    Diarrhea (6%)

                    Fatigue (5%)

                    Urinary tract infection (5%)

                    Memory impairment (3%)

                    Abdominal pain (3%)

                    Tremor (2%)

                    Hypoesthesia (2%)

                    Muscle twitching (2%)

                    Myalgia (2%)

                    Anxiety (2%)

                    Rash (2%)

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                    Warnings

                    Black Box Warnings

                    Causes driving impairment due to CNS depressant effects

                    Advise patients not to drive or engage in other potentially hazardous activities until at least 12 hr after 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

                    Contraindications

                    None

                    Cautions

                    Causes driving impairment due to CNS depressant effects

                    May cause fetal harm when administered to pregnant females

                    CNS depressant effects

                    • CNS depressant effects reported (eg, somnolence, confusion)
                    • Patients may be at higher risk of falls
                    • Other CNS depressants (eg, 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
                    • Reduce risk of CNS depressant effects and/or mitigate CNS depression
                      • If CNS depressant effects develop, consider dosage reduction or discontinuation
                      • If use with another CNS depressant is unavoidable, consider dosage reduction
                      • Reduce dosage in patients taking strong CYP3A4 inhibitors

                    Suicidal thoughts and behavior

                    • In pooled analyses of placebo-controlled trials of long-term administration of antidepressant drugs (SSRIs and other antidepressants), the incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged ≤24 yr was greater than in placebo-treated patients
                    • Zuranolone does not directly affect monoaminergic systems; because of this and the comparatively low number of exposures to zuranolone, risk of developing suicidal thoughts and behaviors is unknown
                    • Consider changing the therapeutic regimen, including discontinuing zuranolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors

                    Drug interaction overview

                    • CNS depressants
                      • Avoid or modify dose
                      • Coadministration with CNS depressants (eg, alcohol, opioids, benzodiazepines) may have additive pharmacological effects and increase impairment of psychomotor performance or CNS depressant effects
                      • If unavoidable, consider reducing zuranolone dose
                    • CYP3A4 inducers
                      • Avoid
                      • CYP3A4 inducers decrease zuranolone systemic exposure, which may reduce efficacy
                    • Strong CYP3A4 inhibitors
                      • Modify (reduce) zuranolone dose
                      • Strong CYP3A4 inhibitors increase zuranolone systemic exposure, which may increase adverse effects
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                    Pregnancy & Lactation

                    Pregnancy

                    Based on findings from animal studies, zuranolone may cause fetal harm

                    Advise pregnant women of potential risk to a fetus

                    Pregnancy exposure registry

                    • Registry monitors pregnancy outcomes in women exposed to antidepressants during pregnancy
                    • Clinicians are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online

                    Contraception

                    • Advise female patients of reproductive potential to use effective contraception during treatment and for 1 week after final dose

                    Animal studies

                    • Administration to pregnant rats during organogenesis resulted in increased incidences of fetal malformations, reductions in embryofetal survival, and reduced fetal body weights
                    • Administration to rats throughout pregnancy and into lactation resulted in increased perinatal mortality and persistent bodyweight reductions in the offspring at the mid and high doses
                    • Oral administration of a single dose (0, 2.5, or 7.5 mg/kg) to rats on postnatal day 7 resulted in increased apoptotic neurodegeneration in the brain at the highest dose tested
                    • Increased maternal mortality and sedation was also observed at the highest dose

                    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 effects of zuranolone on breastfed infants and limited data regarding effects on milk production

                    Pregnancy Categories

                    A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                    B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                    C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                    D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                    X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                    NA: Information not available.

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                    Pharmacology

                    Mechanism of Action

                    Oral neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM)

                    The GABA system is the major inhibitory signaling pathway of the brain and CNS and contributes to regulating brain function (eg, mood, arousal, behavior, cognition)

                    Mechanism of action for the treatment of PPD is not fully understood; believed to be related to positive allosteric modulation of both synaptic and extrasynaptic GABA-A receptors

                    Absorption

                    Peak plasma time: 5-6 hr

                    Effect of food

                    Administer with fat-containing food

                    Peak plasma concentration (Cmax) increased by ~3.5-fold and AUC increased by ~1.8-fold with a low-fat meal (400-500 calories, 25% fat) compared to fasted conditions

                    Cmax increased by ~4.3-fold and AUC increased by ~2-fold with a high-fat meal (800-1,000 calories, 50% fat) compared to fasted conditions

                    Distribution

                    Protein bound: >99.5%

                    Vd: >500 L

                    Mean blood-to-plasma concentration ratio: 0.54-9.58

                    Metabolism

                    Undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved

                    Elimination

                    Half-life: 19.7-24.6 hr

                    Clearance: 33 L/hr

                    Excretion: Urine 45% (negligible unchanged drug); feces 41% (<2% unchanged)

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                    Administration

                    Oral Administration

                    Administer with fat-containing food (eg, 400-1,000 calories, 25-50% fat)

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

                    Missed dose

                    • If dose missed, take next dose at the regular time the following evening
                    • Do not double dose to make up for missed dose
                    • Continue taking once daily until the remaining 14-day treatment course is completed

                    Storage

                    Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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                    Images

                    No images available for this drug.
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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

                    FormularyPatient Discounts

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                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
                    PA Prior Authorization
                    Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                    QL Quantity Limits
                    Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                    ST Step Therapy
                    Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
                    OR Other Restrictions
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.