zuranolone (Rx)

>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%)

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

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.

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 (C_max) 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

C_max 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)

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)