Zuranolone

Due to additive pharmacological effects, the concomitant use of CNS depressant drugs, including alcohol, may increase impairment of psychomotor performance or CNS depressant effects.

If use with another CNS depressant is unavoidable, consider dosage reduction. Caution should be used when zuranolone is administered in combination with other CNS drugs or alcohol.

Concomitant use of zuranolone with a CYP3A4 inducer decreases the exposure of zuranolone, which may reduce the efficacy of zuranolone.

Avoid concomitant use of zuranolone with CYP3A4 inducers.

Concomitant use of zuranolone with a strong CYP3A4 inhibitor increases the exposure of zuranolone which 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.

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

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

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.

Data

Animal Data

Oral administration of zuranolone (0, 2.5, 7.5, or 22.5 mg/kg/day) to pregnant rats during organogenesis resulted in increased incidences of fetal malformations, reductions in embryofetal survival, and reduced fetal body weights as well as maternal mortality and sedation at the highest dose. The no effect dose (7.5 mg/kg/day) for adverse effects on embryofetal development was associated with maternal exposures (AUC) approximately 7 times that in humans at the MRHD of 50 mg.

Potential adverse effects of zuranolone on embryofetal development in pregnant rabbits were not adequately assessed.

Oral administration of zuranolone (0, 1, 4, or 10 mg/kg/day) 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, which also produced maternal mortality and adverse clinical signs. The no-effect dose (1 mg/kg/day) for adverse effects on pre- and postnatal development in rats was associated with maternal exposures (AUC) approximately 2 times that in the humans at the MRHD.

Oral administration of a single dose of zuranolone (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. The no-effect dose (2.5 mg/kg) was associated with plasma exposures (AUC) comparable to that in humans at the MRHD. Brain development on PND 7 in rats corresponds to a period of brain development that begins during the third trimester of pregnancy in humans and continue up to a few years after birth.

Risk Summary

Available data from a clinical lactation study in 14 women indicate that zuranolone is present in low levels in human milk (see Data). There are no data on the effects of zuranolone on a breastfed infant 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.

Data

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. At steady state (Day 5), the calculated maximum relative infant dose for zuranolone was <1%. The daily infant dose was low (approximately 0.0013 mg/kg/day), reflecting a mean relative infant dose of 0.357% compared to the maternal dose. Concentrations of zuranolone in breastmilk were below the level of quantification limit (BQL) by 4-6 days after the last dose.

Impairment of Fertility

Oral administration of zuranolone (0, 3, 10, or 30 mg/kg/day) to male rats prior to and during mating with untreated females resulted in increased post-implantation loss and a corresponding decrease in the number of viable embryos at the high dose, which was also paternally toxic. There were no adverse effects on fertility or sperm parameters. Adverse effects on reproduction were not observed when males were remated after a 6-week treatment-free period. The no effect dose (10 mg/kg/day) for male reproductive toxicity was associated with a plasma zuranolone exposure (AUC) of approximately 4 times the human exposure at the MRHD. Oral administration of zuranolone (0, 1, 3, or 10 mg/kg/day) to female rats prior to and throughout mating and continuing through early gestation resulted in disruption of estrous cyclicity at the high dose, but there were no adverse effects on fertility or early embryonic development. The no-effect dose (3 mg/kg/day) for female reproductive toxicity was associated with exposures approximately 4 times that in humans at the MRHD.

Carcinogenesis

Oral administration of zuranolone in a 26-week carcinogenicity study in transgenic mice (0, 10, 30, or 100 mg/kg/day), and in a 104-week carcinogenicty study in rats (0, 2, 6, or 20 mg/kg/day in males and 0, 0.2, 0.6, or 1.5 mg/kg/day in females) was not associated with increases in tumors in either species. Plasma exposures (AUC) in rats at the highest dose tested were approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 50 mg.

Mutagenesis

Zuranolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosome aberration assay in Chinese hamster ovary cells, and an in vivo bone marrow micronucleus assay in rats.

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.

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of zuranolone for the treatment of postpartum depression (PPD) was evaluated in two placebo-controlled clinical studies in 347 women with PPD treated with 50 mg of zuranolone (Study 1), or with another zuranolone capsule formulation approximately equivalent to 40 mg of zuranolone (Study 2) once daily for 14 days. The studies included adult patients age 18 to 44 years diagnosed with PPD.

Across PPD clinical studies at all doses studied (Studies 1 and 2), serious adverse reactions included confusional state (1%).

In Study 1, the incidence of adverse reactions that led to discontinuation in patients treated with 50 mg of zuranolone and placebo was 2% and 1%, respectively. The most common adverse reaction leading to treatment discontinuation in zuranolone-treated patients was somnolence.

Dosage reduction due to an adverse reaction occurred in 14% of zuranolone-treated patients. The most common adverse reactions leading to dosage reduction in zuranolone-treated patients were somnolence (10%) and dizziness (6%).

The most common adverse reactions (≥5% and greater than placebo) in zuranolone-treated patients were somnolence, dizziness, diarrhea, fatigue, and urinary tract infection.

Table 1 summarizes the adverse reactions that occurred in ≥2% of patients with PPD treated with 50 mg of zuranolone and at a higher incidence than in patients who received placebo in Study 1.

Table 1. Adverse Reactions that Occurred in ≥2% of Patients with PPD Treated with 50 mg of Zuranolone and Greater than in Patients Treated with Placebo (Study 1):

¹ Somnolence includes sedation and hypersomnia
² Dizziness includes vertigo
³ Fatigue includes asthenia
⁴ Abdominal pain includes upper abdominal pain

In Study 2, the incidence of adverse reactions that led to discontinuation in patients who received another zuranolone capsule formulation (approximately equivalent to 40 mg of zuranolone) and placebo was 1% and 0%, respectively. The adverse reaction that led to treatment discontinuation was somnolence.

Dosage reduction due to an adverse reaction occurred in 4% of zuranolone-treated patients. The adverse reactions that led to dosage reduction were somnolence and confusional state.

The most common (≥5% and greater than placebo) adverse reactions in zuranolone-treated patients were somnolence, nasopharyngitis, dizziness, fatigue, and diarrhea.

Table 2 summarizes the adverse reactions that occurred in ≥2% of zuranolone-treated patients with PPD and at a higher incidence than in placebo-treated patients in Study 2.

Table 2. Adverse Reactions that Occurred in ≥2% of Patients with PPD Treated with Another Zuranolone Capsule Formulation^* and Greater than in Patients Treated with Placebo (Study 2):

¹ Somnolence includes sedation
² Nasopharyngitis includes upper respiratory tract infection
³ Fatigue includes lethargy
^* This capsule formulation of zuranolone is approximately equivalent to 40 mg of zuranolone.