Zuranolone is the first oral medication indicated to treat postpartum depression (PPD) in adults and is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator. Efficacy was demonstrated in 2 randomized, double-blind, placebo-controlled, multicenter studies. The trial participants were women with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-5 criteria for Study 1 and DSM-IV for Study 2) and whose symptoms began in the third trimester or within 4 weeks of delivery. These studies included patients with a Hamilton Depression Rating Scale (HAM-D)-17 score of 26 or more at baseline. In Study 1, patients received 50 mg of zuranolone or placebo once daily in the evening for 14 days. In Study 2, patients received another zuranolone product (approximately 40 mg of zuranolone) or placebo, also for 14 days. Patients in both studies were allowed to continue existing oral antidepressant treatment as long as the dose had been stable and the medication had been taken for at least 30 days prior to baseline assessment. Patients were monitored for at least 4 weeks after the 14-day treatment course. The primary endpoint of both studies was the change in depressive symptoms using the total score from the HAMD-17, measured at day 15. Patients in the zuranolone groups showed significantly more improvement in their symptoms versus placebo groups. The treatment effect was maintained at 4 weeks (42 days) after the last dose. The labeling contains a boxed warning noting that zuranolone can impact a person's ability to drive and perform other potentially hazardous activities. Patients also may not be able to assess their degree of impairment. To reduce the risk of harm, patients should not drive or operate heavy machinery for at least 12 hours after taking a dose of the medication. The recommended treatment regimen is zuranolone 50 mg once daily in the evening for 14 days, given with a fat-containing meal (e.g. 400 to 1,000 calories; 25% to 50% fat). For patients experiencing CNS depressant effects within the 14-day period, a dose reduction to 40 mg should be considered for the remaining treatment duration. The FDA-approved zuranolone under fast track, priority review in August 2023.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer capsules once daily in the evening with fat-containing food (e.g., such as a fatty meal containing 400 to 1,000 calories, 25% to 50% fat).
-Missed dose: If an evening dose is missed, the patient should skip the missed dose and take the next dose at the regular time the following evening. The patient should then continue taking the capsules once daily in the evening until the remainder of the 14-day treatment course is completed.
No evidence for increased suicidal ideation or suicidal behavior was observed compared with baseline, measured by the Columbia-Suicide Severity Rating Scale, during one placebo-controlled clinical trial study with zuranolone for the treatment of postpartum depression. Previous pooled analyses of placebo-controlled trials that included approximately 77,000 adults and 4,500 pediatric patients showed that the incidence of suicidal thoughts and behaviors in pediatric patients and young adults (up to 24 years of age) was greater than in placebo-treated patients for most antidepressants studied (SSRIs and others). These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in adults over 24 years of age; there was a reduction in risk with antidepressant use in patients 65 years and older. Because zuranolone does not directly affect monoaminergic systems and there is a low number of exposures to zuranolone, the risk of suicidal ideation in relation to this pooled analyses is unknown. Consider changing the therapeutic regimen, including discontinuation of zuranolone, in patients with worsening depression or emergent suicidality.
During clinical trials for postpartum depression, somnolence was the most commonly reported adverse reaction to zuranolone, affecting 36% of patients receiving zuranolone 50 mg/day and 19% of patients receiving zuranolone 40 mg/day (compared to 6% to 11% reported with placebo). Somnolence (including drowsiness, hypersomnia, and sedation in some studies) was also the most common side effect leading to zuranolone discontinuation (2%) and was a common reason for zuranolone dose reduction (10%). Dizziness (including vertigo) was also a common adverse reaction reported at an incidence greater than with placebo (13% with zuranolone 50 mg/day and 8% with 40 mg/day) and was an additional side effect that led to dose reduction in some patients (6%). Other reported side effects in zuranolone-treated patients that occurred more commonly than with placebo included fatigue (including asthenia and lethargy in some studies) (5%), memory impairment (3%), and anxiety (2%). Across postpartum depression clinical studies at all doses studied, confusion (1%) was a serious adverse reaction to zuranolone treatment.
In clinical trials of zuranolone for the treatment of postpartum depression, abdominal pain (including upper abdominal pain) was reported in 3% of patients on a 50 mg/day dose of zuranolone (no reports in placebo arm). Diarrhea was reported in 5% to 6% of patients on zuranolone (40 mg/day and 50 mg/day, respectively) with 2% to 6% of patients on placebo also reporting these effects.
In clinical trials of zuranolone for the treatment of postpartum depression, infection was reported more commonly in patients receiving zuranolone than with placebo. Reported infections in treated patients included urinary tract infection (5%), COVID-19 (2%), and naso-pharyngitis/upper respiratory infection (9%). Sinus congestion (nasal congestion) was also reported in 3% of patients taking zuranolone.
In clinical trials of zuranolone for treatment of postpartum depression, several musculoskeletal adverse effects were reported more commonly with zuranolone treatment than with placebo, including hypoesthesia (2%), muscle twitching (myoclonia) (2%), myalgia (2%), and tremor (2%).
In clinical trials of zuranolone for the treatment of postpartum depression, xerostomia (dry mouth) occurred in 4% of patients while dental pain (toothache) was reported in 3% of patients treated with zuranolone. There were no reports of either of these adverse effects in patients receiving placebo.
In clinical trials of postpartum depression, 2% of patients taking zuranolone 50 mg/day reported a rash vs. 1% of patients taking placebo.
Zuranolone use is associated with CNS depression (e.g., somnolence, confusion, and also dizziness, gait disturbance). In particular, patients should abstain from driving or operating machinery or performing other potentially hazardous activities for at least 12 hours after taking a dose and also for the duration of the 14-day treatment course; the prescribing label contains a boxed warning for this effect. Patients may not be able to assess their own driving competence or the degree of impairment caused by zuranolone. If patients develop CNS depressant effects, consider dosage reduction or discontinuation. Coadministration with other CNS depressants and alcohol (ethanol ingestion) should be avoided due to the risk of additive sedation and CNS depression. If use with another CNS depressant or a drug which might reduce zuranolone metabolism is unavoidable, consider dosage reduction of zuranolone.
A pooled analysis of placebo-controlled trials including approximately 77,000 adults and 4,500 pediatric patients showed that the incidence of suicidal thoughts and behaviors in pediatric patients and young adults (up to 24 years of age) was greater than in placebo-treated patients for most antidepressants studied (SSRIs and others). Because zuranolone does not directly affect monoaminergic systems and there is a low number of exposures to zuranolone, the risk of suicidal ideation is unknown. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation before treatment have an increased risk for suicidal ideation or attempts and should be closely monitored. Consider changing the therapeutic regimen, including the discontinuation of zuranolone, in patients with worsening depression or emergent suicidality.
Findings from animal studies indicate that zuranolone may cause fetal harm when administered during pregnancy. In rat studies following exposure during gestation or throughout gestation and lactation, adverse effects on development (such as fetal malformations, embryofetal and offspring mortality, and 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. Pregnant patients should be advised of the potential risk to an infant exposed to zuranolone in utero. Females of reproductive potential should be advised to use effective contraception during treatment with zuranolone and for 1 week after the final dose. 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/.
Based on findings from animal studies, zuranolone may cause fetal harm when administered to a pregnant patient. Contraception requirements should be discussed with all female patients of reproductive potential prior to initiating treatment with zuranolone. Patients should be advised to use effective contraception throughout treatment and for 1 week after the final dose.
Use zuranolone with caution during breast-feeding. Available data from a clinical lactation study in 14 women indicate that zuranolone is present in low levels in human milk. Patients were treated with zuranolone 30 mg/day for 5 days. At steady state, the calculated maximum relative infant dose was less than 1%. The daily infant dose was low (approximately 0.0013 mg/kg/day), reflecting a mean infant dose of 0.357% compared to the maternal dose. Concentrations in breast milk were below the level of quantification limit by 4 to 6 days after the last dose. 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 breast-feeding should be considered along with the clinical need for zuranolone and any potential adverse effects on the breastfed child from zuranolone or from the underlying maternal condition.
For the treatment of postpartum depression:
Oral dosage:
Adults: 50 mg PO once daily in the evening, with a fatty meal or food, for 14 days. If a patient experiences CNS depression during the 14-day course, may reduce the dose to 40 mg PO once daily in the evening. Safety and efficacy have not been established for beyond 14 days of use. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
50 mg/day PO.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment: No dosage adjustment needed.
Severe (Child-Pugh Class C) hepatic impairment: 30 mg PO once daily in the evening for 14 days.
Patients with Renal Impairment Dosing
Mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2): No dosage adjustment necessary.
Moderate or severe renal impairment (eGFR less than 60 mL/min/1.73 m2): 30 mg PO once daily in the evening for 14 days.
*non-FDA-approved indication
Acetaminophen; Aspirin; Diphenhydramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Acetaminophen; Caffeine; Pyrilamine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Chlorpheniramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Codeine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Diphenhydramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Acetaminophen; Hydrocodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Acetaminophen; Oxycodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Acetaminophen; Pamabrom; Pyrilamine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Adagrasib: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with adagrasib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Alfentanil: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Alprazolam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Amitriptyline: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Amobarbital: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Amoxapine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with clarithromycin is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Apalutamide: (Major) Avoid concomitant use of zuranolone and apalutamide. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Apomorphine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Aripiprazole: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Asenapine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose. (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Aspirin, ASA; Oxycodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Atazanavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with atazanavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Atazanavir; Cobicistat: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with atazanavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold. (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Atropine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Atropine; Difenoxin: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Azelastine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Azelastine; Fluticasone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Baclofen: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Barbiturates: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Belladonna; Opium: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Benzhydrocodone; Acetaminophen: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Brexpiprazole: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Brompheniramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Brompheniramine; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Brompheniramine; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Buprenorphine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Buprenorphine; Naloxone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose. (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose. (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Butorphanol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Cannabidiol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Capsaicin; Metaxalone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Carbamazepine: (Major) Avoid concomitant use of zuranolone and carbamazepine. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Carbidopa; Levodopa: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Carbidopa; Levodopa; Entacapone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Carbinoxamine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Cariprazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Carisoprodol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Celecoxib; Tramadol: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Cenobamate: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ceritinib: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ceritinib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Cetirizine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Cetirizine; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlophedianol; Dexbrompheniramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chloramphenicol: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with chloramphenicol is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Chlorcyclizine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlordiazepoxide: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlordiazepoxide; Amitriptyline: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm. (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlordiazepoxide; Clidinium: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Codeine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose. (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Dextromethorphan: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Hydrocodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose. (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpheniramine; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorpromazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Chlorzoxazone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clarithromycin: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with clarithromycin is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Clemastine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clobazam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clomipramine: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clonazepam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clonidine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clorazepate: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clozapine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
CNS Depressant Medications (selected non-opioid): (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Cobicistat: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Codeine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Codeine; Guaifenesin: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Codeine; Phenylephrine; Promethazine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose. (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Codeine; Promethazine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose. (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Cyclobenzaprine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Cyproheptadine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dantrolene: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Darunavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with darunavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Darunavir; Cobicistat: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold. (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with darunavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold. (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with darunavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Delavirdine: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with delavirdine is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Desipramine: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Deutetrabenazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dexbrompheniramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dexbrompheniramine; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dexchlorpheniramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dexmedetomidine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Diazepam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Dimenhydrinate: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Diphenhydramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Diphenhydramine; Ibuprofen: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Diphenhydramine; Naproxen: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Diphenhydramine; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Diphenoxylate; Atropine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Doxepin: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Doxylamine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Doxylamine; Pyridoxine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Dronabinol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Droperidol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Encorafenib: (Major) Avoid concomitant use of zuranolone and encorafenib. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Entacapone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Enzalutamide: (Major) Avoid concomitant use of zuranolone and enzalutamide. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Estazolam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Eszopiclone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Etomidate: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Fenfluramine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Fentanyl: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Flibanserin: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Fluphenazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Flurazepam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosphenytoin: (Major) Avoid concomitant use of zuranolone and fosphenytoin. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Gabapentin: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during zuranolone treatment due to the risk of increased zuranolone exposure and adverse reactions. Zuranolone is a CYP3A substrate and grapefruit juice is a CYP3A inhibitor.
Guanfacine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Haloperidol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Homatropine; Hydrocodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Hydrocodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Hydrocodone; Ibuprofen: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Hydromorphone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Hydroxyzine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ibuprofen; Oxycodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Idelalisib: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with idelalisib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Iloperidone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Imipramine: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Indinavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with indinavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Isocarboxazid: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Isoflurane: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of zuranolone and rifampin. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use reduced zuranolone overall exposure by 85%.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of zuranolone and rifampin. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use reduced zuranolone overall exposure by 85%.
Itraconazole: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with itraconazole is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use increased zuranolone overall exposure by 1.62-fold.
Ketamine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ketoconazole: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ketoconazole is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with clarithromycin is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Lasmiditan: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Lemborexant: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Letermovir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with combination letermovir plus cyclosporine is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and combination letermovir plus cyclosporine is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Levodopa: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Levoketoconazole: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ketoconazole is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Levorphanol: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Lofexidine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Lonafarnib: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with lonafarnib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Lopinavir; Ritonavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ritonavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Lorazepam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Loxapine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of zuranolone and lumacaftor; ivacaftor. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of zuranolone and lumacaftor; ivacaftor. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Lumateperone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Lurasidone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Maprotiline: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Meclizine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Melatonin: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Meperidine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Meprobamate: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Metaxalone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Methadone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Methocarbamol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Methohexital: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Methyldopa: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Metoclopramide: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Midazolam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Mifepristone: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with mifepristone is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Mirtazapine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Mitotane: (Major) Avoid concomitant use of zuranolone and mitotane. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Molindone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Morphine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Morphine; Naltrexone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Nabilone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Nalbuphine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Nefazodone: (Major) Avoid concomitant use of zuranolone and nefazodone. Concomitant use may increase zuranolone exposure and may also increase the risk for additive CNS depression. If concomitant use is necessary, decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate, nefazodone is a strong CYP3A inhibitor, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Nelfinavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with nelfinavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Nirmatrelvir; Ritonavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ritonavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Nortriptyline: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Olanzapine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Olanzapine; Fluoxetine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Olanzapine; Samidorphan: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Oliceridine: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Opiate Agonists: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Orphenadrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Oxazepam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Oxycodone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Oxymorphone: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Paliperidone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Pentazocine; Naloxone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Pentobarbital: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Perampanel: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Perphenazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Perphenazine; Amitriptyline: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm. (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Phenelzine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Phenobarbital: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%. (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Phenytoin: (Major) Avoid concomitant use of zuranolone and phenytoin. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Pimavanserin: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Pimozide: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Posaconazole: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with posaconazole is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Pramipexole: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Pregabalin: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Primidone: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Prochlorperazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Promethazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Promethazine; Dextromethorphan: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Promethazine; Phenylephrine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Propofol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Protriptyline: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Quazepam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Quetiapine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ramelteon: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Rasagiline: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Remifentanil: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Remimazolam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ribociclib: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ribociclib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Ribociclib; Letrozole: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ribociclib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Rifampin: (Major) Avoid concomitant use of zuranolone and rifampin. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use reduced zuranolone overall exposure by 85%.
Rifapentine: (Major) Avoid concomitant use of zuranolone and rifapentine. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Risperidone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ritonavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with ritonavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Ropinirole: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Rotigotine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Safinamide: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Saquinavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with saquinavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Scopolamine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Secobarbital: (Major) Avoid concomitant use of zuranolone and barbiturates. Concurrent use may decrease zuranolone exposure which may reduce its efficacy; use may also increase the risk for CNS depression. Zuranolone is a CYP3A substrate, barbiturates are strong CYP3A inducers, and both medications have been associated with CNS depression. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Selegiline: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Sevoflurane: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Sodium Oxybate: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of zuranolone and St. John's wort. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
Stiripentol: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Sufentanil: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Suvorexant: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Tapentadol: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Tasimelteon: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Temazepam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Tetrabenazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Thalidomide: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Thioridazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Thiothixene: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Tipranavir: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with tipranavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Tizanidine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Tolcapone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Tramadol: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Tramadol; Acetaminophen: (Major) Avoid concomitant use of opioids and other CNS depressants, such as zuranolone. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Tranylcypromine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Trazodone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Triazolam: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Tricyclic antidepressants: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Trifluoperazine: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Trimipramine: (Moderate) Concomitant use of multiple sedating agents, such as zuranolone and tricyclic antidepressants, may result in additive CNS depression. Monitor for additive CNS depressant effects and consider taking additional steps to minimize the risk for over sedation, such as avoidance or a downward dose adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Tucatinib: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with tucatinib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Valerian, Valeriana officinalis: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Valproic Acid, Divalproex Sodium: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with clarithromycin is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Voriconazole: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with voriconazole is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Zaleplon: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Ziprasidone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Zolpidem: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
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 gamma aminobutyric acid-A (GABA-A) receptors. In the postpartum period, there are disruptions of perinatal GABA signaling and dramatic perinatal changes in circulating levels of allopregnanolone, a neuroactive steroid GABA-A receptor positive allosteric modulator. Dramatic alterations in allopregnanolone in brain regions associated with emotion and self-perception, which are supported by GABAergic signaling, can occur following delivery. These changes have been associated with postpartum depression compared to healthy postpartum female individuals. Administration of zuranolone helps to modulate these changes by acting at both synaptic and extrasynaptic GABA-A receptors, decreasing the effects of alterations in endogenous allopregnanolone.
Zuranolone is administered orally. Following administration, steady state is achieved in 3 to 5 days. The volume of distribution of zuranolone following oral administration is greater than 500 L. The mean blood-to-plasma concentration ratio ranges from 0.54 to 0.58. Plasma protein binding is greater than 99.5%. Zuranolone is extensively metabolized, with CYP3A4 identified as the primary enzyme involved. In pharmacokinetic studies, there were no circulating human metabolites greater than 10% of total drug-related materials and none were considered to contribute to the therapeutic effects of zuranolone. Following oral administration, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone.
Affected cytochrome p450 isoenzymes and drug transporters: CYP3A4
Zuranolone is primarily metabolized by CYP3A4. Concomitant use of strong CYP3A4 inhibitors increases zuranolone exposure (approximately 1.6-fold) and the risk of zuranolone-associated adverse reactions, and a zuranolone dose reduction is recommended. Because CYP3A4 inducers significantly reduce exposure to zuranolone and may decrease medication efficacy, concurrent use of CYP3A4 inducers should be avoided. Zuranolone is not an inhibitor of CYP1A2, 2B6, 2C19, 2C8, 2C9, 2D6 or 3A4. Zuranolone is not an inducer for CYP1A2, CYP2B6 or CYP3A4 at the therapeutic dose range. Zuranolone is not a substrate of and does not inhibit any of the major known drug transporters, including P-glycoprotein (P-gp).
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, peak zuranolone concentrations (Tmax) occur at 5 to 6 hours. Absolute bioavailability has not been evaluated. Zuranolone exposure (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). Following administration of 30 mg of zuranolone to healthy subjects, the Cmax increased by approximately 3.5-fold and the AUC increased by approximately 1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The Cmax increased by approximately 4.3-fold and the AUC increased by approximately 2-fold with a high-fat meal (800 to 1,000 calories; 50% fat) compared to fasted conditions. The Tmax was not impacted by food.
-Special Populations
Hepatic Impairment
Exposure to zuranolone was increased significantly (approximately 1.54-fold) in patients with severe hepatic impairment; dosage reductions are recommended in this population. In patients with mild or moderate hepatic impairment (Child-Pugh A or B), exposures are similar to those with normal hepatic function.
Renal Impairment
Exposure to zuranolone was increased in patients with moderate (eGFR 30 to 59 mL/minute/1.73 m2) and severe (eGFR 15 to 29 mL/minute/1.73 m2) renal impairment and dosage reduction is recommended in these patients. Zuranolone exposure in patients with mild renal impairment (eGFR 60 to 89 mL/minute/1.73 m2) is similar to those with normal renal function. Zuranolone pharmacokinetics have not been studied in patients with eGFR less than 15 mL/minute/1.73 m2 or patients requiring dialysis.
Pediatrics
The pharmacokinetic parameters of zuranolone have not been studied in pediatric patients.
Geriatric
Relative to younger adults 18 to 45 years, the Cmax and exposure to zuranolone was approximately 1.27 and 1.32-fold higher in participants 65 years and older.
Ethnic Differences
Black or African American participants had a 14% higher mean apparent clearance (CL/F) compared to participants of other races (Asian, White, or other). However, no adjustments of zuranolone dosage are recommended.