Version May 2024
Zuranolone causes driving impairment due to central nervous system (CNS) depressant effects. Advise patients not to drive or engage in other potentially hazardous activities until at least 12 hours after zuranolone administration for the duration of the 14-day treatment course. Inform patients that they may not be able to assess their own driving competence, or the degree of driving impairment caused by zuranolone.
Note: Administer with a fat-containing food (400 to 1,000 calories, 25% to 50% fat) for adequate absorption.
Depression, postpartum: Oral: 50 mg once daily in the evening for 14 days; may reduce to 40 mg once daily in the evening based on tolerability (eg, CNS depressant effects).
Missed doses: If a dose is missed, administer the next dose at the regularly scheduled time the next evening; do not administer an extra dose on the same day to make up for the missed dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 15 to 59 mL/minute/1.73 m2: 30 mg once daily in the evening for 14 days.
eGFR <15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Child-Turcotte-Pugh class A or B: No dosage adjustment necessary.
Child-Turcotte-Pugh class C: 30 mg once daily in the evening for 14 days.
Refer to adult dosing; has not been studied.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%: Nervous system: Dizziness (13%; including vertigo), drowsiness (36%; including hypersomnia and sedated state)
1% to 10%:
Dermatologic: Skin rash (2%)
Gastrointestinal: Abdominal pain (3%), diarrhea (6%)
Genitourinary: Urinary tract infection (5%)
Nervous system: Anxiety (2%), fatigue (5%; including asthenia), hypoesthesia (2%), memory impairment (3%), tremor (2%)
Neuromuscular & skeletal: Muscle twitching (2%), myalgia (2%)
Frequency not defined: Nervous system: Confusion
There are no contraindications listed in the manufacturer's labeling.
Major psychiatric warnings:
• Suicidal thinking/behavior: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years of age. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during therapy and within 1 to 2 months following therapy.
• The possibility of a suicide attempt is inherent in postpartum depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, including somnolence and confusion, which may impair physical or mental abilities and cause significant driving impairment. Patients should not engage in activities requiring mental alertness, such as driving or operating heavy machinery, for at least 12 hours after administration for the duration of the 14-day course of therapy. Patients may be unable to assess their own driving competence or degree of impairment.
• Falls: Patients may be at risk for falls due to CNS depressant effects.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with severe hepatic impairment
• Renal impairment: Use with caution in patients with moderate or severe renal impairment.
Other warnings/precautions:
• Abuse, misuse, and substance use disorder: Zuranolone has abuse potential.
• Physical dependence: Zuranolone may produce physical dependence. Patients may experience withdrawal symptoms (eg, insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, paranoia) after abrupt discontinuation or significant dose reduction. Risk is higher in patients taking higher than recommended doses or durations.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Zurzuvae: 20 mg, 25 mg, 30 mg
No
Capsules (Zurzuvae Oral)
20 mg (per each): $681.43
25 mg (per each): $681.43
30 mg (per each): $1,362.86
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
C-IV
Oral: Administer with a fat-containing food (400 to 1,000 calories, 25% to 50% fat) in the evening.
Depression, postpartum: Treatment of postpartum depression in adults.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CNS Depressants: Zuranolone may enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Zuranolone. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Zuranolone. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Zuranolone. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Zuranolone. Management: Reduce the zuranolone dose to 30 mg once daily when used concomitantly with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Administration of a high-fat meal (800 to 1,000 calories, 50% fat) increases Cmax by 4.3-fold and AUC by 2-fold; administration of a smaller meal (400 to 500 calories, 25% fat) increases Cmax by 3.5-fold and AUC by 1.8-fold. Management: Administer with fat-containing food (400 to 1,000 calories, 25% to 50% fat).
Patients of reproductive potential should use effective contraception during therapy and for 1 week after the last dose of zuranolone.
Based on data from animal reproduction studies, in utero exposure to zuranolone may cause fetal harm.
Data collection to monitor pregnancy and infant outcomes following exposure to zuranolone is ongoing. Health care providers are encouraged to enroll patients exposed to zuranolone during pregnancy in the National Pregnancy Registry for Antidepressants (844-405-6185 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/).
Zuranolone is present in breast milk.
Data related to the presence of zuranolone in breast milk are available from 14 women administered zuranolone 30 mg daily for 5 days. Per product labeling, the relative infant dose (RID) of zuranolone on day 5 was <1%, providing an estimated daily dose to the infant of ~0.0013 mg/kg/day. Zuranolone breast milk concentrations were below the level of quantification 4 to 6 days after the last dose.
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. When treating postpartum depression, infant feeding options should be made as part of a shared decision-making process; until additional data become available, options may include pumping and discarding breast milk during therapy and for 1 week after the last zuranolone dose (ACOG 2023).
Administer with a fat-containing food (400 to 1,000 calories, 25% to 50% fat).
Suicidality, signs of abuse/dependence.
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 (GABAA) receptors.
Absorption: Administration with fat-containing food increases absorption.
Distribution: Vd >500 L.
Protein binding: >99.5%.
Metabolism: Primarily hepatic via CYP3A4; no active metabolites.
Half-life elimination: ~19.7 to 24.6 hours.
Time to peak: 5 to 6 hours.
Excretion: Urine: 45%; feces: 41% (<2% as unchanged drug).
Altered kidney function: Exposure to zuranolone was increased in patients with eGFR <60 mL/minute/1.73 m2.
Hepatic function impairment: Exposure to zuranolone was increased in patients with Child-Turcotte-Pugh class C impairment.
Race/ethnicity: Black or African American participants had a 14% higher CL/F compared to participants of other races (Asian, White, or other).
Impact of food: Following administration of 30 mg of zuranolone to healthy subjects, the Cmax increased by ~3.5-fold and the AUClast increased by ~1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The Cmax increased by ~4.3-fold and the AUClast increased by ~2-fold with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions.
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