Zurzuvae (zuranolone)

When used concomitantly with a strong cytochrome P-450 (CYP) 3A4 inhibitor, reduce the zuranolone dosage to 30 mg orally once daily in the evening for 14 days.

No dosage modification is recommended when zuranolone is used concomitantly with a moderate CYP3A4 inhibitor.

Avoid concomitant use of zuranolone with CYP3A4 inducers.

If patients experience CNS depressant effects within the 14-day treatment period, consider reducing the dosage of zuranolone to 40 mg orally once daily in the evening.

Zuranolone is administered orally as capsules.

Zuranolone should be taken with fat-containing food (e.g., 400--1000 calories, 25% to 50% fat).

Zuranolone can be used alone or as an adjust to oral antidepressant therapy.

The safety and efficacy of zuranolone use beyond 14 days in a single treatment course have not been established.

If a zuranolone evening dose is missed, the patient should be advised to take the next dose at the regular time the following evening. The patient should be advised to not take extra capsules on the same day to make up for the missed dose. The patient should then continue taking zuranolone once daily until the remainder of the 14-day treatment course is complete.

Store zuranolone capsules at 20-25degreesC; excursions permitted between 15-30degreesC.

No dosing information is available for this tab.

Zuranolone is a substrate of cytochrome P-450 (CYP) 3A4.

Zuranolone is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, or CYP3A4. Zuranolone is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at the therapeutic dosage range.

Zuranolone is not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, or OATP1B3. Zuranolone does not inhibit P-gp, BCRP, bile salt export pump (BSEP), OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT2, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1 or MATE2.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Zuranolone/Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)

DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Zuranolone/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of zuranolone, including somnolence and CNS depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US prescribing information recommends dose adjustment if zuranolone is to be given with a strong CYP3A4 inhibitor. Reduce the zuranolone dose to 30 mg orally once daily in the evening for 14 days when used concurrently with strong CYP3A4 inhibitors.(1)

DISCUSSION: Coadministration of zuranolone with itraconazole (a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) by 25% and area-under-curve (AUC) by 62%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

*None.

There are no contraindication contraindications for this drug.

• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Suicidal ideation

• Kidney disease with likely reduction in glomerular filtration rate (GFr)

The most common adverse effects of zuranolone (>=5% of patients) reported in clinical studies include somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.

Less Frequent

• Suicidal ideation

More Frequent

• Diarrhea
• Dizziness
• Drowsy
• Fatigue
• Nasal passage irritation
• Urinary tract infection

Less Frequent

• Accidental fall
• Acute abdominal pain
• Hypoesthesia
• Memory impairment
• Muscle fasciculation
• Myalgia
• Sinusitis
• Skin rash
• Symptoms of anxiety
• Toothache
• Tremor
• Xerostomia

No enhanced messaging available.

Safety and effectiveness of zuranolone in pediatric patients have not been established.

There is insufficient evidence with zuranolone in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on findings from animal studies, zuranolone may cause fetal harm. Advise pregnant women of the potential risk to a fetus.

In animals, oral administration of zuranolone to pregnant rats during organogenesis resulted in developmental toxicity, including embryofetal death and fetal malformations, with a no adverse effect level (NOAEL) associated with maternal plasma exposures 7 times greater than in humans at the maximum recommended human dose (MRHD) of 50 mg. Oral administration of zuranolone to rats during pregnancy and lactation resulted in developmental toxicity in the offspring, including perinatal mortality, at maternal exposures similar to that in humans at the MRHD. Development toxicity was observed at doses that were also maternally toxic. Neuronal death was observed in rats exposed to zuranolone during a period of brain development that begins during the third trimester of pregnancy in humans and continues up to a few years after birth.

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/.

Available data from a clinical lactation study in 14 lactating women indicate that zuranolone is present in low levels in human milk. There are no data on the effects of zuranolone on the breast-fed infant and limited data on the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for zuranolone and any potential adverse effects on the breast-fed child from zuranolone or from the underlying maternal condition.

A steady-state milk study was conducted in 14 healthy lactating women treated with daily oral administration of 30 mg of zuranolone for 5 days. At steady state (Day 5), the calculated maximum relative infant dose for zuranolone was <1%. The daily infant dose was low (approximately 0.0013 mg/kg per day), reflecting a mean relative infant dose of 0.357% compared to the maternal dose. Concentrations of zuranolone in breast milk were below the level of quantification limit by 4--6 days after the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

There is no experience with zuranolone in geriatric patients with postpartum depression.