DRUG INTERACTIONS-(summary)-

 • CNS Depressants: Concomitant use may increase impairment of psychomotor performance or CNS depressant effects. If use with another CNS depressant is unavoidable, consider dosage reduction.

 • Strong CYP3A4 Inhibitors: Concomitant use may increase the risk of ZURZUVAE-associated adverse reactions. Reduce the ZURZUVAE dosage to 30 mg orally once daily in the evening for 14 days when used concomitantly with a strong CYP3A4 inhibitor.

 • CYP3A4 Inducers: Concomitant use may decrease the efficacy of ZURZUVAE. Avoid concomitant use. 

BRIEF SUMMARY

ZURANOLONE-(Aug 2023)

Indn-   To treat  postpartum depression      

Dosage • Recommended dosage is 50 mg orally once daily in the evening for 14 days, can be reduced to 40 mg once daily if CNS depressant effects occur.

ADR- Most common adverse reactions  were somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.

DI-  ZURZUVAE can cause CNS depressant effects such as somnolence and confusion. If patients develop CNS depression, consider dosage reduction or discontinuation of ZURZUVAE.

 CI - none

Pat Inform- ZURZUVAE causes driving impairment. Advise patients to take ZURZUVAEn the evening.

Patients adviced  not to drive a motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness, such as operating machinery, until at least 12 hours after ZURZUVAE administration

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 30

Name-                       ZUZUVAE

Acive  Ingredient -   Zuranolone

Pharmacological clssificiation-        To treat  postpartum depression                                                                                                                                                                                   

 Date of Approval-         8/4/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                          ZURZUVAE safely and effectively.

See full prescribing information for ZURZUVAE. ZURZUVAETM (zuranolone) capsules, for oral use, [controlled substance schedule pending]

Initial U.S. Approval: [pending controlled substance scheduling]

WARNING:                                                                                                                  IMPAIRED ABILITY TO DRIVE OR EZ

ZURZUVAE 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 administration. Patients may not be able to assess their own driving competence or the degree of impairment caused by ZURZUVAE 

INDICATIONS AND USAGE-

ZURZUVAE is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator indicated for the treatment of postpartum depression (PPD) in adults.

 ADVERSE REACTIONS-

 Most common adverse reactions (incidence =5% and greater than placebo) were somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.

 CONTRAINDICATIONS-

None. 

WARNINGS AND PRECAUTIONS-

 • CNS Depressant Effects: ZURZUVAE can cause CNS depressant effects such as somnolence and confusion. If patients develop CNS depression, consider dosage reduction or discontinuation of ZURZUVAE.

 • Suicidal Thoughts and Behavior: Consider changing the therapeutic regimen, including discontinuing ZURZUVAE, in patients whose PPD worsens, or who experience emergent suicidal thoughts and behaviors.

 • Embryo-fetal Toxicity: May cause fetal harm. Advise a pregnant woman of the potential risk to an infant exposed to ZURZUVAE in utero. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during ZURZUVAE treatment and for one week after the final dose.

DOSAGE AND ADMINISTRATION-

 • Administer with fat-containing food.

 • Recommended dosage is 50 mg orally once daily in the evening for 14 days.

 • Dosage may be reduced to 40 mg once daily if CNS depressant effects occur.

 • ZURZUVAE can be used alone or as an adjunct to oral antidepressant therapy.

 • Severe Hepatic Impairment: Recommended dosage is 30 mg orally once daily in the evening for 14 days.

 • Moderate or Severe Renal Impairment: Recommended dosage is 30 mg orally once daily in the evening for 14 days.

DOSAGE FORMS AND STRENGTHS-

 Capsules: 20 mg, 25 mg, and 30 mg. 

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

 Impaired Ability to Drive or Engage in Other Potentially Hazardous Activities

Inform patients that ZURZUVAE causes driving impairment. Advise patients to take ZURZUVAE in the evening.

Advise patients not to drive a motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness, such as operating machinery, until at least 12 hours after ZURZUVAE administration.

Warn patients that they may not be able to assess their own ability to drive or the degree of impairment caused by ZURZUVAE 

Central Nervous System -

Depressant Effects-

 Inform patients that ZURZUVAE can cause somnolence, dizziness, sedation, and confusion.

Advise patients to use caution if taking ZURZUVAE in combination with alcohol, other CNS depressants, or medications that increase the concentration of ZURZUVAE

Suicidal Thoughts and Behavior-

 Advise patients to look for the emergence of suicidal thoughts and behaviors and instruct them to report such symptoms to the healthcare provider immediately

Administration-

 Instructions-

Inform patients to take ZURZUVAE with fat-containing food

Instruct patients that if a daily dose is missed, the missed dose should be taken the next day as scheduled.

Patients should be advised not to take extra capsules to make up for the missed dose 

Abuse, Misuse, and Physical Dependence

Advise patients that ZURZUVAE has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction and that ZURZUVAE is associated with the potential for physical dependence

Pregnancy-

Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZURZUVAE.

Advise female patients of reproductive potential to use effective contraception during treatment with ZURZUVAE and for one week after the final dose

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZURZUVAE during pregnancy

Manufactured for: Biogen Inc. 225 Binney Street Cambridge, MA 02142 USA

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

The mechanism of action of zuranolone in the treatment of PPD is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors.

2. Pharmacodynamics Cardiac Electrophysiology -                                                      

 At two times the maximum recommended dose, ZURZUVAE does not cause clinically significant QTc interval prolongation.

Psychomotor Performance with Alcohol or Alprazolam Co-administration of repeated 50 mg daily doses of ZURZUVAE with alcohol or alprazolam led to impairment in psychomotor performance

3. Pharmacokinetics-

Zuranolone exposure (Cmax and AUC) increased approximately dose proportionally with doses ranging from 30 mg to 60 mg (1.2 times of the recommended dosage of ZURZUVAE) with a moderate-fat meal (700 calories; 30% fat).

Once-daily administration of ZURZUVAE resulted in accumulation of approximately 1.5-fold in systemic exposures and steady state was achieved in 3 to 5 days.

Absorption-                                                                                                           Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours (Tmax). The absolute bioavailability of ZURZUVAE was not evaluated.

Effect of Food-                                                                                                              Following administration of 30 mg of ZURZUVAE to healthy subjects, the Cmax increased by approximately 3.5-fold and the AUClast 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 AUClast 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.

Distribution -

The volume of distribution of zuranolone following oral administration is greater than 500 L. The mean blood-to-plasma concentration ratio ranged from 0.54 to 0.58. Plasma protein binding is greater than 99.5%.

Elimination-

The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours in an adult population. The mean apparent clearance (CL/F) of zuranolone is 33 L/h.

Metabolism-

 Zuranolone undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved. There were no circulating human metabolites greater than 10% of total drug-related materials and none are considered to contribute to the therapeutic effects of zuranolone.

Excretion-

Following oral administration of radiolabeled zuranolone, 45% of the dose was recovered in urine as metabolites with neglible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone.

Specific Populations-

 Racial Groups-                                                                                                                 Black or African American participants had a 14% higher CL/F compared to participants of other races (Asian, White, or other). Male and Female Patients, Patients with Renal Impairment,

Patients with Hepatic Impairment -                                                                                 Exposures of zuranolone in specific populations are summarized in Figure 1 [see

Dosage and Administration-

Data have  shown for participants =65 years relative to younger participants (18 to 45 years); female participants relative to male participants; renal and hepatic impairment relative to participants with normal renal and hepatic function, respectively.

Hepatic impairment:

Mild (Child-Pugh Class A); moderate (Child-Pugh Class B); severe (Child-Pugh Class C). Renal impairment: Mild (eGFR 60-89 mL/min/1.73m2); moderate (eGFR 30-59 mL/min/1.73m2); severe (eGFR <30 mL/min/1.73m2 and not on dialysis). CI = confidence interval; GMR = geometric mean ratio

USE IN SPECIFIC POPULATIONS

1. Pregnancy -Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including ZURZUVAE, during pregnancy.

Risk Summary -

Based on findings from animal studies, ZURZUVAE may cause fetal harm. Advise pregnant women of the potential risk to a fetus.

Available data on ZURZUVAE use in pregnant women from the clinical development program are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2. Lactation Risk Summary

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

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZURZUVAE and any potential adverse effects on the breastfed child from ZURZUVAE or from the underlying maternal condition.

3. Females and Males of Reproductive Potential Based on animal studies, ZURZUVAE may cause embryo-fetal harm when administered to a pregnant woman

Contraception-                                                                                                               Advise female patients of reproductive potential to use effective contraception during treatment with ZURZUVAE and for one week after the final dose.

4. Pediatric Use-

The safety and effectiveness of ZURZUVAE in pediatric patients have not been established.

5. Geriatric Use -

PPD is a condition associated with pregnancy; there is no geriatric experience with ZURZUVAE in patients with PPD.

6. Hepatic Impairment-

 Exposure to zuranolone was increased in patients with severe hepatic impairment. The recommended ZURZUVAE dosage in patients with severe hepatic impairment (Child-Pugh C) is lower than patients with normal hepatic function

The recommended ZURZUVAE dosage in patients with mild or moderate hepatic impairment (Child-Pugh A or Child-Pugh B) is the same as those with normal hepatic function

7. Renal Impairment-

Exposure to zuranolone was increased in patients with moderate (eGFR 30 to 59 mL/min/1.73 m2 ) and severe (eGFR 15 to 29 mL/min/1.73 m2 ) renal impairment

The recommended ZURZUVAE dosage in patients with moderate and severe renal impairment is lower than those with normal renal function.

 The recommended dosage in patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 ) is the same as those in patients with normal renal function.

ZURZUVAE has not been studied in patients with eGFR of < 15 mL/min/1.73 m2 or patients requiring dialysis.

 DRUG ABUSE AND DEPENDENCE

1. Controlled Substance-                                                                                         ZURZUVAE contains zuranolone (Controlled substance schedule to be determined after review by the Drug Enforcement Administration.).  

2 Abuse-                                                                                                               Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction. Abuse is the intentional non-therapeutic use of a drug, even once, for its desired psychological or physiological effects.

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Individuals with a history of drug abuse or substance use disorders may be at a greater risk of these outcomes with ZURZUVAE.

 Dependence                                                                                                           -ZURZUVAE may produce physical dependence.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (on the 7th day subjects received 50 mg or 100 mg ) included: insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia.

OVERDOSAGE

There was a case of intentional overdose with ZURZUVAE reported during premarketing clinical trials. The patient took 330 mg (6.5 times the maximum recommended dose) of  ZURZUVAE and was reported to be in an altered state of consciousness.

The event resolved the next day, following treatment with intravenous fluids.

Overdosage with ZURZUVAE may result in excessive CNS depressant effects such as somnolence and disturbance in consciousness. There is no specific antidote for ZURZUVAE overdosage.

Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.