DRUG INTERACTIONS

1. CNS Depressants                                                                                             Concomitant use of ZULRESSO with CNS depressants (e.g., opioids, benzodiazepines) may increase the likelihood or severity of adverse reactions related to sedation 

2. Antidepressants                                                                                                               In the placebo-controlled studies, a higher percentage of ZULRESSO-treated patients who used concomitant antidepressants reported sedation-related events 

BRIEF SUMMARY

BREXANOLONE-(Mar 2019)

Indn-   To treat postpartum depression in adult women                                                 

Comp-  Injection: 100 mg/20 mL (5 mg/mL) single-dose vial. • Administered as a continuous intravenous infusion over 60 hours (2.5 days) as follows ): o 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour 

ADR- Most common adverse reactions (incidence =5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush. 

CI- None. 

WARNINGS-  Suicidal Thoughts and Behaviors: Consider changing the therapeutic regimen, including discontinuing  in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors. 

Pat Inform-                                                                                                           Excessive Sedation and Sudden Loss of Consciousness                                      Patients may experience loss of consciousness or altered state of consciousness during the ZULRESSO infusion. Advise patients to report signs of excessive sedation that may occur during the infusion.

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U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No- 4

 ADVERSE REACTIONS

 Most common adverse reactions (incidence =5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush. 

 CONTRAINDICATIONS 

None. 

WARNINGS AND PRECAUTIONS

 Suicidal Thoughts and Behaviors: Consider changing the therapeutic regimen, including discontinuing ZULRESSO, in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors. 

o 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (alternatively consider a dosage of 60 mcg/kg/hour for those who do not tolerate 90 mcg/kg/hour)

o 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour

o 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour • Dilution required prior to administration. 

DOSAGE FORMS AND STRENGTHS

 Injection: 100 mg/20 mL (5 mg/mL) single-dose vial. 

 PATIENT COUNSELING INFORMATION

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

Excessive Sedation and Sudden Loss of Consciousness                                      Patients may experience loss of consciousness or altered state of consciousness during the ZULRESSO infusion. Advise patients to report signs of excessive sedation that may occur during the infusion.

Patients must not be the primary caregiver of dependents and must be accompanied during interactions with their child(ren) 

ZULRESSO Risk Evaluation and Mitigation Strategy (REMS)                          ZULRESSO is available only through a restricted program called the ZULRESSO REMS. Inform the patient of the following notable requirements:

• Patients must be enrolled in the ZULRESSO REMS Program prior to administration.

• Patients must be monitored during administration of ZULRESSO and report any signs and symptoms of excessive sedation to a healthcare provider.

Potential for Abuse Advise patients that ZULRESSO can be abused or lead to dependence 

Concomitant Medications Caution patients that opioids or other CNS depressants, such as benzodiazepines, taken in combination with ZULRESSO may increase the severity of sedative effects 

Drug Interactions

 Suicide Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidal thoughts and behavior and instruct them to report such symptoms to the healthcare provider.

Pregnancy Advise women to notify their healthcare provider if they could possibly be pregnant prior to therapy with ZULRESSO.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

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

Manufactured for: Sage Therapeutics, Inc., Cambridge, MA 02142 USA ZULRESSO, the ZULRESSO logo, SAGE THERAPEUTICS, and the SAGE THERAPEUTICS logo are trademarks of Sage Therapeutics, Inc.

All other trademarks referenced herein are the properties of their respective owners.

 CLINICAL PHARMACOLOGY

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

2. Pharmacodynamics                                                                                   Brexanolone potentiated GABA-mediated currents from recombinant human GABAA receptors in mammalian cells expressing a1ß2?2 receptor subunits, a4ß3d receptor subunits, and a6ß3d receptor subunits.                                                                   Brexanolone exposure-response relationships and the time course of pharmacodynamics response are unknown.

Cardiac Electrophysiology                                                                                          The effect of brexanolone on the QT interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, three-period crossover thorough QT study in 30 healthy adult subjects. At 1.9-times the exposure occurring at the highest recommended infusion rate (90 mcg/kg/hour), brexanolone did not prolong the QT interval to a clinically relevant extent.

3. Pharmacokinetics                                                                                       Brexanolone exhibited dose proportional pharmacokinetics over a dosage range of 30 mcg/kg/hour to 270 mcg/kg/hour (three times the maximum recommended dosage). Mean steady state exposure at 60 mcg/kg/hour and 90 mcg/kg/hour was around 52 ng/mL and 79 ng/mL, respectively

Distribution                                                                                                                   The volume of distribution of brexanolone was approximately 3 L/kg, suggesting extensive distribution into tissues. Plasma protein binding was greater than 99% and is independent of plasma concentrations.

Elimination                                                                                                                    The terminal half-life of brexanolone is approximately 9 hours. The total plasma clearance of brexanolone is approximately 1 L/h/kg.

Metabolism                                                                                                          Brexanolone is extensively metabolized by non-CYP based pathways via three main routes - keto-reduction (AKRs), glucuronidation(UGTs), and sulfation (SULTs). There are three major circulating metabolites that are pharmacologically inactive and do not contribute to the overall efficacy of ZULRESSO.

Excretion                                                                                                                Following administration of radiolabeled brexanolone, 47% was recovered in feces (primarily as metabolites) and 42% in urine (with less than 1% as unchanged brexanolone). 

 Specific Populations                                                                                                        No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal impairment (severe) study or hepatic impairment (mild, moderate, severe) study. The effect of end stage renal disease (ESRD, eGFR < 15 mL/minute/1.73 m2 ) on brexanolone pharmacokinetics is unknown.

However, avoid use of ZULRESSO in patients with ESRD 

Drug Interaction Studies                                                                                               No studies were conducted to evaluate the effects of other drugs on ZULRESSO. No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when it was used concomitantly with brexanolone.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Pregnancy Exposure                                                                         There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry.

Risk Summary                                                                                                              Based on findings from animal studies of other drugs that enhance GABAergic inhibition, ZULRESSO may cause fetal harm. There are no available data on ZULRESSO use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

All pregnancies have 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.

3.Lactation-                                                                                                                        There were no reports of effects of ZULRESSO on milk production. There are no data on the effects of ZULRESSO on a breastfed infant. Available data on the use of ZULRESSO during lactation do not suggest a significant risk of adverse reactions to breastfed infants from exposure to ZULRESSO.

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

4.Pediatric Use                                                                                                               The safety

5.Geriatric Use                                                                                                             PPD is a condition associated with pregnancy; there is no geriatric experience with ZULRESSO.

6. Hepatic Impairment                                                                                               Dosage adjustment in patients with hepatic impairment is not necessary. Modest increases in exposure to unbound brexanolone and modest decreases in exposure to total brexanolone were observed in patients with moderate to severe hepatic impairment (Child-Pugh=7) with no associated change in tolerability 

7. Renal Impairment                                                                                                            No dosage adjustment is recommended in patients with mild (eGFR 60 to 89 mL/minute/1.73 m2 ), moderate (eGFR 30 to 59 mL/minute/1.73 m2 ) or severe (eGFR 15 to 29 mL/minute/1.73 m2 ) renal impairment

Avoid use of ZULRESSO in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium 

 DRUG ABUSE AND DEPENDENCE                                                                       1.Controlled Substance                                                                                          ZULRESSO contains brexanolone. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration

2. Abuse In a human abuse potential study, 90 mcg/kg, 180 mcg/kg (two times the maximum recommended infusion rate), and 270 mcg/kg (three times the maximum recommended infusion rate) ZULRESSO infusions over a one

3. Dependence In the PPD clinical studies conducted with ZULRESSO, end of treatment occurred through tapering. Thus, in these studies it was not possible to assess whether abrupt discontinuation of ZULRESSO produced withdrawal symptoms indicative of physical dependence.

It is recommended that ZULRESSO be tapered according to the dosage recommendations, unless symptoms warrant immediate discontinuation.

OVERDOSAGE

Human Experience There is limited clinical trial experience regarding human overdosage with ZULRESSO. In premarketing clinical studies, two cases of accidental overdosage due to infusion pump malfunction resulted in transient loss of consciousness.

Both patients regained consciousness approximately 15 minutes after discontinuation of the infusion without supportive measures. After full resolution of symptoms, both patients subsequently resumed and completed treatment.

Overdosage may result in excessive sedation, including loss of consciousness  and the potential for accompanying respiratory changes.

Management of Overdose

In case of  overdosage, stop the infusion immediately and initiate supportive measures as necessary. Brexanolone is rapidly cleared from plasma 

Consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.