A Clinical Overview of the First FDA-Indicated Drug Approved for Postpartum Depression

ZULRESSO (brexanolone) was approved in March 2019 as the first FDA-indicated medication used in adults for postpartum depression. ^1Pharmacologic category is Gamma-Aminobutyric Acid (GABA) A receptor positive Modulator^2.

Mechanism of Action^2,3

• Mechanism of action is not fully understood, but is thought to be related to positive allosteric modulation of GABA-A receptors

Adverse Effects^1,2,3

• Loss of Consciousness

• Drowsiness

• Sedation

• Dizziness

• Vertigo

• Dry Mouth 

• Flushing/ Hot Flashes

Black Box Warning of excessive sedation and sudden loss of consciousness during administration. Patients must enroll in Risk Evaluation and Mitigation Strategy (REMS) program due to this side effect.

* Patients who are pregnant or think you may be pregnant should not take this medication since fetal harm may occur.

Brexanolone Dose^2,4

• Administer as a continuous IV infusion over a total of 60 days. Start infusion early enough in the day to allow for recognition of excessive sedation. Titrate the dose as detailed. 

     -Phase 1: Initiate at 30 mcg/kg/hour for 4 hours

     -Phase 2: Increase to 60 mcg/kg/hour from hour 4 to 24th hour

     -Phase 3: Increase to 90 mcg/kg/hour from hour 24 to 52nd hour; may reduce dose to 60 mcg/kg/hour based on tolerability

     -Phase 4: Decrease dose to 60 mcg/kg/hour from hour 52 to 56th hour

-Phase 5: Decrease to 30 mcg/kg/hour from hour 56 to the 60th hours

*Monitor patient for hypoxia using continuous pulse oximetry equipped with an alarm. Asses for excessive sedation every 3hours during planned, non-sleep periods.

*Renal Impairment: due to heavily excreted and filtered through kidneys. Clearance is 1 L/hr/kg

  -If Use not recommended in patients with end stage renal disease with eGFR < 15 mL/minute/1.73 m2

-No hepatic adjustment necessary

Systematic Review^4

Open-Label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. 

• Four women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD) score of ≥20, received brexanolone, titrated to a dose reflecting third-trimester allopregnanolone levels. 

• After 36-hours maintenance infusion, tapering occurred over 12 hours.

• Primary outcome was safety. Secondary outcome was efficacy.

• All patients completed the study. Fourteen adverse events were reported, non-were severe.

• Conclusions: brexanolone was well tolerated and proven to be efficacious. 

REMS Program^2

• Purpose of this program is to reduce the risk of serious harm from excessive sedation and sudden loss of consciousness.  Patients are informed of the risk while taking this medication and enrolled in this program for safety precautions. 

• There are no prescriber requirements. However, there are health care setting certification requirements. There must be a designated authorized representative that carries out the certification process and oversees the procedures and policy on behalf of the health care setting. Representative must review the training for health care setting, submit healthcare setting knowledge assessment, enroll health care setting into REMS Program, and train all relevant staff that are involved with prescribing and dispensing and administering Zulresso. In addition to that, the health care setting must verify that patient is enrolled in REMS program, has completed proper patient enrollment paper work, and has been counseled on signs and symptoms of black box warning and given a copy of material. Health care setting can no distribute, transfer, loan or sell Zulresso. Must maintain all records of staff training, shipments, and patient information. Including but not limited to dose, name, number of vials, and date administered. Can be audited and must comply. Health care setting must recertify if there has been a new authorized representative.

• Pharmacy must be certified and designated a representative to carry out the certification process on behalf of the pharmacy. This representative will review over the program; enrollment, training all relevant staff who dispense Zulressomedication at that pharmacy, and establish process and procedures at that pharmacy to ensure compliance. Each time Zulresso is about to be prepared, the pharmacist must verify certification of good standing of the health care center that will be administrating Zulresso. Pharmacy must agree to not distribute, transfer, loan or sell Zulresso unless receiving facility is also REMS certified.  

• Patient must be monitored for excessive sedation and loss of consciousness every 2 hours during administration. As well as monitoring patient oxygen saturation with pulse oximetry. 

• Within 3 business days Zulresso administration must be documented by post infusion form filled out by the health care facility. Should also document any excessive sedation or loss of conscious using the Excessive Sedation maintain records. In addition, health care facility must document every shipment received and dispensed. 

Summary

• ZULRESSO (brexanolone) mechanism of action is not fully understood but is thought to be related to positive allosteric modulation of GABA-A receptors

• Only comes in IV form and administered in a healthcare facility with medical supervision.

• First FDA approved drug that is indicated in postpartum depression

• Other Information:

~More studies need to be conducted to determine the significance of using

bexanolone in postpartum depression. 

~Must be a part of the REMS program

References: 

1. ZULRESSO Prescribing Information. Cambridge, MA: Stage therapeutics, Inc: 6/2019

2. Brexanolone In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated 2019 September 16

3. Zulresso. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated 2019 September 16

4. Brexanolone In: Micromedex Online [Internet Database]. IBM Micromedex, Corporation Updated 2019 September 16

5.  Kanes SJ, Colquhoun H, Doherty J, et al. Open-Label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Hum Psychopharmacol Clin Exp. 2017;32:e2576.https://doi.org/10.1002/hup.2576