Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2019012
Category:	Pharmacy
Initiated:	November 2019
Last Review:	November 2023

Brexanolone (e.g., Zulresso™)

Description:

Brexanolone is a neuroactive steroid gamma-aminobutyric acid (GABA). A receptor positive modulator indicated for the treatment of postpartum depression (PPD) in adults. This is the first drug approved by the FDA specifically for PPD, and received approval on March 19, 2019.

PPD is a temporal major depressive episode that may occur during pregnancy or within 4 weeks of delivery with an estimated prevalence of approximately 12% of births.1 As per estimates by Sage Therapeutics, the sponsor of brexanolone, PPD may affect 1 in 9 women who give birth in the U. S. per year which translates to 400000 incident cases annually.

As with other forms of depression, it is characterized by sadness and/or loss of interest in activities that one used to enjoy and a decreased ability to feel pleasure (anhedonia) and may present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, or suicidal ideation. Brexanolone is chemically similar to endogenous hormone allopregnanolone, which is a positive allosteric modulator of GABAA (γ aminobutyric acid-ligand gated chloride channel) receptors. The level of endogenous allopregnanolone increases during pregnancy, reach a peak during the third trimester but fall abruptly after delivery. It is hypothesized that a one-time administration of brexanolone infusion ameliorates symptoms of postpartum depression via positive allosteric modulation of both synaptic and extra synaptic GABAA receptors.

Brexanolone has a black box warning because individuals are at risk of excessive sedation or sudden loss of consciousness during administration. They must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring. Individuals must be accompanied during interactions with their child(ren). In addition, a healthcare provider must be available on site to continuously monitor the individual, and intervene as necessary, for the duration of the infusion.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

As of November 1, 2019 Prior Approval will be required for Brexanalone (e.g., Zulresso™)

The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.

EFFECTIVE November 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

Brexanolone meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for one time use per pregnancy for the treatment of severe postpartum depression in adult women when ALL the following conditions are met:

The individual is 15 years of age or older (FDA, 2019); AND

2. The individual must be < 6 months of delivery (Meltzer, 2018); AND

3. Individual meets the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for a major depressive episode by a structured clinical interview DSM-5 disorders; AND

4. Individual has an onset of depressive episode between 3rd trimester through 4 weeks post-partum (Meltzer, 2018); AND

5. Individual has a diagnosis of moderate to severe postpartum depression based on either of the following (Meltzer, 2018)*:

a. Hamilton Rating Scale for depression (Ham-D) score >20; OR

b. Individual Health Questionnaire – 9 (PHQ-9) score > 15; AND

*If Edinburg Postnatal Depression Scale (EPDS) > 10, further delineation of severity is required.

6. The individual must not have any of the following (Kanes, 2017):

a. Active psychosis; OR

b. Attempted suicide associated with index case of PPD; OR

c. History of seizures, bipolar disorder, schizophrenia, or schizoaffective disorder; OR

d. End-stage renal disease; AND

7. The prescriber is a specialist in the area of the individual's diagnosis (e.g. psychiatrist, Ob-Gyn) or the prescriber has consulted with a specialist in the area of the individual's diagnosis; AND

8. Must be performed in a contracted hospital facility (administration in ER or ASC is not allowed); a healthcare provider must be available on-site to continuously monitor the individual during the duration of the infusion (FDA, 2019); AND

9. The facility must be REMS certified for use of brexanolone* (FDA, 2019); AND

10. Must be dosed in accordane with the FDA label.

Dosage and Administration

Dosing per FDA Guidelines

Brexanolone is administered as an intravenous infusion over a total of 60 hours, (2.5 days) as follows:

0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hr
4 to 24 hours: Increase dosage to 60 mcg/kg/hr
24 to 52 hours: Increase dosage to 90 mcg/kg/hr (a reduction in dosage to 60 mcg/kg/hr may be considered during this time period for individuals who do not tolerate 90 mcg/kg/hr)
52 to 56 hours: Decrease dosage to 60 mcg/kg/hr
56 to 60 hours: Decrease dosage to 30 mcg/kg/hr

Brexanolone is available as 100 mg/20 mL (5 mg/mL) single-dose vial.

*Brexanolone is available only through a restricted program called the ZULRESSO REMS. Notable requirements include the following:

Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to individuals who are enrolled in the ZULRESSO REMS.

2. Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the ZULRESSO REMS.

3. Individuals must be enrolled in the ZULRESSO REMS prior to administration of brexanolone.

4. Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies.

Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for

pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of Brexanolone, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, brexanolone, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

EFFECTIVE August 24, 2022 to October 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Brexanolone meets primary coverage criteria that there be scientific evidence of effectiveness for one time use per pregnancy for the treatment of severe postpartum depression in adult women when ALL of the following conditions are met:

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

The individual is 15 years of age or older (FDA, 2019) AND

2. The individual must be <6 months of delivery (Meltzer, 2018) AND

3. Individual meets the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for a major depressive episode by a structured clinical interview DSM-5 disorders.

4. Individual has an onset of depressive episode between 3rd trimester through 4 weeks post-partum (Meltzer, 2018) AND

5. Individual has a diagnosis of moderate to severe postpartum depression based on either of the following (Meltzer, 2018)*:

Hamilton Rating Scale for depression (Ham-D) score >20 OR
Individual Health Questionnaire – 9 (PHQ-9) score > 15 AND

*If Edinburg Postnatal Depression Scale (EPDS) > 10, further delineation of severity is required.

6. The individual must not have any of the following (Kanes, 2017):

Active psychosis OR
Attempted suicide associated with index case of PPD OR
History of seizures, bipolar disorder, schizophrenia, or schizoaffective disorder OR
End-stage renal disease AND

7. The prescriber is a specialist in the area of the individual's diagnosis (e.g. psychiatrist, Ob-Gyn) or the prescriber has consulted with a specialist in the area of the individual's diagnosis AND

8. Must be performed in a contracted hospital facility (administration in ER or ASC is not allowed); a healthcare provider must be available on-site to continuously monitor the individual during the duration of the infusion (FDA, 2019) AND

9. The facility must be REMS certified for use of brexanolone* (FDA, 2019)

Dosage and Administration

Brexanolone is administered as an intravenous infusion over a total of 60 hrs, (2.5 days) as follows:

0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hr
4 to 24 hours: Increase dosage to 60 mcg/kg/hr
24 to 52 hours: Increase dosage to 90 mcg/kg/hr (a reduction in dosage to 60 mcg/kg/hr may be considered during this time period for individuals who do not tolerate 90 mcg/kg/hr)
52 to 56 hours: Decrease dosage to 60 mcg/kg/hr
56 to 60 hours: Decrease dosage to 30 mcg/kg/hr

*Brexanolone is available only through a restricted program called the ZULRESSO REMS. Notable requirements include the following:

Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to individuals who are enrolled in the ZULRESSO REMS.
Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the ZULRESSO REMS.
Individuals must be enrolled in the ZULRESSO REMS prior to administration of brexanolone.
Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies.

Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for

pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of Brexanolone does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than Severe Postpartum Depression.

For members with contracts without primary coverage criteria, brexanolone is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

EFFECTIVE JANUARY 2022 to August 23, 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

The individual is 18 yrs of age or older (FDA, 2019) AND

2. The individual must be <6 months of delivery (Meltzer, 2018) AND

3. Must meet the DSM-V criteria for a major depressive episode with onset of symptoms in the 3rd trimester or post-partum (Meltzer, 2018) AND

4. There is a diagnosis of severe postpartum depression based on either of the following (Meltzer, 2018)*:

Hamilton Rating Scale for depression (Ham-D) score >20 OR
Patient Health Questionnaire – 9 (PHQ-9) score > 15 AND

*If Edinburg Postnatal Depression Scale (EPDS) > 10, further delineation of severity is required.

5. The individual meets ONE of the following (Viguera, 2019):

Has tried and had an inadequate response to two antidepressant agents (individually or concurrently) from 2 different antidepressant classes (i.e. SSRIs, SNRIs, TCAs, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:

The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treatment physician at the generally accepted doses (and may begin with onset in the 2nd trimester): AND
The individual was >80% adherent to the agent during the trial OR

Has a documented intolerance or FDA labeled contraindication, to ALL classes of antidepressant agents; OR
Shows a potential risk of harm to self and/or others as determined by the treatment physician and supported by documentation AND

6. The member must not have any of the following (Kanes, 2017):

Active psychosis OR
Attempted suicide associated with index case of PPD OR
History of seizures, bipolar disorder, schizophrenia, or schizoaffective disorder OR
End-stage renal disease AND

7. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. psychiatrist, Ob-Gyn) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND

8. Must be performed in a contracted hospital facility (administration in ER or ASC is not allowed); a healthcare provider must be available on-site to continuously monitor the member during the duration of the infusion (FDA, 2019) AND

9. The facility must be REMS certified for use of brexanolone* (FDA, 2019)

Dosage and Administration

Zulresso is administered as an intravenous infusion over a total of 60 hrs, (2.5 days) as follows:

0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hr
4 to 24 hours: Increase dosage to 60 mcg/kg/hr
24 to 52 hours: Increase dosage to 90 mcg/kg/hr (a reduction in dosage to 60 mcg/kg/hr may be considered during this time period for patients who do not tolerate 90 mcg/kg/hr)
52 to 56 hours: Decrease dosage to 60 mcg/kg/hr
56 to 60 hours: Decrease dosage to 30 mcg/kg/hr

*Brexanolone is available only through a restricted program called the ZULRESSO REMS. Notable requirements include the following:

Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to patients who are enrolled in the ZULRESSO REMS.
Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the ZULRESSO REMS.
Patients must be enrolled in the ZULRESSO REMS prior to administration of brexanolone.
Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies.

Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for

pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

EFFECTIVE NOVEMBER 2019- DECEMBER 31, 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The individual is 18 yrs of age or older (FDA, 2019) AND

2. The individual must be <6 months of delivery (Meltzer, 2018) AND

3. Must meet the DSM-V criteria for a major depressive episode with onset of symptoms in the 2nd trimester or post-partum (Meltzer, 2018) AND

4. There is a diagnosis of severe postpartum depression based on either of the following (Meltzer, 2018)*:

Hamilton Rating Scale for depression (Ham-D) score >20 OR
Patient Health Questionnaire – 9 (PHQ-9) score > 15 AND

*If Edinburg Postnatal Depression Scale (EPDS) > 10, further delineation of severity is required.

5. The individual meets ONE of the following (Viguera, 2019):

Has tried and had an inadequate response to two antidepressant agents (individually or concurrently) from 2 different antidepressant classes (i.e. SSRIs, SNRIs, TCAs, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:

The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treatment physician at the generally accepted doses (and may begin with onset in the 2nd trimester): AND
The individual was >80% adherent to the agent during the trial OR

Has a documented intolerance or FDA labeled contraindication, to ALL classes of antidepressant agents; OR
Shows a potential risk of harm to self and/or others as determined by the treatment physician and supported by documentation AND

6. The member must not have any of the following (Kanes, 2017:

a. Active psychosis OR

b. Attempted suicide associated with index case of PPD OR

c. History of seizures, bipolar disorder, schizophrenia, or schizoaffective disorder OR

d. End-stage renal disease AND

7. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. psychiatrist, Ob-Gyn) or

the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND

8. Must be performed in a contracted hospital facility (administration in ER or ASC is not allowed); a healthcare provider must be available on-site to continuously monitor the member during the duration of the infusion (FDA, 2019) AND

9. The facility must be REMS certified for use of brexanolone* (FDA, 2019)

Dosage and Administration

Zulresso is administered as an intravenous infusion over a total of 60 hrs, (2.5 days) as follows:

0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hr
4 to 24 hours: Increase dosage to 60 mcg/kg/hr
24 to 52 hours: Increase dosage to 90 mcg/kg/hr (a reduction in dosage to 60 mcg/kg/hr may be considered during this time period for patients who do not tolerate 90 mcg/kg/hr)
52 to 56 hours: Decrease dosage to 60 mcg/kg/hr
56 to 60 hours: Decrease dosage to 30 mcg/kg/hr

*Brexanolone is available only through a restricted program called the ZULRESSO REMS. Notable requirements include the following:

Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to patients who are enrolled in the ZULRESSO REMS.
Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the ZULRESSO REMS.
Patients must be enrolled in the ZULRESSO REMS prior to administration of brexanolone.
Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies.

Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, brexanolone is considered investigational.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

A total of 267 patients were randomized in the 3 trials but 20 were not dosed and withdrew for personal reasons (n = 10) or were withdrawn because they no longer met study criteria in the time between randomization and scheduled treatment (n = 10). Overall, 94.7% of all patients completed the study. All 3 trials demonstrated a statistically and clinically significant difference in the least mean square change in HAM-D score at 60 hours after the infusion. However, the larger phase 3 trial (202B and 202C) revealed a smaller treatment effect than what was observed in the initial phase 2 trial (202A) (3.7 and 2.5 vs 12.2 respectively). The placebo-subtracted difference in HAM-D scores for both the 60 and 90 μg/kg/h doses (- 5.5 and -3.7, respectively) are consistent with the efficacy results of other, approved antidepressants. Clinically significant improvements in depression was also observed in the placebo arm. This was likely due to increased attention and care received from trained health professionals, as well as supportive care for babies while staying in the hospital.

Overall, the incidence of adverse events was similar between brexanolone and placebo arms (50 % vs 50.5% respectively). Two cases of serious adverse events were reported in brexanolone treated patients compared to none in placebo. In one patient in the 202B trial, a patient who received brexanolone 60 μg/kg/h reported suicidal ideation 2 days after infusion while another patient in the 202C trial who received brexanolone 90 μg/kg/h arm suffered from syncope/altered consciousness. In general, the incidence of sedation-related adverse events were observed at a higher frequency in brexanolone vs placebo-treated patients which is reflective of the primary pharmacology of brexanolone. The incidence of sedation/somnolence was 6% and 15% in patients treated with placebo and brexanolone (any dose) respectively. The incidence of dizziness, lightheadedness, presyncope or vertigo was 7% and 12% respectively.

The major safety concern observed with brexanolone was six subjects experienced loss of consciousness/syncope/presyncope during infusion. Of these six, one fainted with blood draw (fear of needles), one suffered presyncope/vertigo standing which was resolved after sitting and four appeared to have suddenly fallen asleep. These effects were resolved with dose interruption and all patients recovered in 10 to 60 minutes after loss of consciousness. As per the FDA the loss of consciousness can be abrupt, there is no known way to predict the risk of loss of consciousness which could result in serious harm, accident, or injury to the mother and, potentially to the infant. The observed incidence of loss of consciousness occurred in a clinical trial setting that required overnight accommodations for patients for approximately 72 hours, IV infusion capabilities, and the presence of a healthcare professional on site at all times. While the healthcare professional credentials varied between sites such as emergency medical technicians, nurses, and physicians, the majority of patients (85%) were dosed in a variety of non-hospital clinical research environments and 15% were dosed at units that were part of a hospital environment. In order to mitigate the risk of sudden loss of consciousness, the FDA has mandated a Risk Evaluation and Mitigation Strategy that requires administration of brexanolone only in medically-supervised settings.

The American Psychiatric Association guidelines for treatment of women with a major depressive disorder and who are pregnant or breastfeeding recommended psychotherapy without medication as a first-line treatment when the depression or anxiety is mild. For women with moderate or severe depression or anxiety, antidepressant medication should be considered as a primary treatment, according to the guidelines. 6

Antidepressant options during pregnancy:

Selective serotonin reuptake inhibitors (SSRIs): Work with your physician, but note that some SSRIs have been associated with a rare but serious lung problem in newborn babies (persistent pulmonary hypertension of the newborn).
Serotonin and norepinephrine reuptake inhibitors (SNRIs)
Bupropion (Wellbutrin)

Tricyclic antidepressants (TCAs)

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

Epperson CN, Rubinow DR, Meltzer-Brody S, et.al.,(2023) Effect of brexanolone on depressive symptoms, anxiety, and insomnia in women with postpartum depression: Pooled analyses from 3 double-blind, randomized, placebo-controlled clinical trials in the HUMMINGBIRD clinical program. J Affect Disord. 2023 Jan 1;320:353-359. doi: 10.1016/j.jad.2022.09.143. Epub 2022 Sep 30. PMID: 36191643.

Gelenberg A, Freeman M, Markowitz J, et al.(2010) Practice Guideline for the Treatment of Patients With Major Depressive Disorder (Third Edition) Accessed August 15, 2019

Kanes S, Colquhoun H, Gunduz-Bruce H, et al.(2017) Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. Jul 29 2017;390(10093):480-489. PMID 28619476 20.

Ko JY, Rockhill KM, Tong VT, et al.(2017) Trends in Postpartum Depressive Symptoms - 27 States, 2004, 2008, and 2012. MMWR Morb Mortal Wkly Rep. Feb 17 2017;66(6):153-158. PMID 28207685

Kroenke K, Spitzer RL.(2002) The PHQ-9: A New Depression Diagnostic and Severity Measure. Psychiatric Annals 2002; 32:509-521

Meltzer-Brody S, Colquhoun H, Riesenberg R, et al.(2018) Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. Sep 22 2018;392(10152):1058-1070. PMID 30177236 21.

U.S. Food and Drug Administration (FDA).(2021) 2019 Zulresso. Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211371s002lbl.pdf Last accessed August 24, 2021.

Viguera, A.(2019) Severe postpartum unipolar major depression: Choosing treatment. UpToDate. Retrieved August 24, 2021, from https://www.uptodate.com/contents/severe-postpartum-unipolar-major-depression-choosing-treatment?search=post%20partum%20depression%20treatment&source=search_result&selectedTitle=2~124&usage_type=default&display_rank=2 .

Zimmerman M, Martinez JH, Young D, et al.(2013) Severity classification on the Hamilton Depression Rating Scale. J Affect Disord. 2013 Sept 5;150(2):384-8. doi: 10.1016/j.jad.2013.04.028. Epub 2013 Jun 4.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.