Postpartum depression is a mood disorder that can affect women after childbirth. In the United States, the reported rate of clinical postpartum depression among new mothers is between 10% to 20%. Although, there is a lack of official treatment guidelines for PPD, the choice of treatment has be guided by the same principles used for major depressive disorder (MDD), in addition to literature on breast milk exposure, and medication history, medications tried (successful and unsuccessful) of the mother. Current treatment includes cognitive-behavioral therapy and the use of antidepressants; selective serotonin reuptake inhibitors have become the mainstay of treatment for moderate to severe postpartum major depression.

The efficacy of Zulresso (brexanolone) in the treatment of postpartum depression (PPD) was demonstrated in two multicenter, randomized, double-blind, placebo-controlled studies in women 18 to 45 years with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-IV) with onset of symptoms in the third trimester or within 4 weeks of delivery. In these studies, patients received a 60-hour continuous intravenous infusion of Zulresso (brexanolone) or placebo and were then followed for 4 weeks. Study 1 (NCT02942004) included patients with severe PPD (Hamilton Depression Rating Scale (HAM-D) score ≥ 26), and Study 2 (NCT02942017) included patients with moderate PPD (HAM-D score of 20 to 25). A titration to the recommended target dosage of 90 mcg/kg/hour was evaluated in both studies (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 20 hours, 90 mcg/kg/hour for 28 hours, followed by a taper to 60 mcg/kg/hour for 4 hours and then 30 mcg/kg/hour for 4 hours). In both studies enrollees were followed for 30 days following infusion, no data is available past this 30 day mark.

The primary endpoint was the mean change from baseline in depressive symptoms as measured by the HAM-D total score at the end of the infusion (hour 60). A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at day 30. In both placebo-controlled studies, titration to a target dose of Zulresso (brexanolone) 90 mcg/kg/hour was superior to placebo in improvement of depressive symptoms. In study 1, results showed a mean change of -17.7 points from a mean baseline HAM-D score of 28.4 compared to a mean change of -14 points from a baseline HAM-D score of 28.6 in the placebo group. This was equivalent to a -3.7 point difference favoring Zulresso. In a group of 38 patients in Study 1, a Zulresso (brexanolone) titration to a target dose of 60 mcg/kg/hour was also superior to placebo in improvement of depressive symptoms; with a -5.5 point difference favoring Zulresso (brexanolone).

In study 2, patients received Zulresso at a target dose of 90mcg/kg/hr versus placebo. The primary endpoint was the same in Study 1, with a -2.5 point difference in the mean change from baseline in depressive symptoms measured by the HAM-D total score favoring Zulresso.

The 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.

As per the FDA approved package inset, Zulresso (brexanolone) has a Black Box Warning for Excessive Sedation and Sudden Loss Of Consciousness. Patients are at risk of excessive sedation or sudden loss of consciousness during administration of Zulresso. Because of the risk of serious harm, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring. Patients must be accompanied during interactions with their child(ren). Zulresso is available only through a restricted program called the Zulresso REMS.

As per the FDA approved package insert, available data from a lactation study in 12 women indicate that Zulresso (brexanolone) is transferred to breast milk in nursing mothers. The relative infant dose (RID) is low, 1% to 2% of the maternal weight-adjusted dosage. Also as Zulresso (brexanolone) has low oral bioavailability (<5%) in adults, infant exposure is expected to be low.

Policy:
(Note: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

1. Zulresso (brexanolone) is medically necessary for the following FDA approved indications when ALL of the following criteria are met:
• For the treatment of postpartum depression (PPD) in adults with all of the following:
  • Major Depressive Episode as diagnosed by Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) or Structured Clinical Interview for DSM-5 (SCID-5); AND
  • Member is ≤ 6 months postpartum; AND
  • Symptoms of depression began no earlier than the third trimester and no later than the first 4 weeks following delivery; AND
  • Member's diagnosis of moderate to severe postpartum depression is based on either of the following:
    • Hamilton Rating Scale for Depression (HAM-D) score ≥ 20; OR
    • Edinburgh Postnatal Depression Scale (EPDS) score ≥ 13; AND
  • The prescriber is a specialist in the area of the patient’s diagnosis (e.g. psychiatrist) or has consulted with a specialist in the area of the patient’s diagnosis AND
  • Provider, member, facility, and pharmacy must be enrolled in the Zulresso REMS (Risk Evaluation and Mitigation Strategy) program; AND
  • Member meets one of the following:
    • Has tried and had an inadequate response to one antidepressant agent 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:
      a. The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treating physician at the generally accepted doses; and
      b. Member 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 immediate harm to self and/or others as determined by the treating physician and supported by documentation.
[INFORMATIONAL NOTE: Hamilton Rating Scale for Depression (HAM-D) is a 21-question clinician-administered survey. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. The HAM-D is designed to rate the severity of depression in patients. The Score is based on first 17 questions. The HAM-D score classification may vary. Hamilton Rating Scale for Depression (HAM-D)
• As per the Journal of Neurology and Psychiatry:
  • 0-7: No Depression
  • 8-13: Mild Depression
  • 14-18: Moderate depression
  • 19-22: Severe Depression
  • ≥23: Very Severe Depression ]
• As per the Journal of Affective Disorders:
  • 0–7: No depression
  • 8–16: Mild Depression
  • 17–23: Moderate Depression
  • ≥24: Severe Depression

Edinburgh Postnatal Depression Scale (EPDS) is a self-report instrument containing 10 items that are ranked from 0 to 3 that reflect the patient's experience over the past week. The total score ranges from 0 to 30. An EPDS ≥ 13 is an acceptable cut-point for identifying women at risk for major depression in clinical settings.



EPDS Score	Interpretation	Action
Less than 8	Depression not likely	Continue support
9-11	Depression possible	Support, re-screen in 2-4 weeks. Consider referral to primary care provider (PCP)
12-13	Fairly high possibility of depression	Monitor, support and offer education. Refer to PCP
14 and higher (positive screen)	Probable depression	Diagnostic assessment and treatment by PCP and/or specialist
Positive score (1, 2, or 3) on question 10 (suicidality risk)		Immediate discussion required. Refer to PCP and/or mental health specialist or emergency resource for further assessment and intervention as appropriate. Urgency of referral will depend on several factors including: whether the suicidal ideation is accompanied by a plan, whether there has been a history of suicide attempts, whether symptoms of a psychotic disorder are present and/or there is a concern about harm to the baby

DSM-IV Criteria for Major Depressive Disorder (MDD)
A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly attributable to another medical condition.
1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.)
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation).
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.)
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.
B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C. The episode is not attributable to the physiological effects of a substance or another medical condition.
D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders.
E. There has never been a manic episode or a hypomanic episode.

DSM-V Criteria was published in 2013 by the American Psychiatric Association as an update to DSM-IV criteria. In terms of diagnosis criteria for depression there are no changes. The only change included removal of the bereavement exclusion: Highlighted change from DSM-IV to DSM-V: Depression (as per the American Psychiatric Association)

In DSM-IV, there was an exclusion criterion for a major depressive episode that was applied to depressive symptoms lasting less than 2 months following the death of a loved one (i.e., the bereavement exclusion). This exclusion is omitted in DSM-5 for several reasons, including the recognition that bereavement is a severe psychosocial stressor that can precipitate a major depressive episode in a vulnerable individual, generally beginning soon after the loss, and can add an additional risk for suffering, feelings of worthlessness, suicidal ideation, poorer medical health, and worse interpersonal and work functioning. It was critical to remove the implication that bereavement typically lasts only 2 months, when both physicians and grief counselors recognize that the duration is more commonly 1–2 years. A detailed footnote has replaced the more simplistic DSM-IV exclusion to aid clinicians in making the critical distinction between the symptoms characteristic of bereavement and those of a major depressive disorder. Finally, a new specifier to indicate the presence of mixed symptoms has been added across both the bipolar and the depressive disorders.]

2. When Zulresso (brexanolone) is medically necessary, therapy will be approved at the FDA recommended dosage of:
• Administered as a continuous intravenous infusion over 60 hours (2.5 days) as follows
  • 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour
  • 4 to 24 hours: Increase dosage to 60 mcg/kg/hour
  • 24 to 52 hours: Increase dosage to 90 mcg/kg/hour*
  • 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour
  • 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour
[INFORMATIONAL NOTE: *A dosage of 60 mcg/kg/hour can be considered for those who do not tolerate 90 mcg/kg/hour.]

3. Use of Zulresso (brexanolone) beyond one treatment course per pregnancy is considered investigational.

[INFORMATIONAL NOTE: Patients in clinical trials received only 1 dose of treatment and were followed out to 30 days post treatment. No long term data is currently available on repeat dosing regarding multiple pregnancies.]

4. Other uses of Zulresso (brexanolone) are considered investigational.


Medicare Coverage

There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this drug. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ medical policy.