Out Of The Pipeline

Brexanolone injection for postpartum depression

Current Psychiatry. 2019 September;18(9):43-48

References

1. Ko JY, Rockhill KM, Tong VT, et al. Trends in postpartum depressive symptoms - 27 states, 2004, 2008, and 2012. MMWR Morb Mortal Wkly Rep. 2017;66(6):153-158.
2. Frieder A, Fersh M, Hainline R, et al. Pharmacotherapy of postpartum depression: current approaches and novel drug development. CNS Drugs. 2019;33(3):265-282.
3. Brexanolone injection [package insert]. Cambridge, MA: Sage Therapeutics, Inc.; 2019.
4. Bodnar-Deren S, Klipstein K, Fersh M, et al. Suicidal ideation during the postpartum period. J Womens Health (Larchmt). 2016;25(12):1219-1224.
5. Netsi E, Pearson RM, Murray L, et al. Association of persistent and severe postnatal depression with child outcomes. JAMA Psychiatry. 2018;75(3):247-253.
6. Goodman JH. Paternal postpartum depression, its relationship to maternal postpartum depression, and implications for family health. J Adv Nurs. 2004;45(1):26-35.
7. Gelenberg AJ, Freeman MP, Markowitz JC, et al; American Psychiatric Association Work Group on Major Depressive Disorder. Practice guidelines for the treatment of patients with major depressive disorder. 3rd ed. Washington, DC: American Psychiatric Association; 2010.
8. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
9. Molyneaux E, Telesia LA, Henshaw C, et al. Antidepressants for preventing postnatal depression. Cochrane Database Syst Rev. 2018;4:CD004363.
10. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390(10093):480-489.
11. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058-1070.
12. Melon LC, Hooper A, Yang X, et al. Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice. Psychoneuroendocrinology. 2018;90:182-193.
13. Deligiannidis KM, Fales CL, Kroll-Desrosiers AR, et al. Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study. Neuropsychopharmacology. 2019;44(3):546-554.
14. Licheri V, Talani G, Gorule AA, et al. Plasticity of GABAA receptors during pregnancy and postpartum period: from gene to function. Neural Plast. 2015;2015:170435. doi: 10.1155/2015/170435.
15. Luisi S, Petraglia F, Benedetto C, et al. Serum allopregnanolone levels in pregnant women: changes during pregnancy, at delivery, and in hypertensive patients. J Clin Endocrinol Metab. 2000;85(7):2429-2433.
16. Hoffmann E, Wald J, Dray D, et al. Brexanolone injection administration to lactating women: breast milk allopregnanolone levels [30J]. Obstetrics & Gynecology. 2019;133:115S.

Suicidality. The risk of developing suicidal thoughts and behaviors with brexanolone is unknown, due to the relatively low number of exposures to brexanolone injection during clinical development and a mechanism of action distinct from that of existing antidepressant medications.³

Pharmacokinetics

In clinical trials, brexanolone exhibited dose-proportional pharmacokinetics, and the terminal half-life is approximately 9 hours (Table 4³). Brexanolone is metabolized by non-cytochrome P450 (CYP)-based pathways, including keto-reduction, glucuronidation, and sulfation.³ No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal or hepatic impairment, and no studies were conducted to evaluate the effects of other drugs on brexanolone.³

Lactation. A population pharmacokinetics model constructed from studies in the clinical development program calculated the maximum relative infant dose for brexanolone during infusion as 1.3%.³ Given the low oral bioavailability of brexanolone (<5%) in adults, the potential for breastfed infant exposure is considered low.³

Clinical considerations

Risk Evaluation and Mitigation Strategies (REMS) requirements. Brexanolone injection is a Schedule IV controlled substance. It has a “black-box” warning regarding excessive sedation and sudden loss of consciousness, which has been taken into account within the REMS drug safety program. Health care facilities and pharmacies must enroll in the REMS program and ensure that brexanolone is administered only to patients who are enrolled in the REMS program. Staff must be trained on the processes and procedures to administer brexanolone, and the facility must have a fall precautions protocol in place and be equipped with a programmable peristaltic IV infusion pump and continuous pulse oximetry with alarms.³

Monitoring. A REMS-trained clinician must be available continuously on-site to oversee each patient for the duration of the continuous IV infusion, which lasts 60 hours (2.5 days) and should be initiated early enough in the day to allow for recognition of excessive sedation. Patients must be monitored for hypoxia using continuous pulse oximetry equipped with an alarm and should also be assessed for excessive sedation every 2 hours during planned, non-sleep periods. If excessive sedation occurs, the infusion should be stopped until symptoms resolve, after which the infusion may be resumed at the same or a lower dose as clinically appropriate. In case of overdosage, the infusion should be stopped immediately and supportive measures initiated as necessary. Patients must not be the primary caregiver of dependents, and must be accompanied during interactions with their child(ren).

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Brexanolone injection for postpartum depression

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Pharmacokinetics

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