Brexanolone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Zulresso: 100 mg/20 mL (20 mL)

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: ~3 L/kg

Metabolism

Extensively metabolized by keto-reduction (AKRs), glucuronidation (UGTs), and sulfation (SULTs) to inactive metabolites

Excretion

Feces: 47%; Urine: 42% (<1% as unchanged drug)

Half-Life Elimination

~9 hours

Protein Binding

>99%

Use: Labeled Indications

Depression, postpartum: Treatment of postpartum depression (PPD) in adults

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Depression, postpartum: IV: Note: Initiate 60-hour continuous infusion early enough in the day to allow for recognition of excessive sedation. Titrate the dose as detailed.

0 to 4 hours: 30 mcg/kg/hour

4 to 24 hours: 60 mcg/kg/hour

24 to 52 hours: 90 mcg/kg/hour; may reduce dose to 60 mcg/kg/hour based on tolerability

52 to 56 hours: 60 mcg/kg/hour

56 to 60 hours: 30 mcg/kg/hour

Dosing: Adjustment for Toxicity

Excessive sedation: Immediately stop infusion at any sign of excessive sedation. After symptoms resolve, infusion may be resumed at the same or reduced dose, as clinically appropriate.

Hypoxia: Immediately stop infusion if pulse oximetry indicates hypoxia. Do not resume therapy.

Reconstitution

Withdraw 20 mL of brexanolone from the vial and place in a polyolefin, non-DHEP, nonlatex bag. Dilute with 40 mL SWFI and further dilute with 40 mL NS to a total volume of 100 mL (target concentration 1 mg/mL). Each 60-hour infusion will generally require preparation of 5 infusion bags; additional bags may be required for patients weighing ≥90 kg.

Administration

IV: Administer as a continuous infusion over 60 hours in a dedicated line using a programmable peristaltic infusion pump. Prime infusion administration sets with admixture before inserting into the pump and connecting to the venous catheter. Use a PVC, non-DHEP, nonlatex infusion set; do not use in-line filter infusion sets.

Storage

Undiluted vials: Store vials at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light.

Diluted infusion solution: Infusion bags may be used at room temperature for up to 12 hours or stored under refrigeration for up to 96 hours.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

BuPROPion: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Isocarboxazid: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Moclobemide: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenelzine: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Selegiline: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Serotonin Reuptake Inhibitor/Antagonists: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tranylcypromine: May enhance the CNS depressant effect of Brexanolone. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Presyncope (≤13%)

Central nervous system: Drowsiness (≤21%), sedated state (≤21%), dizziness (≤13%), vertigo (≤13%)

Gastrointestinal: Xerostomia (3% to 11%)

1% to 10%:

Cardiovascular: Flushing (≤5%), tachycardia (3%)

Central nervous system: Loss of consciousness (3% to 5%)

Endocrine & metabolic: Hot flash (≤5%)

Gastrointestinal: Diarrhea (2% to 3%), dyspepsia (2%)

Respiratory: Oropharyngeal pain (2% to 3%)

<1%, postmarketing, and/or case reports: Impaired consciousness

Warnings/Precautions

Concerns related to adverse effects:

• Excessive sedation and sudden loss of consciousness: [US Boxed Warning]: Patients treated with brexanolone are at risk of excessive sedation or sudden loss of consciousness during administration. 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). Consider dose interruption and/or reduction, or discontinuation with excessive sedation. Time to full recovery after dose interruption following altered or loss of consciousness ranged from 15 to 60 minutes. Caution patients about performing tasks that require mental alertness following the infusion (eg, operating machinery or driving).
• Suicidal thoughts and behaviors: The risk of suicidal thoughts and behaviors with brexanolone is unknown. Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor all patients for clinical worsening, suicidality, or unusual changes in behavior. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients who experience worsening depression or emergent suicidal thoughts and behaviors.

Disease-related concerns:

• Drug abuse and dependence: May lead to abuse and dependence. Taper according to dose recommendations unless toxicity requires immediate interruption/discontinuation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Risk Evaluation and Mitigation Strategy (REMS): [US Boxed Warning]: Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness, brexanolone is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZULRESSO REMS. Healthcare facilities and pharmacies must be certified with the REMS program and patients must enroll in the program prior to administration. A list of certified healthcare facilities is available at www.zulressorems.com or 1-844-472-4379.

Monitoring Parameters

Continuous pulse oximetry; sedation every 2 hours during planned, non-sleep periods; suicidal ideation

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to brexanolone may cause fetal harm.

In clinical studies for postpartum depression, treatment was started within 6 months after delivery. Study participants were required to have a negative pregnancy test and use contraception during therapy and for 30 days after completion of the brexanolone infusion (Meltzer-Brody 2018).

Data collection to monitor pregnancy outcomes following exposure to brexanolone is ongoing. Health care providers are encouraged to enroll females exposed to brexanolone during pregnancy in the National Pregnancy Registry for Antidepressants (844-405-6185) or https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants/.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience dizziness, dry mouth, or flushing. Have patient report immediately to prescriber signs of depression (thoughts of suicide, anxiety, emotional instability, or confusion), agitation, irritability, panic attacks, behavioral changes, mood changes, severe fatigue, or passing out (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.