Version May 2024
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).
Because of these risks, brexanolone is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZULRESSO REMS.
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
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR ≥15 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <15 mL/minute/1.73 m2: Use not recommended.
No dosage adjustment necessary.
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.
(For additional information see "Brexanolone: Pediatric drug information")
Depression, postpartum: Note: A health care provider must be onsite to monitor and intervene as necessary for entire duration of the infusion.
Adolescents ≥15 years: Continuous IV infusion over 60 hours; initiate continuous infusion early enough in the day to allow for recognition of excessive sedation; titrate the dose as follows:
0 to 4 hours: IV: 30 mcg/kg/hour.
4 to 24 hours: IV: 60 mcg/kg/hour.
24 to 52 hours: IV: 90 mcg/kg/hour; may reduce to 60 mcg/kg/hour if higher dose not tolerated.
52 to 56 hours: IV: 60 mcg/kg/hour.
56 to 60 hours: IV: 30 mcg/kg/hour.
Dosage adjustment for toxicity: Adolescents ≥15 years:
Excessive sedation: Immediately stop infusion at any sign of excessive sedation; after resolution, may resume infusion at the same or reduced dose, as clinically appropriate.
Hypoxia: Immediately stop infusion if pulse oximetry indicates hypoxia; do not resume therapy.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Adolescents ≥15 years:
eGFR ≥15 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <15 mL/minute/1.73 m2: Avoid use due to potential accumulation of solubilizing agent, betadex sulfobutyl ether sodium.
Adolescents ≥15 years: No dosage adjustment necessary.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Excessive sedation and sudden loss of consciousness: 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.
Other warnings/precautions:
• Risk Evaluation and Mitigation Strategy (REMS): 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. Health care 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Zulresso: 100 mg/20 mL (20 mL)
No
Solution (Zulresso Intravenous)
100 mg/20 mL (per mL): $447.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
C-IV
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.
IV: Administer as a continuous IV infusion over 60 hours; infusion rate is weight-based and titrated throughout infusion (see "Dosing: Pediatric"); use 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. Monitor sedation levels and pulse oximetry for duration of the infusion.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Zulresso: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211371s007lbl.pdf#page=20
Depression, postpartum: Treatment of postpartum depression in patients ≥15 years of age.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification
BuPROPion: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: 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. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: 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. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Isocarboxazid: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Moclobemide: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Phenelzine: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Selegiline: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Serotonin Reuptake Inhibitor/Antagonists: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Tranylcypromine: May enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
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).
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to brexanolone may cause fetal harm.
Data collection to monitor pregnancy outcomes following exposure to brexanolone is ongoing. Health care providers are encouraged to enroll patients exposed to brexanolone during pregnancy in the National Pregnancy Registry for Antidepressants (844-405-6185) or https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants/.
Brexanolone is present in breast milk.
Information related to the presence of brexanolone in breast milk is available from 12 lactating females ≤6 months postpartum following infusion of brexanolone over 60 hours (maximum dose 90 mcg/kg/hour). Breast milk concentrations approximated those in the maternal plasma (average concentration 70.56 ng/mL) and rapidly declined to below the limit of detection (<10 ng/mL) in 95% of the women within 36 hours after completion of the infusion. Infants were not breastfed during the study (Hoffmann 2019). The manufacturer calculated the maximum relative infant dose (RID) of brexanolone during the infusion to be 1% to 2% of the weight adjusted maternal dose. In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
In addition to limited concentrations of brexanolone in breast milk, the low oral bioavailability of brexanolone (<5%) should also limit potential infant exposure via breast milk; however, patients are at risk of excessive sedation or sudden loss of consciousness during administration of brexanolone. Because of the risk of serious harm, patients must be supervised during interactions with their children or infants. A caregiver should be present to assist patients who are breastfeeding or who pump breast milk to maintain milk supply during the infusion (Rosen-Carole 2021).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Patients breastfeeding prior to infusion should receive education regarding the need for close supervision if breastfeeding is continued. If the decision is made not to breastfeed during therapy, the patient should be supported in maintaining a milk supply and other feeding options if breast milk is not available (Rosen-Carole 2021).
Continuous pulse oximetry; sedation every 2 hours during planned, non-sleep periods; suicidal ideation
Mechanism of action is not fully understood, but is thought to be related to positive allosteric modulation of GABA-A receptors.
Distribution: Vd: ~3 L/kg
Protein binding: >99%
Metabolism: Extensively metabolized by keto-reduction (AKRs), glucuronidation (UGTs), and sulfation (SULTs) to inactive metabolites
Half-life elimination: ~9 hours
Excretion: Feces: 47%; Urine: 42% (<1% as unchanged drug)
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