Esketamine (SPRAVATO™) – Janssen

Kristen Schroeder, Pharm.D., St. Cloud VA

Indication: Esketamine is indicated for treatment-resistant major depressive disorder in adults.

Mechanism of Action: As suggested by its name, esketamine is the (S)-enantiomer of ketamine. It is a non-competitive NMDA receptor; however, the mechanism for its antidepressant effects remain unclear.

Dosage and Administration: Esketamine is administered intranasally. Each nasal spray device contains 28 mg esketamine. There are also 56 mg and 84 mg kits available. The dose is dependent on phase of therapy. During the induction phase (weeks 1-4), esketamine is given twice weekly. The first dose should be 56 mg, while all subsequent doses may be either 56 mg or 84 mg. During the maintenance phase (weeks 5-8), it is administered once weekly, and thereafter it may be given once or twice weekly based on response. The dose must be administered in a clinician’s office to allow for at least 2 hours of post-dose monitoring. Also, it is recommended that patients avoid eating for at least 2 hours and drinking for at least 30 minutes prior to use to decrease nausea risk.

Short-term study: In a 4-week study, esketamine in conjunction with a newly initiated oral antidepressant (AD) showed statistical superiority in reducing the Montgomery-Asberg Depression Rating Scale (MADRS) total score as compared to placebo plus an oral AD (least squares mean difference 4.0 [95% CI -7.3 - -0.6]).
Long-term study: Patients considered stable responders or remitters after at least 16 weeks of esketamine use were randomized to either continued esketamine or placebo. All subjects were taking concomitant oral AD. The primary endpoint was time to relapse, specified by MADRS score or other clinically relevant indication of relapse. Relapse was significantly delayed in the esketamine group compared to the placebo group. In the stable responders, the estimated hazard ratio of esketamine relative to placebo was 0.30 [95% CI 0.16 - 0.55]. In remitters, the estimated hazard ratio was 0.49 [95% CI 0.29 - 0.84], though noted this ratio was inconsistent throughout the trial.

Safety: Esketamine carries potential for misuse, and therefore was approved as a C-III drug with a risk evaluation and mitigation strategy (REMS).
Boxed warnings: Dissociation, sedation, and suicidal thoughts
Adverse effects: Impaired attention, judgment, thinking, reaction speed, and motor skills; nausea; dizziness; anxiety; transient blood pressure elevations (warranting monitoring before and after administration)
Contraindications: Aneurysmal vascular disease or arteriovenous malformation, intracerebral hemorrhage, or known hypersensitivity to ketamine. Esketamine should not be used in pregnant or breastfeeding women.

Place in Therapy: Esketamine may decrease depression symptoms and delay time to relapse when used as an adjunct to an oral AD in patients with treatment-resistant major depression. Clinical trials indicate that esketamine may provide benefit in those who have failed at least two other antidepressant therapies, and it is notable that careful adherence to REMS criteria is warranted. Cost is also likely to play a role in place in therapy, as Reuters predicts a cost of $590 for a 56 mg dose and $885 for an 84 mg dose.

1. Kelley KJ. FDA Approves Intranasal Esketamine as Adjunctive Treatment for Depression. NEJM Journal Watch. Published March 9, 2019. Accessed March 11, 2019.

2. SPRAVATO™ [package insert]. Titusville, NJ: Janssen Pharmaceutical Companies; 2019. Accessed March 11, 2019.