New Drug Review: Spravato

In March, the FDA approved intranasal esketamine (Spravato, Janssen), when used in conjunction with an oral antidepressant, for treatment of depression in adults who have not benefitted from other antidepressant medications. Esketamine is the s-enantiomer of racemic ketamine and functions as an N-methyl-D-aspartate (NMDA) receptor antagonist that leads to alleviation of treatment-resistant depression (TRD).¹

Efficacy

Esketamine was evaluated in two phase 3 randomized double-blind multicenter placebo-controlled trials. In one trial, patients meeting DSM-V criteria for TRD (defined as treatment with at least two different antidepressants trialed for adequate dose and duration) were randomized to receive flexible dose (56 mg or 84 mg) intranasal esketamine plus an oral antidepressant or intranasal placebo plus an oral antidepressant. Esketamine and oral antidepressant was significantly better at controlling depression; a significant reduction (-4) in the change from baseline score in the Montgomery-Asberg Depression Rating Scale (MADRS) at week 4.² In the second trial, patients who were responders or remitters to esketamine after at least 16 weeks of therapy were randomized to either continue receiving intranasal treatment and an oral antidepressant or placebo and an oral antidepressant for long-term variable duration. The primary efficacy measure was time to relapse. Both responder and remitter patients experienced a statistically significant longer time to relapse with esketamine compared to the placebo.³

Safety

The most common adverse events were dissociation (41%), dizziness (29%), nausea (28%), sedation (23%), vertigo (23%), headache (20%), dysgeusia (19%), hypoesthesia (18%), lethargy (11%), and increased blood pressure (10%). Drug-related side effects could affect driving; patients should not drive or operate heavy machinery until the next day, after a restful sleep.

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Geriatric use of esketamine was supported by data from clinical trials. No significant differences in safety were observed between the 65 and older group and younger groups. 

Physical dependence is reported with prolonged use of large doses of ketamine; no withdrawal symptoms were reported with recommended esketamine use up to 4 weeks after discontinuation. However, dependence may occur in patients who abuse esketamine or take doses larger than recommended.

Dosing

Esketamine induction phase dosing is 56 mg intranasally on day 1, then twice weekly administration of 56 mg or 84 mg weeks 1 through 4. During weeks 5 through 8 of the maintenance phase, patients are administered 56 mg or 84 mg intranasally once weekly. During weeks 9 and onwards, patients are maintained at 56 mg or 84 mg intranasally once weekly or once every 2 weeks.⁴

A healthcare provider must administer this drug in a clinic. The patient must remain for at least 2 hours and have prearranged transportation home. Patients must also enroll in the risk evaluation and mitigation strategy program. Blood pressure should be monitored before and after treatment. If blood pressure is under 140/90 mmHg, consider waiting for blood pressure to fall before administering esketamine. After administration, blood pressure should be monitored for 2 hours. If blood pressure remains elevated 40 minutes postdose, refer patient for immediate emergency care. 

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Patients using a nasal decongestant or nasal corticosteroid should administer medications at least 1 hour before esketamine use. Because nausea and vomiting are common side effects, patients should avoid eating food for at least 2 hours and avoid drinking liquids for at least 30 minutes before administration. 

Dose adjustments are not recommended for patients with renal or hepatic insufficiency. Use of esketamine is not recommended in patients with Child-Pugh C hepatic dysfunction.

_References

_{1. Spravato [package insert]. Janssen Pharmaceuticals, Inc; 2019. Available at https://bit.ly/2Yo7fFA.}

_{2. ClinicalTrials.gov. Identified NCT02418585; A study to evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression (TRANSFORM-2), Available at https://bit.ly/2sHj6ia.} 

_{3. ClinicalTrials.gov. Identified NCT02493868; A study of intranasal esketamine plus an oral antidepressant for relapse prevention in adult participants with treatment-resistant depression (SUSTAIN-1). Available at https://bit.ly/2sj1ifD.} 

_{4. Esketamine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Accessed March 7, 2019.}