Clinical Pharmacology Corner: FDA Approves SPRAVATO (Esketamine) Nasal Spray in Conjunction with an Oral Antidepressant for the Treatment of Treatment-Resistant Depression (TRD) in Adults

FDA Approves SPRAVATO (Esketamine) Nasal Spray in Conjunction with an Oral Antidepressant for the Treatment of Treatment-Resistant Depression (TRD) in Adults

On March 5, 2019, the U.S. Food and Drug Administration (FDA) approved SPRAVATO (esketamine) nasal spray in conjunction with an oral antidepressant for the treatment of treatment-resistant depression (TRD) in adults. The approved recommended dosage of SPRAVATO is the following: 

• Induction Phase (Weeks 1 to 4): Administer a Day 1 starting dose of 56 mg and subsequent doses of 56 mg or 84 mg twice per week

• Maintenance Phase (Weeks 5 to 8): Administer 56 or 84 mg once weekly

• Maintenance Phase (Weeks 9 and After): Administer 56 mg or 84 mg every 2 weeks or once weekly with dosing frequency being individualized to the least frequent dosing to maintain remission/response

Administer SPRAVATO intranasally under the supervision of a healthcare provider. Assess blood pressure prior to dosing with SPRAVATO, after dosing with SPRAVATO at approximately 40 minutes (which corresponds with the C_max), and subsequently as clinically warranted. Dosage adjustments should be made based on efficacy and tolerability. Evaluate patient for evidence of therapeutic benefit at the end of the induction phase to determine need for continued treatment. Additional information regarding dosage and administration can be found in the full prescribing information linked below.

SPRAVATO is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral hemorrhage. Due to risk of sedation and dissociation after administration, monitor patients for at least two hours after administration followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting. Monitor patients for signs of abuse or misuse. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Additional information regarding contraindications, warnings, and precautions can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Esketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.

General PK: Increases in esketamine C_max and AUC values were less than dose-proportional between 28 mg and 56 mg or 84 mg, but were nearly dose proportional between 56 mg and 84 mg. No accumulation of esketamine in plasma was observed following twice a week administration.

Absorption: The mean absolute bioavailability is approximately 48% following nasal spray administration. Esketamine T_max is 20 to 40 minutes after the last nasal spray of a treatment session.  

Distribution: The mean steady-state volume of distribution of esketamine administered by the intravenous route is 709 L. Protein binding of esketamine was approximately 43% to 45%. The brain-to-plasma ratio of noresketamine, the primary metabolite of esketamine, is 4- to 6-times lower than that of esketamine.

Elimination: Mean terminal half-life (t_1/2) ranged from 7 to 12 hours for esketamine and was approximately 8 hours for noresketamine. Mean clearance of esketamine is approximately 89 L/hour following intravenous administration.

Metabolism: Esketamine is primarily metabolized to noresketamine metabolite via CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19. Noresketamine is metabolized via CYP-dependent pathways and certain subsequent metabolites undergo glucuronidation.

Excretion: Less than 1% of a dose of nasal esketamine is excreted as unchanged drug in urine. Following intravenous or oral administration, esketamine-derived metabolites were primarily recovered in urine (≥ 78% of a radiolabeled dose) and to a lesser extent in feces (≤ 2% of a radiolabeled dose).

Drug Interactions

• Central Nervous System Depressants: Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants. Concomitant use with CNS depressants may increase sedation.

• Psychostimulants: Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants. Concomitant use with psychostimulants may increase blood pressure.

• Monoamine Oxidase Inhibitors: Closely monitor blood pressure with concomitant use of SPRAVATO with MAOIs. Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure.

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of SPRAVATO nasal spray were observed based on age, sex, race/ethnicity, total body weight (> 39 to 170 kg), and renal impairment.  The pharmacokinetics of SPRAVATO nasal spray has not been studied in patients on renal dialysis.
 
Hepatic Impairment
Mean esketamine AUC and t_1/2 values were higher in patients with moderate hepatic
impairment compared to those with normal hepatic function. SPRAVATO-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time. SPRAVATO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and therefore use in this population is not recommended.

Efficacy and Safety

Efficacy of SPRAVATO was demonstrated in a randomized, placebo-controlled, double-blind, multicenter short-term (4 week), Phase 3 study in adult patients 18 to < 65 years old with treatment-resistant depression (TRD), and in a long-term randomized, double-blind, parallel-group, multicenter maintenance-of-effect study in adults 18 to < 65 years of age who were known remitters and responders to SPRAVATO. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.

The most commonly observed adverse reactions (incidence ≥ 5% and at least twice that of placebo plus oral antidepressant) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk.

_________________________________________________________________________

Full prescribing information is available at https://go.usa.gov/xEHkm.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at https://updates.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.