ppetite, and anxiety. Therefore, monitor SPRAVATO-treated patients forsymptoms and signs of physical dependence upon the discontinuation of the drug.
Tolerance has been reported with prolonged use of ketamine. Tolerance is a physiological statecharacterized by a reduced response to a drug after repeatedadministration (i.e., a higher dose ofa drug is required to produce the same effect that was once obtained at a lower dose). Similar
tolerance would be expected with prolonged use of esketamine.
10 OVERDOSAGE
Management of Overdosage
There is no specific antidote for esketamine overdose. In the case of overdose, the possibility ofmultiple drug involvement should be considered. Contact a Certified Poison Control Center forthe most up to date information on the management of overdosage (1-800-222-1222 orwww.poison.org).
11 DESCRIPTION
SPRAVATO contains esketamine hydrochloride, a non-competitive N-methyl-D-aspartate(NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine. The
chemical name is (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. Itsmolecular formula is C13H16ClNO.HCl and its molecular weight is 274.2. Thestructural formula
is:
Esketamine hydrochloride is a white or almost white crystalline powder that is freely soluble inwater and in methanol, and soluble in ethanol.
SPRAVATO nasal spray is intended for nasal administration. Esketamine hydrochloride iscontained as a solution in a stoppered glass vial within the nasal spray device. Each devicedelivers two sprays with a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg ofesketamine) in 0.2 mL of a clear, colorless aqueous solution with a pH of 4.5.
The inactive ingredients are citric acid monohydrate, edetate disodium, sodium hydroxide, andwater for injection.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitiveantagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.
Themechanism by which esketamine exerts its antidepressant effect is unknown. The majorcirculating metabolite of esketamine (noresketamine) demonstrated activity at the same receptorwith less affinity.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of SPRAVATO (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infusedover 40 minutes) on the QTc interval was eva luated in a randomized, double-blind, placebo-, andpositive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. Alarge increase in heart rate (i.e. >10 bpm) was observed in both intranasal and intravenousesketamine treatment groups. The totality of evidence from the nonclinical and clinical dataindicates a lack of clinically relevant QTc prolongation at the therapeutic dose of esketamine.
12.3 Pharmacokinetics
Esketamine exposure increases with dose from 28 mg to 84 mg. The increase in Cmax and AUC
values was less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was 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.
The time to reach maximum esketamine plasma concentration is 20 to 40 minutes after the lastnasal spray of a treatment session.
The inter |
