endpoint of change from baseline to Week 4 on the Montgomery-Asberg Depression Rating Scale(MADRS).
8.6 Hepatic Impairment
The mean esketamine AUC and t1/2 values were higher in patients with moderate hepaticimpairment compared to those with normal hepatic function [see Clinical Pharmacology (12.3)].
SPRAVATO-treated patients with moderate hepatic impairment may need to be monitored foradverse reactions for a longer period of time.
SPRAVATO has not been studied in patients with severe hepatic impairment(Child-Pugh class C). Use in this population is not recommended [see Clinical Pharmacology
(12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
SPRAVATO contains esketamine hydrochloride, the (S)-enantiomer of ketamine and a ScheduleIII controlled substance under the Controlled Substances Act.
9.2 Abuse
Individuals with a history of drug abuse or dependence may be at greater risk for abuse andmisuse of SPRAVATO. Abuse is the intentional, non-therapeutic use of a drug, even once, for itspsychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, ofa drug by an individual in a way other than prescribed by a health care provider or for whom itwas not prescribed. Careful consideration is advised prior to use of individuals with a history ofsubstance use disorder, including alcohol.
SPRAVATO may produce a variety of symptoms including anxiety, dysphoria, disorientation,insomnia, flashback, hallucinations, and feelings of floating, detachment and to be “spaced out”.Monitoring for signs of abuse and misuse is recommended.
Abuse Potential Study
A cross-over, double-blind abuse potential study of SPRAVATO and ketamine was conducted inrecreational polydrug users (n=34) who had experience with perception-altering drugs, includingketamine. Ketamine, the racemic mixture of arketamine and esketamine, is a Schedule IIIcontrolled substance and has known abuse potential. In this study, the mean “Drug Liking at theMoment” and “Take Drug Again” scores for single doses of intranasal SPRAVATO (84 mg and112 mg – the maximum recommended dose and 1.3 times the maximum recommended dose,respectively) were similar to these scores in the intravenous ketamine (0.5 mg/kg infused over40 minutes) control group. However, these scores were greater in the SPRAVATO and ketaminegroups compared to the placebo group. The 112 mg dose of intranasal SPRAVATO wasassociated with significantly higher scores for “Hallucinating,” “Floating,” “Detached,” and“Spaced Out” than the 84 mg dose of intranasal SPRAVATO and the intravenous ketamine dose.
9.3 Dependence
Physical dependence has been reported with prolonged use of ketamine. Physical dependence isa state that develops as a result of physiological adaptation in response to repeated drug use,manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosagereduction of a drug. There were no withdrawal symptoms captured up to 4 weeks after cessationof esketamine treatment. Withdrawal symptoms have been reported after the discontinuation offrequently used (more than weekly) large doses of ketamine for long periods of time. Suchwithdrawal symptoms are likely to occur if esketamine were similarly abused. Reportedsymptoms of withdrawal associated with daily intake of large doses of ketamine include craving,fatigue, poor a |
