The Food and Drug Administration (FDA) has issued an alert regarding the potential risks associated with the use of compounded ketamine nasal spray to treat psychiatric disorders.
Compounded drugs are not FDA-approved and have not been evaluated for safety, efficacy, or quality prior to marketing. Ketamine is a racemic mixture containing 2 mirror image molecules, R- and S-ketamine. Ketamine hydrochloride (Ketalar), a schedule III controlled substance, is FDA-approved for induction and maintenance of general anesthesia and is administered by the intravenous or intramuscular route. The FDA-approved labeling for ketamine warns of potential hemodynamic instability and emergence reactions, including delirium and neuropsychological manifestations.
Esketamine (Spravato), the S-enantiomer of racemic ketamine, is a schedule III controlled substance approved by the FDA in a nasal spray formulation for treatment-resistant depression in adults, as well as depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Spravato carries a Boxed Warning regarding the risk for sedation, dissociation, abuse/misuse, and suicidal thoughts and behaviors. It is only available through a restricted program called the Spravato REMS.
Esketamine and racemic ketamine are not the same drug. In animal studies, the use of racemic ketamine has been shown to cause brain lesions in rodents, whereas this association was not observed with esketamine. The relevance of this finding to humans is unknown.
In recent years, the FDA has received a number of reports of pharmacies compounding nasal spray formulations of ketamine either alone or in combination other ingredients. A search of the FDA Adverse Event Reporting System (FAERS) database and the medical literature revealed 5 cases that were associated with psychiatric events, as well as abuse and misuse between 2016 and 2021. The reported concentrations of compounded ketamine nasal spray ranged from 125 to 200mg/mL, and the frequency of use ranged from 3 sprays 3 times a day to 6 sprays 8 times a day. The amount of medication administered to the patient with each spray was unknown.
Compounded ketamine nasal spray is not FDA-approved and does not have an FDA-approved dosing regimen. According to the FDA, the dose and frequency of nasal administration in these cases implies that “it is plausible that, in addition to the warnings and precautions associated with FDA-approved ketamine, psychiatric events could be induced or worsened.” The use of compounded ketamine nasal spray for home use therefore places a patient at risk for serious psychiatric adverse events, misuse, and abuse.
Health care professionals should report adverse events or quality problems associated with the use of compounded drugs to the FDA’s MedWatch Adverse Event Reporting program.
FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray. News release. US Food and Drug Administration. February 16, 2022. Accessed February 17, 2022. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-professionals-potential-risks-associated-compounded-ketamine-nasal-spray