Spravato Drug Interactions

Pharmacodynamic interactions: Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation. Closely monitor for sedation with concomitant use of Esketamine (Spravato) with CNS depressants.
Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure. Closely monitor blood pressure with concomitant use of Esketamine (Spravato) with psychostimulants.
Concomitant use with monoamine oxidase inhibitors (MAOIs) (e.g., tranylcypromine, selegiline, phenelzine) may increase blood pressure. Closely monitor blood pressure with concomitant use of Esketamine (Spravato) with MAOIs.
Pharmacokinetic interactions: Esketamine is extensively metabolized in the liver. The primary metabolic pathway of esketamine in human liver microsomes is N‑demethylation to form noresketamine. The main cytochrome P450 (CYP) enzymes responsible for esketamine N‑demethylation are CYP2B6 and CYP3A4 (see Pharmacology: Pharmacokinetics under Actions).
Effect of other drugs on esketamine: Hepatic enzyme inhibitors: Pretreatment of healthy subjects with oral ticlopidine, an inhibitor of hepatic CYP2B6 activity, (250 mg twice daily for 9 days prior to and on the day of esketamine administration) had no effect on the maximum plasma concentration (C_max) of esketamine administered as a nasal spray. The area under the plasma concentration‑time curve (AUC_∞) of esketamine was increased by approximately 29%. The terminal half‑life of esketamine was not affected by ticlopidine pretreatment.
Pretreatment with oral clarithromycin, an inhibitor of hepatic CYP3A4 activity, (500 mg twice daily for 3 days prior to and on the day of esketamine administration) increased the mean C_max and AUC_∞ of nasally administered esketamine by approximately 11% and 4%, respectively. The terminal half‑life of esketamine was not affected by clarithromycin pretreatment.
Hepatic enzyme inducers: Pretreatment with oral rifampicin, a potent inducer of the activity of multiple hepatic CYP enzymes such as CYP3A4 and CYP2B6, (600 mg daily for 5 days prior to esketamine administration) decreased the mean C_max and AUC_∞ values of esketamine administered as a nasal spray by approximately 17% and 28%, respectively.
Other Nasal Spray Products: Concomitant use of Esketamine (Spravato) with other nasally administered medicinal products has been evaluated in the following pharmacokinetic interaction studies. Pretreatment of subjects with history of allergic rhinitis and pre‑exposed to grass pollen with oxymetazoline administered as a nasal spray (2 sprays of 0.05% solution administered at 1 hour prior to nasal administration of esketamine) had minor effects on the pharmacokinetics of esketamine.
Pretreatment of healthy subjects with nasal administration of mometasone furoate (200 mcg per day for 2 weeks with the last mometasone furoate dose administered at 1 hour prior to nasal administration of esketamine) had minor effects on the pharmacokinetics of esketamine.
Effect of esketamine on other drugs: Nasal administration of 84 mg esketamine twice a week for 2 weeks reduced the mean plasma AUC_∞ of oral midazolam (single 6 mg dose), a substrate of hepatic CYP3A4, by approximately 16%.
Nasal administration of 84 mg esketamine twice a week for 2 weeks did not affect the mean plasma AUC_∞ of oral bupropion (single 150 mg dose), a substrate of hepatic CYP2B6.