Drug Interactions between aspirin / caffeine / dihydrocodeine and esketamine

MONITOR CLOSELY: Coadministration with psychostimulants (e.g., amphetamines) or monoamine oxidase inhibitors (MAOIs) may potentiate the hypertensive effects of esketamine. According to the prescribing information, esketamine causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after esketamine administration and last about 4 hours. In clinical studies, approximately 8% to 17% of esketamine-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP within 1.5 hours after administration at least once during the first 4 weeks of treatment, compared to 1% to 3% of placebo-treated patients. A substantial increase in BP could occur after any dose, even if smaller BP effects were observed with previous administrations. The mean placebo-adjusted increases in systolic and diastolic blood pressure (SBP and DBP) over time were about 7 to 9 mmHg in SBP and 4 to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients receiving esketamine with oral antidepressants.

MANAGEMENT: Caution is advised and blood pressure should be closely monitored during concomitant use of esketamine with psychostimulants or MAOIs. All patients receiving esketamine should have BP assessed prior to administration. If BP is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), a delay in esketamine treatment may be necessary, taking into consideration the benefits versus risks in individual patients. BP should be monitored for at least 2 hours after esketamine administration, starting at approximately 40 minutes post-dose and subsequently as clinically warranted. In patients with a history of hypertensive encephalopathy, more intensive monitoring is warranted due to increased risk for developing encephalopathy with even small increases in BP. If at any point BP is elevated and remains high, promptly seek assistance from practitioners experienced in BP management. Patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness or focal neurological deficits) should be immediately referred for emergency care.

MONITOR CLOSELY: Concomitant use of esketamine with central nervous system (CNS) depressants may increase sedation and impairment of attention, judgment, thinking, reaction speed, and psychomotor skills. In clinical trials, 49% to 61% of esketamine-treated patients developed sedation based on the Modified Observer's Alertness/Sedation scale (MOAA/s), and 0.3% of esketamine-treated patients experienced loss of consciousness (MOAA/s score of 0). In the MOAA/s scale, 5 means "responds readily to name spoken in normal tone" and 0 means "no response after painful trapezius squeeze," and any decrease in MOAA/s from pre-dosing of esketamine is considered to indicate presence of sedation. Dose-related increases in the incidence of sedation were also observed in a fixed-dose study. Additionally, cognitive performance decline was reported in a study in healthy volunteers who received a single intranasal dose of esketamine. Compared to placebo-treated subjects, esketamine-treated subjects required a greater effort to complete cognitive tests at 40 minutes post-dose, although results were comparable between the two groups at 2 hours post-dose. Drowsiness was comparable after 4 hours post-dose.

MANAGEMENT: Caution is advised and patients should be closely monitored during concomitant use of esketamine with CNS depressants or other drugs that can cause sedation or dizziness. Due to the risk of delayed or prolonged sedation and other adverse effects, patients should be monitored for at least 2 hours after esketamine administration, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting. Patients should be instructed not to engage in potentially hazardous activities that require complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day after a restful sleep.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.