Drug Interactions between esketamine and Stalevo 200

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.

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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.

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MONITOR: When catechol-O-methyltransferase (COMT) inhibitors are administered together with levodopa/carbidopa, they may increase the relative bioavailability (AUC) of levodopa. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). Adverse effects such as dyskinesia, somnolence, and orthostatic hypotension may be potentiated. In the presence of the decarboxylase inhibitor carbidopa, COMT is the major metabolizing enzyme for levodopa. In clinical trials of COMT inhibitors administered concomitantly with levodopa, patients required a dosage reduction in levodopa if their daily dose of levodopa was greater than 600 mg with tolcapone or 800 mg with entacapone, or if they had moderate or severe dyskinesia before beginning COMT inhibitor treatment. In patients receiving once daily opicapone at bedtime with levodopa/carbidopa administered every three or four hours, levodopa peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 43% to 44% and 62% to 94%, respectively, compared to administration of levodopa/carbidopa alone.

MANAGEMENT: Although COMT inhibitors are intended for use with levodopa/carbidopa, clinicians should be aware that dose reduction of levodopa may be necessary during coadministration. This is especially true if the patient is experiencing dyskinesia induced by levodopa. Use with caution in patients with severe dyskinesia or dystonia. Likewise, when discontinuing a COMT inhibitor, monitor patients and consider adjustment of other dopaminergic therapies as needed. In addition, some authorities advise that opicapone should be administered as a once-daily dose at least one hour before or after combinations containing levodopa so as to avoid any interaction with the absorption of levodopa (AU, UK).

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