Drug Interaction Report

GENERALLY AVOID: Coadministration with viloxazine may increase the plasma concentrations and risk of adverse effects, including agranulocytosis and QT prolongation, of clozapine. The proposed mechanism is viloxazine inhibition of the CYP450 3A4-mediated metabolism of clozapine. Inhibition of CYP450 2D6 and 3A4 may also contribute. In a pharmacokinetic study in 16 patients with schizophrenia receiving clozapine under steady-state conditions, coadministration of fluvoxamine (a potent CYP450 1A2 inhibitor) for 14 days, increased mean trough concentrations of clozapine and its metabolites 3-fold compared to baseline steady state concentrations. Concomitant administration of viloxazine and clozapine has not been studied, and therefore, the net effect of viloxazine on clozapine and its metabolites is unclear.

MANAGEMENT: Concomitant use of viloxazine with clozapine is not recommended; however, if coadministration is necessary, pharmacologic response and plasma clozapine concentrations should be monitored closely and the clozapine dosage adjusted as necessary. Patients should be advised to report symptoms such as somnolence, disorientation, slurred speech, seizures, uncontrolled movements, dizziness, irregular heartbeat, palpitations, fever, or hypersalivation to their doctor.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

Caffeine may increase clozapine serum concentrations and exacerbate psychotic symptoms. The mechanism is unknown but may be related to competition for the same metabolic pathway. No specific intervention is necessary; however, if an interaction is suspected it is recommended that caffeine intake be avoided.