Drug Interactions between fluvoxamine and tizanidine

CONTRAINDICATED: Coadministration with fluvoxamine may significantly increase the plasma concentrations and pharmacologic effects of tizanidine. The proposed mechanism is fluvoxamine inhibition of tizanidine metabolism via CYP450 1A2. In 10 healthy volunteers, pretreatment with fluvoxamine (100 mg orally once daily for 4 days) increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of tizanidine (4 mg single oral dose) by an average of 12- and 33-fold, respectively, compared to placebo. The mean elimination half-life of tizanidine was prolonged from 1.5 to 4.3 hours by fluvoxamine. Pharmacologic effects of tizanidine as measured by changes in blood pressure, heart rate, performance testing, subjective drug effect, and drowsiness were also significantly greater with fluvoxamine. Particularly alarming was the decrease in systolic blood pressure to a level of 80 mmHg or lower in some cases. The interaction was also suspected in a case report of a 70-year-old hospitalized patient who developed low heart rate, low body temperature, dry mouth, and anuresis during tizanidine administration two weeks after initiating fluvoxamine. A retrospective review of patient medical records at the hospital revealed a significantly higher incidence of tizanidine-related adverse effects in patients treated concomitantly with fluvoxamine than that reported for tizanidine alone in the product labeling (26.1% vs. 5.3%), and those who experienced adverse effects were older and received higher dosages of both drugs than those who did not have adverse effects with the combination.

MANAGEMENT: Given the magnitude of the interaction, use of tizanidine with fluvoxamine is considered contraindicated. Other SSRIs such as citalopram, escitalopram, fluoxetine, paroxetine, or sertraline may be safer alternatives in tizanidine-treated patients, since they are generally believed to have little, if any, effect on CYP450 1A2.