Drug interactions between acyclovir and tizanidine

GENERALLY AVOID: Coadministration with inhibitors of CYP450 1A2 may significantly increase the plasma concentrations and pharmacologic effects of tizanidine, which is a substrate of the isoenzyme. In 10 healthy volunteers, pretreatment with the potent CYP450 1A2 inhibitor 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. Similarly, pretreatment with ciprofloxacin (500 mg orally twice daily for 3 days) increased the Cmax and AUC of tizanidine (4 mg single oral dose) by an average of 7- and 10-fold, respectively, compared to placebo. In addition, pharmacologic effects of tizanidine as measured by changes in blood pressure, heart rate, performance testing, subjective drug effect, and drowsiness were significantly greater with fluvoxamine and ciprofloxacin compared to placebo. The interaction was also suspected in a case report of a 70-year-old 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. Another CYP450 1A2 inhibitor, rofecoxib, has also been reported to potentiate the adverse effects of tizanidine. There have been postmarketing reports of adverse events mostly involving the nervous system (e.g., hallucinations, psychosis, somnolence, hypotonia) and cardiovascular system (e.g., hypotension, tachycardia, bradycardia) during concomitant use of tizanidine and rofecoxib. In all cases, adverse events resolved following discontinuation of one or both drugs. Rechallenges were not performed.

MANAGEMENT: The use of tizanidine in combination with CYP450 1A2 inhibitors should generally be avoided. Caution is advised if concurrent use is clinically necessary. Dosage adjustments may be required in patients who experience excessive adverse effects of tizanidine such as drowsiness, dizziness, lightheadedness, hypotension, or bradycardia.