Drug Interaction Report

MONITOR: The sedative effect of tizanidine may be potentiated by concomitant use of other agents with central nervous system (CNS) depressant effects. In addition, tizanidine and many of these agents (e.g., alcohol, anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, muscle relaxants) also can exhibit hypotensive effects, which may be additive during coadministration and may increase the risk of symptomatic hypotension and orthostasis, particularly during initiation of therapy or dose escalation. Tizanidine itself is a central alpha-2 adrenergic agonist. Pharmacologic studies have found tizanidine to possess between 1/10 to 1/50 of the potency of clonidine, a structurally similar agent, in lowering blood pressure. In a single-dose study where blood pressure was monitored closely after dosing, two-thirds of patients treated with an 8 mg dose had a 20% reduction in either the diastolic or systolic blood pressure. The reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing, and was associated at times with bradycardia, orthostatic hypotension, lightheadedness, dizziness, and rarely, syncope. The hypotensive effect of tizanidine is dose-related and has been measured following single doses of 2 mg or more.

MANAGEMENT: Caution is advised and more gradual dose titration may be appropriate when tizanidine is used with other substances that can cause CNS depression and/or hypotension, particularly in elderly or debilitated patients. 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 avoid rising abruptly from a sitting or recumbent position. Patients should contact their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or excessive CNS effects that interfere with their normal activities.

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

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.