Drug Interactions between Premphase 14/14 and tizanidine

Consumer information for this interaction is not currently available.

GENERALLY AVOID: Coadministration with oral contraceptives may significantly increase the plasma concentrations and pharmacologic effects of tizanidine. The proposed mechanism is inhibition of tizanidine metabolism via CYP450 1A2. Retrospective evaluation of population pharmacokinetic data following single- and multiple-dose administration of tizanidine revealed an approximately 50% decrease in the clearance of tizanidine in women receiving oral contraceptives compared to women not receiving oral contraceptives. In a study of 30 healthy volunteers administered a single 4 mg dose of tizanidine, mean peak plasma concentration (Cmax) of tizanidine was 3.0 times higher and mean area under the plasma concentration-time curve (AUC) was 3.9 times greater in women using an oral contraceptive containing ethinyl estradiol and gestodene than in women not on the contraceptive. In one contraceptive user, the tizanidine AUC exceeded the mean AUC of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma (Tmax) of tizanidine between the groups. Tizanidine to metabolite ratios in plasma and urine were 2 to 10 times higher in the contraceptive users than in control subjects, and the excretion of unchanged tizanidine into urine was on average 3.8 times greater in the contraceptive group. In addition, both the systolic and diastolic blood pressures were lowered by tizanidine more in the contraceptive users (29 mmHg and 21 mm Hg, respectively) than in the control subjects (17 mmHg and 13 mmHg, respectively). The interaction has also been reported with other CYP450 1A2 inhibitors such as fluvoxamine, ciprofloxacin, and rofecoxib.

MANAGEMENT: The use of tizanidine in combination with oral contraceptives or other 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, bradycardia, or syncope.

Consumer information for this interaction is not currently available.

GENERALLY AVOID: Coadministration with inhibitors of CYP450 1A2 may significantly increase the plasma concentrations and pharmacologic effects of tizanidine, which is a sensitive substrate of the isoenzyme. In 10 healthy volunteers, administration of a single 4 mg dose of tizanidine following pretreatment with the potent CYP450 1A2 inhibitor fluvoxamine (100 mg orally once daily for 4 days) increased tizanidine peak plasma concentration (Cmax) and systemic exposure (AUC) 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. Similarly, pretreatment with the moderate CYP450 1A2 inhibitor ciprofloxacin (500 mg orally twice daily for 3 days) increased Cmax and AUC of a single 4 mg dose of tizanidine by an average of 7- and 10-fold, respectively, compared to placebo. Pharmacologic effects of tizanidine as measured by changes in blood pressure, heart rate, performance testing, subjective drug effect, and drowsiness were significantly greater with both fluvoxamine and ciprofloxacin compared to placebo. Vemurafenib, another moderate CYP450 1A2 inhibitor, increased tizanidine AUC by 4.7-fold. The interaction was also suspected in a 70-year-old patient treated with tizanidine who developed low heart rate, low body temperature, dry mouth, and anuresis two weeks after initiating fluvoxamine. A retrospective review of patient medical records at the hospital where the patient was admitted 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. Rechallenge's were not performed.

MANAGEMENT: Concomitant use of tizanidine with CYP450 1A2 inhibitors should generally be avoided. Otherwise, caution is advised if coadministration is required. Dosage adjustments may be necessary in patients who experience excessive adverse effects of tizanidine such as drowsiness, dizziness, lightheadedness, hypotension, and bradycardia.