Drug Interactions between Synalgos-DC and tizanidine

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.

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, phenothiazines).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.