Zanaflex Interactions

Acetaminophen
Amiodarone

• Antihypertensive Agents
  
• Antipsychotics
  
• Anxiolytics, Sedatives, and Hypnotics

• Opiate agonists
  
• Oral contraceptives

• Sedating H1-blockers

Zanaflex (Tizanidine) Interactions

NOTE: Tizanidine is primarily metabolized by the hepatic cytochrome isoenzyme CYP1A2.

Tizanidine delays the time to attain peak concentrations (Tmax) of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.

Concurrent use of tizanidine and CNS depressants can cause additive CNS depression. These agents include but are not limited to: antipsychotics, anxiolytics, sedatives, and hypnotics (including barbiturates and benzodiazepines), baclofen, buprenorphine, butorphanol, dronabinol, THC, entacapone, ethanol, nalbuphine, opiate agonists, pentazocine, the sedating H1-blockers or tolcapone. H1-antagonists which do not appear to cause significant CNS depression include: astemizole, fexofenadine, loratadine, and terfenadine. Additionally, ethanol increases the AUC and Cmax of tizanidine by about 20% and 15%, respectively, resulting in an increase in side effects associated with tizanidine.

The use of tizanidine with the phytomedicinals valerian, Valeriana officinalis or kava kava, Piper methysticum could potentiate the sedative effects of either agent.

Tizanidine is a centrally acting alpha2-adrenergic agonist, and should not be used with other central-acting adrenergic agents (e.g., clonidine, methyldopa, guanfacine, guanabenz). Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.

A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take oral contraceptives concurrently with tizanidine.

One case of increased phenytoin serum concentrations (>100%) and associated drowsiness has been reported with the addition of tizanidine therapy. The mechanism and significance of this potential interaction with phenytoin or fosphenytoin is unknown. Cumulative evidence of in vitro studies using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes.

Rofecoxib may potentiate the adverse effects of tizanidine. Eight cases of this interaction have been reported in post-marketing safety reports. Most adverse reactions reported involved the nervous system (e.g., hallucinations, psychosis, somnolence, hypotonia, etc.) and the cardiovascular system (e.g., hypotension, tachycardia, bradycardia). In all cases, discontinuation of tizanidine, rofecoxib, or both resolved adverse effects. Rechallenges with both drugs were not performed. The mechanism of this interaction is unclear.

The combination of tizanidine and fluvoxamine is contraindicated. An in vivo pharmacokinetic study revealed that fluvoxamine may drastically increase the serum concentrations of tizanidine, leading to a severe and prolonged decrease in blood pressure as well as additive CNS effects. The mean maximal effect on blood pressure was a 35 mmHg decrease in systolic blood pressure, a 20 mmHg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on a psychomotor task was significantly impaired. Systolic blood pressures dropped to 80 mmHg or less and somnolence and dizziness were prevalent for 3-6 hours after tizanidine intake. The mechanism appears to be due to inhibition of tizanidine hepatic metabolism (via CYP1A2) by fluvoxamine. Serum concentrations (AUC) of tizanidine (given as a single 4 mg dose) were increased a mean of 33 fold (range 14-103 fold) after 4 days of fluvoxamine 100 mg/day PO or placebo. Tizanidine Cmax was increased approximately 12-fold (range 5-32), elimination half-life was increased almost 3-fold. Serum increases of tizanidine occurred in all 10 subjects receiving active drug.

Ciprofloxacin is a known inhibitor of CYP1A2 isoenzymes. Ciprofloxacin substantially increases the plasma concentrations of tizanidine with potential for enhanced hypotensive and sedative effects; the mechanism is reduced CYP1A2 presystemic metabolism of tizanidine. A randomized, double-blind, placebo-controlled, crossover study of 10 healthy volunteers has evaluated the pharmacokinetics of oral tizanidine when administered after 3 days of an oral ciprofloxacin regimen. Tizanidine 4 mg was administered as a single dose one hour after the last dose of the ciprofloxacin regimen (500 mg twice daily). Ciprofloxacin increases the AUC of tizanidine by 10-fold (range: 6- to 24-fold). The change in AUC correlates with CYP1A2 activity (measured by caffeine test). Tizanidine peak concentrations increase by 7-fold. The elimination half-life is prolonged from 1.5 to 1.8 hours. The pharmacodynamic effects of tizanidine including hypotensive effects (-35 mm Hg vs. -25 mmHg systolic blood pressure) and drowsiness were stronger during the ciprofloxacin versus placebo study phase. In a similar study, another strong inhibitor of CYP1A2, fluvoxamine, has been reported to increase the AUC of tizanidine by 33-fold, leading to severe and prolonged decreases in blood pressure and additive CNS effects. The combination of tizanidine and fluvoxamine is contraindicated by the manufacturer for fluvoxamine. Based on this information, it is prudent to avoid the combination of tizanidine and ciprofloxacin; an alternative fluoroquinolone with minimal effects on CYP1A2 (e.g., gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, or ofloxacin) may be considered. If ciprofloxacin is coadministered with tizanidine, monitor for potential side effects including excessive sedation or hypotensive effects.

Tizanidine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). The presystemic availability of tizanidine has been shown to be substantially increased by coadministration with CYP1A2 inhibitors. Average increases in tizanidine AUC of 10-fold and 33-fold have been reported following administration of ciprofloxacin and fluvoxamine, respectively. These increases in plasma concentrations have been associated with significant hypotensive and sedative effects. Tizanidine and fluvoxamine coadministration is contraindicated. Other CYP1A2 inhibitors include amiodarone , atazanavir, cimetidine (weak inhibitor), enoxacin, mexiletine , norfloxacin (weak inhibitor), tacrine], and zileuton. Until further studies are available, use significant caution in coadministering tizanidine with other CYP1A2 inhibitors; monitor for potential side effects such as excessive sedation or hypotensive effects.

Related entries

• Tizanidine -Zanaflex
  
• Zanaflex Monitoring Parameters
  
• Zanaflex (Tizanidine) Administration
  
• Zanaflex (Tizanidine) Photographs
  
• Zanaflex Contraindications/Precautions
  
• Zanaflex Adverse Reactions
  
• Zanaflex Indications… Dosage
  
• Zanaflex tablets or capsules: Patient Education

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