Tizanidine Fluvoxamine

Fluvoxamine 100 mg/day resulted in a large (about 30-fold) increase in plasma concentrations of tizanidine in 10 healthy volunteers (120). This interaction caused significant physiological consequences, including a substantial fall in systolic blood pressure, perhaps because tizanidine is an a2-adrenoceptor agonist. The authors suggested that the interaction was likely to be due to fluvoxamine -mediated inhibition of CYP3A4, which is involved in the metabolism of tizanidine. 

Grantors MT, Backmann JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine drastically increases concentrations and effects of tizanidine a potentially hazardous interaction. Am Soc Clin Pharmacol Ther 2004 75 331-41. 

Fluvoxamine causes a very marked 33-fold increase in tizanidine levels with a consequent increase in hypotensive and sedative effects. The combination is potentially hazardous and should be avoided. Ciprofloxacin markedly increases tizanidine levels and adverse effects, and particular caution is required if this combination is considered essential Combined oral contraceptives increase tizanidine levels fourfold and might increase adverse effects. other inhibitors of CYP1A2 are predicted to interact similarly. 

In a placebo-controlled, crossover study in 10 healthy subjects fluvoxamine 100 mg once daily for 4 days very markedly increased the AUC of a single 4-mg dose of tizanidine by 33-fold and the maximum level by 12-fold. The elimination half-life was prolonged from 1.5 to 4.3 hours. The hypotensive and sedative effects of tizanidine were also markedly increased by fluvoxamine, with all of the 10 subjects somnolent and dizzy for 3 to 6 hours. ... 

A 70-year-old Japanese woman started taking tizanidine 3 mg daily 15 days after starting fluvoxamine 100 mg increased to 150 mg daily. Her heart rate dropped from about 85 bpm to a range of 56 to 60 bpm. After tizanidine was stopped, the symptoms improved immediately. Retrospective analysis revealed 23 patient who had reeeived tizanidine with fluvoxamine. Of these patients, 6 had adverse effeets ineluding low heart rate, dizziness, drowsiness and hypotension. The patients with adverse effeets were, on average, taking higher doses of fluvoxamine and tizanidine than those without adverse effects. ... 

Tizanidine is a substrate of the cytochrome P450 isoenzyme CYP1A2, which undergoes substantial presystemic metabolism by this isoenzyme. Ciprofloxacin appears to inhibit mainly the presystemic metabolism leading to increased absorption, as reflected by the increase in maximum level without a change in elimination half-life. Rofecoxib and fluvoxamine inhibited both presystemic metabolism and the elimination phase. Fluvoxamine, which is a known potent inhibitor of CYP1A2, had the most marked effect. The contraceptive steroids were modest inhibitors of CYP1A2 by comparison. 

Are there contraindications to concomitant drug use For instance, tizanidine is contraindicated in patients with concomitant use of CYP450 1A2 inhibitors such as fluvoxamine, amiodarone, mexiletine, propafenone, cimetidine, fluoroquinolones (ciprofloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine [27]. 

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