Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction.
OBJECTIVE
Our objective was to study the effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of tizanidine, a centrally acting skeletal muscle relaxant.


METHODS
In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers took 100 mg fluvoxamine or placebo orally once daily for 4 days. On day 4, each ingested a single 4-mg dose of tizanidine. Plasma concentrations of tizanidine and fluvoxamine and pharmacodynamic variables were measured. A caffeine test was performed on day 3 to examine the role of cytochrome P450 (CYP) 1A2 in tizanidine pharmacokinetics.


RESULTS
On average, fluvoxamine increased the total area under the concentration-time curve [AUC(0- infinity )] of tizanidine 33-fold (range, 14-fold to 103-fold; P =.000002) and the peak plasma concentration 12-fold (range, 5-fold to 32-fold; P =.000001). The mean elimination half-life of tizanidine was prolonged from 1.5 to 4.3 hours (P =.00004) by fluvoxamine. The AUC(0- infinity ) of tizanidine and its increase by fluvoxamine correlated with the caffeine/paraxanthine ratio and its increase, respectively (P <.03). All pharmacodynamic variables revealed a significant difference between the fluvoxamine and placebo phases, eg, in the maximal effects on systolic blood pressure (-35 mm Hg, P =.000009), diastolic blood pressure (-20 mm Hg, P =.00002), heart rate (-4 beats/min, P =.007), Digit Symbol Substitution Test (P =.0003), subjective drug effect (P =.0000001), and drowsiness (P =.0002). In particular, the decrease in systolic blood pressure, to the level of 80 mm Hg or even less, was an alarming finding.


CONCLUSIONS
Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Inhibition of tizanidine-metabolizing enzyme(s), mainly CYP1A2, by fluvoxamine seems to explain the observed interaction. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.
Granfors
Marika T
MT
Department of Clinical Pharmacology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland.
Backman
Janne T
JT
Neuvonen
Mikko
M
Ahonen
Jouni
J
Neuvonen
Pertti J
PJ
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D003000:Clonidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004344:Drug Incompatibility; D004347:Drug Interactions; D016666:Fluvoxamine / Q000008:administration & dosage* / Q000097:blood; D006207:Half-Life; D006801:Humans; D008297:Male; D009125:Muscle Relaxants, Central / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011336:Probability; D018570:Risk Assessment
D009125:Muscle Relaxants, Central; C023754:tizanidine; D003577:Cytochrome P-450 Enzyme System; D003000:Clonidine; D016666:Fluvoxamine