Medication Interaction Alert

April 12, 2007

ISSUE:	FDA announces additions to the CONTRAINDICATIONS and WARNINGS sections for tizanidine due to documented interaction with CYP1A2 inhibitors
MEDICATION:	Zanaflex® (tizanidine), Acorda Therapeutics

The following was posted on the FDA Med Watch alert website dated April 11, 2007:
"Acorda Therapeutics and FDA informed healthcare professionals of changes to the CONTRAINDICATIONS and WARNINGS Sections of the product labeling for Zanaflex, a drug used to treat spasticity. In pharmacokinetic studies where tizanidine was coadministered with either fluvoxamine or ciprofloxacin (CYP1A2 inhibitors), the serum concentration of tizanidine was significantly increased and potentiated its hypotensive and sedative effects. Although there are no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, coadministration of tizanidine with other CYP1A2 inhibitors (zileuton, other fluroquinolones, antiarrythmics, cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine) should be avoided."

An excerpt of the Acorda Therapeutics "Dear Healthcare Professional" letter states:

"Acorda Therapeutics would like to inform you that concomitant use of tizanidine with fluvoxamine or ciprofloxacin (potent CYP1A2 inhibitors) is contraindicated. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors may lead to substantial increases in tizanidine blood concentrations. Therefore, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine should ordinarily be avoided. If their use is clinically necessary, they should be used with caution.

Additions to the CONTRAINDICATIONS and WARNINGS sections of the U.S. PI:
Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. Significant alterations of pharmacokinetic parameters of tizanidine including increased AUC, t1/2, Cmax, increased oral bioavailability and decreased plasma clearance have been observed with concomitant administration of either fluvoxamine or ciprofloxacin. This pharmacokinetic interaction can result in potentially serious adverse events.

POTENTIAL INTERACTION WITH FLUVOXAMINE OR CIPROFLOXACIN:
In a pharmacokinetic study, tizanidine serum concentration was significantly increased (Cmax 12-fold, AUC 33-fold) when the drug was given concomitantly with fluvoxamine. Potentiated hypotensive and sedative effects were observed. Fluvoxamine and tizanidine should not be used together. In a pharmacokinetic study, tizanidine serum concentration was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin. Potentiated hypotensive and sedative effects were observed. Ciprofloxacin and tizanidine should not be used together.

POSSIBLE INTERACTION WITH OTHER CYP1A2 INHIBITORS:
Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine should ordinarily be avoided. If their use is clinically necessary, they should be used with caution."