Interactive Properties of Tizanidine (Zanaflex)

Tizanidine (Zanaflex; Novartis) has severalpharmacokinetic and pharmacodynamicproperties that predispose it toadverse drug interactions, including thefollowing:

• Tizanidine is metabolized mainly bycytochrome P-450 1A2 (CYP1A2), acytochrome P-450 isozyme that issusceptible to inhibition by severalother medications
• Tizanidine undergoes considerablefirst-pass metabolism, so drugs thatinhibit tizanidine metabolism mayproduce large increases in tizanidineplasma concentrations
• Tizanidine regularly produces sedation,so concurrent use with othercentral nervous system (CNS) depressantsis likely to produce additiveeffects
• Tizanidine tends to lower blood pressureand may exhibit additive effectswith antihypertensive agents

Pharmacokinetic Interactions

Fluvoxamine

In a randomized controlled study ofhealthy subjects, pretreatment with fluvoxamine(100 mg/day for 4 days) resultedin a dramatic 33-fold increase intizanidine area under the plasma concentration-time curve (AUC).¹ Themarked increases in tizanidine plasmaconcentrations were accompanied bypharmacodynamic changes, such asmarked reduction in systolic blood pressureand increased sedation. These findingssuggest a potentially dangerousdrug interaction, and concurrent use oftizanidine and fluvoxamine is contraindicated.Fluvoxamine is a potent CYP1A2inhibitor, which is probably the primarymechanism for this interaction.

Oral Contraceptives

Retrospective analysis of tizanidinepharmacokinetics in women taking oralcontraceptives found that they hadabout a 50% lower clearance of tizanidine,compared with women not takingoral contraceptives. This finding is consistentwith other evidence showing thatestrogens are modest inhibitors ofCYP1A2. In women taking oral contraceptives,tizanidine should be initiatedwith conservative doses and graduallyincreased based on response.

Other CYP1A2 Inhibitors

Since tizanidine appears to be verysusceptible to interactions with inhibitorsof CYP1A2, one should monitor forincreased tizanidine response if anyCYP1A2 inhibitor is used. Drugs knownto inhibit CYP1A2 include atazanavir(Reyataz), ciprofloxacin (Cipro), enoxacin(Penetrex), mexiletine (Mexitil), tacrine(Cognex), and zileuton (Zyflo). Monitorparticularly for excessive sedation andhypotension.

Pharmacodynamic Interactions

CNS Depressants

Sedation is a prominent side effect oftizanidine, and this is likely to be additivewith any other CNS depressant. Tizanidine-induced sedation appears to bedose-related, so patients on larger tizanidinedoses, and/or reduced CYP1A2activity due to drugs or other reasons,would be at greater risk. Alcohol mayincrease tizanidine plasma concentrationssomewhat and produce additiveCNS depression, so patients should bewarned to limit alcohol intake.

Antihypertensive Agents

Tizanidine, like clonidine, is an alpha²-adrenoreceptor agonist and thus canproduce hypotension when given aloneor can enhance the hypotensive effectsof other drugs. Two cases of acutehypotension have been reported (in a 10-year-old boy and a 48-year-old woman)when tizanidine was added to lisinopriltherapy.^2,3 Monitor blood pressure andpatient response when tizanidine is initiatedin patients receiving angiotensinconvertingenzyme inhibitors or anyother antihypertensive drugs. Sincetizanidine is an alpha-adrenergic agonist,it generally should not be used withother alpha-adrenergic agonists such asclonidine, guanabenz, or guanfacine.

Summary

• Fluvoxamine produces dramaticincreases in tizanidine plasma concentrations,and the combinationshould be absolutely avoided
• Other CYP1A2 inhibitors should beused with tizanidine only if thepatient can be observed carefully foradverse effects such as excessivesedation and hypotension
• Tizanidine is a CNS depressant andproduces additive sedation withother CNS depressants; monitor forexcessive sedation and adjust dosesas needed
• Tizanidine tends to lower blood pressureand produces additive effectswith antihypertensive drugs. Monitorblood pressure closely.

Drs. Horn and Hansten are both professorsof pharmacy at the Universityof Washington School of Pharmacy.For an electronic version of this article,including references if any, visitwww.hanstenandhorn.com.

For a list of references, send astamped, self-addressed envelope to:References Department, Attn. A. Stahl,Pharmacy Times, 241 Forsgate Drive,Jamesburg, NJ 08831; or send an e-mailrequest to: astahl@ascendmedia.com.