Tizanidine + CYP1A2 inhibitors - Drug Interactions

Fluvoxamine causes a very marked 33-fold increase in tizanidinelevels with a consequent increase in hypotensive and sedative effects. The combination is potentially hazardous and should beavoided. Ciprofloxacin markedly increases tizanidine levels andadverse effects,and particular caution is required if this combination is considered essential. Combined oral contraceptivesincrease 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 ciprofloxacin 500mg twice daily for 3 days markedly increased AUC of a single 4mg dose of tizanidine by tenfold and maximum level by sevenfold, without significantly affecting half-life. The hypotensive and sedative effects of tizanidine were also markedly increased by ciprofloxacin (See reference number 1).

A 45-year-old Japanese woman with multiple sclerosis taking tizanidine 3mg daily had a reduction in blood pressure (from 124/88 to 102/74 mmHg) and heart rate (from 86 to 58 bpm) shortly after starting to take ciprofloxacin 400mg daily. After 2 days she complained of drowsiness and her blood pressure was 92/54 mmHg (See reference number 2). Retrospective analysis revealed 8 patients who had received tizanidine and ciprofloxacin concurrently. In these patients, mean reduction in blood pressure on starting ciprofloxacin was 21.3/15.4 mmHg, and heart rate reduction was 14.9 bpm. Adverse effects attributable to tizanidine occurred in three of patients (See reference number 2).

In a placebo-controlled, crossover study in 10 healthy subjects fluvoxamine 100mg once daily for 4 days very markedly increased AUC of a single 4mg dose of tizanidine by 33-fold and 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 10 subjects somnolent and dizzy for 3 to 6 hrs (See reference number 3).

A 70-year-old Japanese woman started taking tizanidine 3mg daily 15 days after starting fluvoxamine 100mg increased to 150mg daily. Her heart rate dropped from about 85 bpm to a range of 56 to 60 bpm. After tizanidine was stopped, symptoms improved immediately (See reference number 4). Retrospective analysis revealed 23 patient who had received tizanidine with fluvoxamine. Of these patients,6 had adverse effects including low heart rate, dizziness, drowsiness and hypotension. The patients with adverse effects were,on average, taking higher doses of fluvoxamine and tizanidine than those without adverse effects (See reference number 4).

In a study in 15 healthy women taking a combined oral contraceptive (ethinylestradiol/gestodene), AUC of a single 4mg dose of tizanidine was 3.9-fold higher than in 15 healthy women not taking an oral contraceptive, without any difference in elimination half-life. In addition, blood pressure-lowering effect of tizanidine was increased by 12/8 mmHg in oral contraceptive users (See reference number 5). The manufacturer also notes that retrospective analysis of population pharmacokinetic data showed that clearance of tizanidine is about 50 % lower in women taking oral contraceptives (See reference number 6,7).

In a placebo-controlled, crossover study in 9 healthy subjects rofecoxib 25mg daily for 4 days markedly increased AUC of a single 4mg dose of tizanidine by 13.6-fold and maximum level by 6.1-fold. The hypotensive and sedative effects of tizanidine were also markedly increased by rofecoxib. There was no evidence of QT prolongation in this study (See reference number 8).

An otherwise healthy 59-year-old woman developed extreme sinus bradycardia (30 bpm) with chest pain and acute right heart failure while taking tizanidine,diclofenac and rofecoxib. This resolved promptly after stopping medication (See reference number 9). Note that rofecoxib was generally withdrawn worldwide in 2004 because of its cardiovascular adverse effects,but these data are included here for completeness.

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

These pharmacokinetic interactions are well established,and clinically important. The common adverse effects of tizanidine, such as hypotension and sedation, are dose related, and consequently manufacturers recommend starting with a low dose of tizanidine (2 or 4 mg) and carefully titrating to usual maximum of 24mg daily, and not exceeding 36mg daily (See reference number 6,7). This represents a maximum 18-fold variation in dosage. Fluvoxamine increases exposure to tizanidine by a mean of 33-fold, which, broadly speaking, changes a 2mg dose into a 66mg dose, which is far higher than maximum recommended dose. For this reason, authors of one of studies conclude that combination is potentially hazardous and should be avoided (See reference number 3). The US manufacturer also contraindicates combination (See reference number 7). Given available data this is sensible advice. Note that other SSRIs are generally not considered to inhibit CYP1A2,see Theophylline + SSRIs interaction, and may therefore be suitable alternatives to fluvoxamine.

For ciprofloxacin,there is a marked tenfold increase in exposure to tizanidine, with a consequent increase in adverse effects. Some authors recommend that this combination be avoided,(See reference number 2) whereas others recommend caution (See reference number 1). The US manufacturer contraindicates combination,(See reference number 7) whereas UK manufacturers do not mention this potential interaction (See reference number 6). If ciprofloxacin is considered most appropriate antibacterial to use in a patient already taking tizanidine, anticipate need to reduce tizanidine dose before starting ciprofloxacin, and closely monitor adverse effects: starting ciprofloxacin may cause marked hypotension, bradycardia, and sedation. Other quinolones also inhibit CYP1A2,but to varying degrees, see table 1 below,.

For combined oral contraceptives, increase in exposure to tizanidine is a more moderate fourfold. The manufacturer states that clinical response or adverse effects might occur at lower doses of tizanidine in patients taking oral contraceptives,(See reference number 6) and that during dose titration,individual doses should be reduced (See reference number 7). Care is needed (See reference number 7).

In addition, US manufacturer also recommends caution if tizanidine is given with other inhibitors of CYP1A2, of which they mention amiodarone, mexiletine, propafenone, cimetidine and ticlopidine (See reference number 7). For a list of clinically important CYP1A2 inhibitors,see table 2 below,.

Granfors MT,Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther (2004) 76, 598–606.

Momo K,Homma M, Kohda Y, Ohkoshi N, Yoshizawa T, Tamaoka A. Drug interaction oftizanidine and ciprofloxacin: case report. Clin Pharmacol Ther (2006) 80, 717–9.

Granfors MT,Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine drasticallyincreases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther (2004) 75, 331–41.

Momo K,Doki K, Hosono H, Homma M, Kohda Y. Drug interaction of tizanidine and fluvoxamine. Clin Pharmacol Ther (2004) 76, 509–10.

Granfors MT,Backman JT, Laitila J, Neuvonen PJ. Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clin Pharmacol Ther (2005) 78, 400–11.

Zanaflex (Tizanidine hydrochloride). Cephalon Ltd. UK Summary of product characteristics,December 2006.

Zanaflex (Tizanidine hydrochloride). Acorda Therapeutics,Inc. US Prescribing information,July 2006.

Backman JT,Karjalainen MJ, Neuvonen M, Laitila J, Neuvonen PJ. Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol (2006) 62, 345–57.

Kick A,Bertoli R, Moschovitis G, Caduff Janosa P, Cerny A. [Extreme sinus bradycardia(30/min) with acute right heart failure under tizanidine (Sirdalud). Possible pharmacologicalinteraction with rofecoxib (Vioxx)]. Med Klin (2005) 100, 213–16.

Table 1 Effect of quinolones on theophylline pharmacokinetics in order of magnitude of the potential interaction
Quinolone (daily dose) Increase in theophylline level Increase in AUC Decrease in clearance Refs
Enoxacin 600 to 1200mg 72 to 243 % 84 to 248 % 42 to 74 % 1–8
Pipemidic acid 800 to 1500mg 71% 76 to 79 % 49% 3, 9
Clinafloxacin 400 to 800mg 46 to 69 % 10
Grepafloxacin 200 to 600mg 28 to 82 % 93 to 113 % 33 to 54 % 11, 12
Ciprofloxacin 600 to 1500mg 17 to 50 % 22 to 52 % 18 to 31 % 2, 3, 13–18
Pazufloxacin 500mg up to 27 % up to 33 % 25% 19
Pefloxacin 400 to 800mg 17 to 20 % 19 to 53 % 29% 2, 3
Norfloxacin 600 to 800mg up to 22 % up to 17 % up to 15 % 7, 16, 20–23
Prulifloxacin 600mg 16% 15% 24
Ofloxacin 400 to 600mg up to 10 % up to 10 % up to 12 % 2, 3, 7, 22, 25– 27
Trovafloxacin 200 to 300mg up to 8 % 28, 29
Fleroxacin 400mg No significant change up to 8 % up to 6 % 30–33
Flumequine 1200mg No significant change No significant change No significant change 34
Gatifloxacin 400mg No significant change No significant change 35
Gemifloxacin 400 to 600mg No significant change No significant change 36
Levofloxacin 300 to 1000mg No significant change No significant change No significant change 11, 37, 38
Lomefloxacin 400 to 800mg No significant change No significant change No significant change 9, 15, 39–42
Moxifloxacin 200mg to 400mg No significant change No significant change No significant change 43
Nalidixic acid 400 to 600mg No significant change No significant change 2, 16
Rufloxacin 200 to 400mg No significant change No significant change No significant change 44, 45
Sparfloxacin 200 to 400mg No significant change No significant change No significant change 46–49
Table 2 Drugs affecting or metabolised by the cytochrome P450 isoenzyme CYP1A2
Inhibitors Cimetidine Fluoroquinolones Ciprofloxacin Enoxacin Grepafloxacin Fluvoxamine Ipriflavone Mexiletine Rofecoxib Tacrine Ticlopidine Zileuton
Inducers Barbiturates Phenytoin Tobacco smoke
Substrates Caffeine Clozapine Duloxetine Flecainide Olanzapine Rasagiline Ropinirole Tacrine Theophylline* Tizanidine* Tricyclic antidepressants Amitriptyline Clomipramine Imipramine Triptans Frovatriptan Zolmitriptan R-Warfarin