Rationale

Tizanidine is an alpha2-adrenergic agonist reducing spasticity, which lead to relaxation of skeletal muscle.(1, 2) Tizanidine is used to treat muscle spasms associated with multiple sclerosis, brain and spinal cord injuries.(2-5) Tizanidine has a low oral bioavailability due to the extensive first-pass metabolism via cytochrome P450 (CYP) 1A2.(1-3, 5, 6)Tizanidine also has a narrow therapeutic range. (6) Concurrent use of tizanidine and strong CYP1A2 inhibitors, such as ciprofloxacin, fluvoxamine, and zafirlukast is not recommended because it may significantly increase tizanidine level which can lead to severe adverse events.(2) Tizanidine adverse events include somnolence, dry mouth, fatigue, weakness, dizziness, hypotension, and bradycardia.(1, 2) Despite these concerns, tizanidine is commonly co-prescribed with CYP1A2 inhibitors.(5) According to a retrospective study of Individual Case Safety Reports (ICSR) registered in the World Health Organization (WHO) global database until March 1, 2017, among 4192 worldwide ICSR on tizanidine, 91 (2.0%) of them taking both tizanidine and ciprofloxacin concurrently.(2)

Algorithm

Explanation

Ciprofloxacin, fluvoxamine and zafirlukast inhibit CYP 1A2 and can increase the tizanidine area-under-the-concentration time curve (AUC) by more than 5-fold increased of tizanidine.(7) Previous studies found that concurrent use tizanidine with ciprofloxacin or fluvoxamine increased tizanidine AUC levels by 10-fold and 33-fold, respectively.(1, 5, 8)

In a pharmacokinetic study, ciprofloxacin increased the area under the plasma-concentration curve of tizanidine by an average of 10-fold (range 6-fold to 24-fold).(1, 6) Concurrent use of tizanidine and ciprofloxacin has been reported to induce adverse effects of tizanidine such as lowering blood pressure (BP), and  heart rate (HR).(9) A retrospective cohort study of 199 patients taking tizanidine plus ciprofloxacin and 960 patients taking tizanidine plus a different antibiotic found that co-administration of tizanidine and ciprofloxacin was associated with an increased risk of hospitalization by 2.19-fold (95% CI, 0.88-5.02) within 7 days after prescription of the antibiotic, 1.52-fold (95% CI, 0.63-3.33) within 14 days and 1.68-fold (95% CI, 0.84-3.17) within 30 days. (6)

In healthy adults, co-administration of  tizanidine and ciprofloxacin can decrease systolic blood pressure by 35 mm Hg.(1) Furthermore, case reports have noted incidences of severe hypotension when tizanidine was administered concomitantly with ciprofloxacin.(4, 9) Also, a retrospective study of ICSRs registered in the WHO global database until March 1, 2017 reported that among 91 patients receiving both tizanidine and ciprofloxacin concurrently, two fatal cases were reported.(2)

A previous study also reported that fluvoxamine increased tizanidine AUC up to 33- fold.(5, 8) Concurrent use of tizanidine and fluvoxamine can reduce systolic blood pressure by 36 mm Hg.(5, 8) Tizanidine adverse symptoms such as low heart rate, low body temperature, dry mouth, and enuresis has been reported in a patient taking tizanidine and fluvoxamine simultaneously.(4) Moreover, a retrospective study of 913 patients treated with tizanidine found that among 23 patients who received fluvoxamine together with tizanidine, 6 patients experienced tizanidine adverse event such as low heart rate, dizziness, low body temperature, drowsiness, hypotension or speech disorder.(4) Case reports have noted instances of dizziness when tizanidine was administered concomitantly with fluvoxamine.(5, 10) Moreover, a cohort study of 1,626 patients prescribed tizanidine and 5,012 prescribed cyclobenzaprine concurrently with a strong CYP1A2 inhibitor (either ciprofloxacin or fluvoxamine), found tizanidine cohort had higher risk of experiencing of hypotension (OR=1.26, 95% CI, 1.03-1.54) and severe hypotension, SBP ≤70 mm Hg, with an OR= OR=1.60, 95% CI, 1.05–2.45) compared to cyclobenzaprine cohort.(5)

Artifacts for implementers

Supporting documentation

Webinar

References

  1. 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(6):598-606. Epub 2004/12/14. doi: 10.1016/j.clpt.2004.08.018. PubMed PMID: 15592331.
  2. Rudolph A, Dahmke H, Kupferschmidt H, Burden A, Weiler S. Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database. Eur J Clin Pharmacol. 2021. Epub 2021/01/07. doi: 10.1007/s00228-020-02981-2. PubMed PMID: 33404754.
  3. Jogiraju VK, Heimbach T, Toderika Y, Taft DR. Physiologically based pharmacokinetic modeling of altered tizanidine systemic exposure by CYP1A2 modulation: Impact of drug-drug interactions and cigarette consumption. Drug Metab Pharmacokinet. 2020;37:100375. Epub 2021/02/10. doi: 10.1016/j.dmpk.2020.100375. PubMed PMID: 33561738.
  4. Momo K, Doki K, Hosono H, Homma M, Kohda Y. Drug interaction of tizanidine and fluvoxamine. Clin Pharmacol Ther. 2004;76(5):509-10. Epub 2004/11/13. doi: 10.1016/j.clpt.2004.08.003. PubMed PMID: 15536467.
  5. Chaugai S, Dickson AL, Shuey MM, Feng Q, Barker KA, Wei WQ, Luther JM, Stein CM, Chung CP. Co-Prescription of Strong CYP1A2 Inhibitors and the Risk of Tizanidine-Associated Hypotension: A Retrospective Cohort Study. Clin Pharmacol Ther. 2019;105(3):703-9. Epub 2018/09/18. doi: 10.1002/cpt.1233. PubMed PMID: 30223305; PMCID: PMC6379114.
  6. Jödicke AM, Curkovic I, Zellweger U, Tomka IT, Neuer T, Kullak-Ublick GA, Roos M, Egbring M. Analysis of Drug-Drug Interactions in Swiss Claims Data Using Tizanidine and Ciprofloxacin as a Prototypical Contraindicated Combination. Ann Pharmacother. 2018;52(10):983-91. Epub 2018/05/12. doi: 10.1177/1060028018775914. PubMed PMID: 29749261; PMCID: PMC6136070.
  7. Horn JR, Hansten PD. The Top 100 Drug Interactions: A Guide to Patient Management: H&h Publications; 2021.
  8. Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther. 2004;75(4):331-41. Epub 2004/04/03. doi: 10.1016/j.clpt.2003.12.005. PubMed PMID: 15060511.
  9. Momo K, Homma M, Kohda Y, Ohkoshi N, Yoshizawa T, Tamaoka A. Drug interaction of tizanidine and ciprofloxacin: case report. Clin Pharmacol Ther. 2006;80(6):717-9. Epub 2006/12/21. doi: 10.1016/j.clpt.2006.08.017. PubMed PMID: 17178273.
  10. Hori S, Matsuo N, Yamamoto A, Hazui T, Yagi H, Nakano M, Suzuki Y, Miki A, Ohtani H, Sawada Y. Piloerection induced by replacing fluvoxamine with milnacipran. Br J Clin Pharmacol. 2007;63(6):665-71. Epub 2007/02/28. doi: 10.1111/j.1365-2125.2006.02838.x. PubMed PMID: 17324248; PMCID: PMC2000592.