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Pediatric Safety of Tizanidine

Clinical Adverse Event Database and Retrospective Chart Assessment

Abstract

Background: Tizanidine is an imidazoline with central α2-adrenoceptor agonist activity at both spinal and supraspinal levels, which is indicated as a short-acting drug for the management of spasticity. Despite being used in pediatric populations, there is no adequate information or well controlled studies to document the safety and efficacy of tizanidine in this group.

Objective: To evaluate the safety of tizanidine in the pediatric population.

Methods: We compared spontaneous adverse event reports in the Acorda Therapeutics worldwide clinical adverse event database for children (≤16 years; n = 99) and adults (>16 years; n= 1153) who had received tizanidine and for whom at least one adverse event was reported, and performed a retrospective chart review of the safety of tizanidine in children (≤16 years; n = 76) at a large US pediatric neurology practice. Causality of adverse events in our worldwide clinical adverse event database were neither assessed nor assigned by the company.

Results: When adverse events from the clinical adverse event database were collapsed into the 25 Medical Dictionary for Regulatory Activities (MedDRA; version 9.0) organ system classes, five classes were more frequent in adults (general disorders and administration site conditions [p = 0.0006], hepatobiliary disorders [p = 0.0031], nervous system disorders [p = 0.0108], skin and subcutaneous disorders [p = 0.0063], and vascular disorders [p = 0.0029]), while one class was more frequent in children (psychiatric disorders [p < 0.0001]). The most common adverse event classes in children were psychiatric disorders (52.5%) followed by nervous system disorders (29.3%), and gastrointestinal disorders (16.2%), whereas the most common adverse event classes in adults were nervous system disorders (42.4%), general disorders and administration site conditions (28.6%), and gastrointestinal disorders (21.3%). Serious adverse events were substantially less frequent in children than adults (19.2% vs 45.9%) in the clinical adverse event database. In the pediatric practice chart review, the incidence of adverse events in the MedDRA psychiatric disorders class was very similar (52.6%) to that for children in the clinical adverse event database, while the next most common classes were gastrointestinal disorders (14.5%), and nervous system disorders (13.2%). There were three deaths in children across the databases, including one from accidental exposure and two from cardiac events; the relationship of cardiac events in relation to tizanidine or other causes was difficult to assess with the limited available information. The major causes of death in adults were related to suicide or overdose. Minor, transient liver transaminase increases were occasionally reported; the effect of tizanidine could not be ruled out.

Conclusion: The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.

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References

  1. 1.

    Nance PW, Shears AH, Nance DM. Clonidine in spinal cord injury. Can Med Assoc J 1985 Jul 1; 133(1): 41–2

  2. 2.

    Nance PW, Shears AH, Nance DM. Reflex changes induced by Clonidine in spinal cord injured patients. Paraplegia 1989; 27(4): 296–301

  3. 3.

    Dall JT, Harmon RL, Quinn CM. Use of Clonidine for treatment of spasticity arising from various forms of brain injury: a case series. Brain Inj 1996 Jun; 10(6): 453–8

  4. 4.

    Coward DM. Tizanidine: neuropharmacology and mechanism of action. Neurology 1994 Nov; 44 (11 Suppl. 9): S6–10

  5. 5.

    Sayers AC, Burki HR, Eichenberger E. The pharmacology of 5-chloro-4-(2-imidazolin-2-yl-amino)-2,l,3-benzothiadiazole (DS 103-282), a novel myotonolytic agent. Arzneimittelforschung 1980; 30(5): 793–803

  6. 6.

    Nomura M, Kusaba-Suzuki M, Kimura T, et al. Cardiovascular effects of tizanidine, a new centrally acting muscle relaxant, in rats and dogs. Pharmacometrics 1985; 29: 477–91

  7. 7.

    Ono H, Matsumoto K, Kato K, et al. Effects of tizanidine, a centrally acting muscle relaxant, on motor systems. GenPharmacol 1986; 17(2): 137–42

  8. 8.

    Skoog B. A comparison of the effects of two antispastic drugs, tizanidine and baclofen, on synaptic transmission from muscle spindle afferents to spinal interneurones in cats. Acta Physiol Scand 1996 Jan; 156(1): 81–90

  9. 9.

    Mathias CJ, Luckitt J, Desai P, et al. Pharmacodynamics and pharmacokinetics of the oral antispastic agent tizanidine in patients with spinal cord injury. J Rehabil Res Dev 1989 Fall; 26(4): 9–16

  10. 10.

    Taittonen M, Raty H, Kirvela O, et al. The metabolic effects of oral tizanidine in healthy volunteers. Acta Anaesthesiol Scand 1995 Jul; 39(3): 628–32

  11. 11.

    Curtis DR, Leah JD, Peet MJ. Spinal interneurone depression by DS103-282. Br J Pharmacol 1983 May; 79(1): 9–11

  12. 12.

    Davies J. Selective depression of synaptic transmission of spinal neurones in the cat by a new centrally acting muscle relaxant, 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1, 3-benzothiodazole(DS103-282). Br JPharmacol 1982 Jul;76(3): 473–81

  13. 13.

    Davies J, Johnston SE. Selective antinociceptive effects of tizanidine (DS 103-282), a centrally acting muscle relaxant, on dorsal horn neurones in the feline spinal cord. Br J Pharmacol 1984 Jun; 82(2): 409–21

  14. 14.

    Kameyama T, Nabeshima T, Sugimoto A, et al. Antinociceptive action of tizanidine in mice and rats. Naunyn Schmiedebergs Arch Pharmacol 1985 Aug; 330(2): 93–6

  15. 15.

    Tanabe M, Kaneko T, Tonohiro T, et al. The pharmacological properties of CS-722, a newly synthesized centrally acting muscle relaxant. Neuropharmacology 1992 Oct; 31(10): 1059–66

  16. 16.

    Knutsson E, Martensson A, Gransberg L. Antiparetic and antispastic effects induced by tizanidine in patients with spastic paresis. J Neurol Sci 1982 Feb; 53(2): 187–204

  17. 17.

    Emre M, Leslie GC, Muir C, et al. Correlations between dose, plasma concentrations, and antispastic action of tizanidine (Sirdalud). J Neurol Neurosurg Psychiatry 1994 Nov; 57(11): 1355–9

  18. 18.

    Newman PM, Nogues M, Newman PK, et al. Tizanidine in the treatment of spasticity. Eur J Clin Pharmacol 1982; 23(1): 31–5

  19. 19.

    Nance PW, Bugaresti J, Shellenberger K, et al., on behalf of the North American Tizanidine Study Group. Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. Neurology 1994 Nov; 44 (11 Suppl. 9): S44–51

  20. 20.

    Smith C, Birnbaum G, Carter JL, et al., on behalf of the US Tizanidine Study Group. Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial. Neurology 1994 Nov; 44 (11 Suppl. 9): S34–42

  21. 21.

    The United Kingdom Tizanidine Trial Group. A double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity caused by multiple sclerosis. Neurology 1994 Nov; 44 (11 Suppl. 9): S70–8

  22. 22.

    Wagstaff AJ, Bryson HM. Tizanidine: a review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders. Drugs 1997 Mar; 53(3): 435–52

  23. 23.

    Nance PW, Sheremata WA, Lynch SG, et al. Relationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis. Arch Neurol 1997 Jun; 54(6): 731–6

  24. 24.

    Foradada III JR. Retrospective study of efficacy in children and young adults with Tourette’s syndrome, motor tic disorders, attention deficit hyperactivity disorder, or attention hyperactivity disorder [abstract]. 28th Annual Meeting of the Child Neurology Society; 1999 Oct 13–16; Nashville (TN)

  25. 25.

    Narayan R, Tata S. Use of tizanidine in a pediatric population: clinical outcomes [poster]. Arch Phy Med Rehabil 2000 Sep; 81(9): 1288

  26. 26.

    Gaebler-Spira D, Tata NS, Revivo, G. The use of tizanidine in a pediatric population: clinical outcome [abstract]. 54th Annual Meeting of the American Academy for Cerebral Palsy and Developmental Medicine; 2000 Sep 20–23; Toronto (ON)

  27. 27.

    Tilton AH. Management of spasticity in children with cerebral palsy. Semin Pediatr Neurol 2004 Mar; 11(1): 58–65

  28. 28.

    Guidance for industry. How to comply with the Pediatric Research Equity Act. Washington, DC: US Food and Drug Administration, Center for Drug Evaluation and Research, 2005 [online]. Available from URL: http://www.fda.gov/Cder/guidance/6215dft.pdf[Accessed 2007 Jul 3]

  29. 29.

    ICH. Harmonised tripartite guideline: structure and content of clinical study reports E3 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIAQ479.pdf [Accessed 2007 May 29]

  30. 30.

    European Agency for the Evaluation of Medicinal Products, International Council on Harmonisation, World Health Organization. Guideline for good clinical practice. ICH topic E6. Geneva: WHO, 2002 [online]. Available from URL: http://www.emea.eu.int [Accessed 2007 Jul 3]

  31. 31.

    Zanaflex® prescribing information [online]. Available from URL: http://www.zanaflexcapsules.com/Zanaflex_Insert.pdf [Accessed 2006 Apr 26]

  32. 32.

    Wallace JD. Summary of combined clinical analysis of controlled clinical trials with tizanidine. Neurology 1994 Nov; 44 (11 Suppl. 9): S60–8

  33. 33.

    Rustemovic N, Huic M, Opacic M. Tizanidine-induced acute toxic hepatitis: case report. Pharmaca 1994; 32: 457–61

  34. 34.

    de Graaf EM, Oosterveld M, Tjabbes T, et al. A case of tizanidine-induced hepatic injury. J Hepatol 1996 Nov; 25(5): 772–3

  35. 35.

    Kitabata M, Orita H, Kamimura M, et al. Symptomatic bradycardia probably due to tizanidine hydrochloride in a chronic hemodialysis patient. Ther Apher Dial 2005; 9(1): 74–7

  36. 36.

    Granfors MT, Backman JT, Neuvonen M, et al. Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther 2004 Apr; 75(4): 331–41

  37. 37.

    Granfors MT, Backman JT, Neuvonen M, et al. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther 2004 Dec; 76(6): 598–606

  38. 38.

    Granfors MT, Backman JT, Laitila J, et al. Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clin Pharmacol Ther 2005 Oct; 78(4): 400–11

  39. 39.

    Backman JT, Karjalainen MJ, Neuvonen M, et al. Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol 2006 Sep; 62(3): 345–57

  40. 40.

    Backman JT, Granfors MT, Neuvonen PJ. Rifampicin is only a weak inducer of CYPIA2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol 2006 Jun; 62(6): 451–61

  41. 41.

    Shimomura T, Awaki E, Kowa H, et al. Treatment of tension-type headache with tizanidine hydrochloride: its efficacy and relationship to the plasma MHPG concentration. Headache 1991 Oct; 3(9): 601–4

  42. 42.

    Fogelholm R, Murros K. Tizanidine in chronic tension-type headache: a placebo controlled double-blind cross-over study. Headache 1992 Nov; 32(10): 509–13

  43. 43.

    Saper JR, Winner PK, Lake III AE. An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache. Headache 2001 Apr; 41(4): 357–68

  44. 44.

    Fryda-Kaurimsky Z, Muller-Fassbender H. Tizanidine (DS 103-282) in the treatment of acute paravertebral muscle spasm: a controlled trial comparing tizanidine and diazepam. J Int Med Res 1981; 9(6): 501–5

  45. 45.

    Hennies OL. A new skeletal muscle relaxant (DS 103-282) compared to diazepam in the treatment of muscle spasm of local origin. J Int Med Res 1981; 9(1): 62–8

  46. 46.

    Berry H, Hutchinson DR. Tizanidine and ibuprofen in acute low-back pain: results of a double-blind multicentre study in general practice. J Int Med Res 1988 Mar–Apr; 16(2): 83–91

  47. 47.

    Skootsky SA, Jaeger B, Oye RK. Prevalence of myofascial pain in general internal medicine practice. West J Med 1989 Aug; 15(2): 157–60

  48. 48.

    Malanga GA, Gwynn MW, Smith R, et al. Tizanidine is effective in the treatment of myofascial pain syndrome. Pain Physician 2002 Oct; 5(4): 422–32

  49. 49.

    Semenchuk MR, Sherman S. Effectiveness of tizanidine in neuropathic pain: an open-label study. J Pain 2000 Winter; 1(4): 285–92

  50. 50.

    GormleyJr ME. Management of spasticity in children: part 2. Oral medications and intrathecal baclofen. J Head Trauma Rehabil 1999 Apr; 14(2): 207–9

  51. 51.

    Patel DR, Soyode O. Pharmacologic interventions for reducing spasticity in cerebral palsy. Indian J Pediatr 2005 Oct; 72(10): 869–72

  52. 52.

    Johnson TR, Tobias JD. Hypotension following the initiation of tizanidine in a patient treated with an angiotensin converting enzyme inhibitor for chronic hypertension. J Child Neurol 2000 Dec; 15(12): 818–9

  53. 53.

    Kurtoglu S, Caksen H, Poyrazoglu MH. Neonatal poisonings in middle Anatolia of Turkey: an analysis of 72 cases. J Toxicol Sci 2000 May; 25(2): 115–9

  54. 54.

    Spiller HA, Bosse GM, Adamson LA. Retrospective review of tizanidine (Zanaflex) overdose. J Toxicol Clin Toxicol 2004; 42(5): 593–6

  55. 55.

    Calderon-Gonzalez R, Calderon-Sepulveda RF. Clinical treatment (non surgical) of spasticity in cerebral palsy [in Spanish]. Rev Neurol 2002 Jan 1–15; 34(1): 1–6

  56. 56.

    Campistol J. Orally administered drugs in the treatment of spasticity [in Spanish]. Rev Neurol 2003 Jul 1–15; 37(1): 70–4

  57. 57.

    Pascual-Pascual SI. The study and treatment of dystonias in childhood [in Spanish]. Rev Neurol 2006 Oct 10; 43Suppl. 1: S161–8

  58. 58.

    Vasquez-Briceno A, Arellano-Saldana ME, Leon-Hernandez SR, et al. The usefulness of tizanidine: a one-year follow-up of the treatment of spasticity in infantile cerebral palsy [in Spanish]. Rev Neurol 2006 Aug 1–15; 43(3): 132–6

  59. 59.

    Shumilina AP, Guzeva VI, Skoromets AA. Sirdalud in the practice of the pediatric neurologist [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 1997; 97(10): 45–6

  60. 60.

    Brin IL, Kurenkov AL, Gotlib V, et al. The use of sirdalud in cerebral palsy in children [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 1999; 99(10): 30–3

  61. 61.

    Maksimov OG, Secheiko MV, Andriichuk EL. The use of sirdalud in the treatment of spasticity in infantile cerebral palsy [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 1999; 99(3): 22–3

  62. 62.

    Tanaka H, Fukuda I, Miyamoto A, et al. Effects of tizanidine for refractory sleep disturbance in disabled children with spastic quadriplegia [in Japanese]. No To Hattatsu 2004 Nov; 36(6): 455–60

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Acknowledgments

The design and development of this study was supported by Acorda Therapeutics, Inc. Herbert R. Henney is an employee of Acorda Therapeutics, Inc., and owns stock options in the company. Michael Chez serves as a consultant to Acorda Therapeutics, Inc., and was compensated for his work on this study. Editorial assistance in the preparation of this article was provided by Peter A. Todd, Tajut Ltd, Kaiapoi, New Zealand, and by Kristina Christian and Matthew Sidovar, both from Acorda Therapeutics, Inc.

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Correspondence to Dr Herbert R. Henney III.

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Henney, H.R., Chez, M. Pediatric Safety of Tizanidine. Pediatr-Drugs 11, 397–406 (2009). https://doi.org/10.2165/11316090-000000000-00000

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Keywords

  • Retrospective Chart Review
  • Tizanidine
  • Nervous System Disorder
  • System Organ Class
  • Accidental Exposure