Professional Drug Information > Zanaflex

Tizanidine (Systemic )

VA CLASSIFICATION
Primary: MS900

Commonly used brand name(s): Zanaflex.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antispastic—

Indications

Accepted

Spasticity (treatment)—Tizanidine is indicated in the acute and intermittent management of increased muscle tone associated with spasticity ^{01} related to multiple sclerosis and spinal cord injury ^{{02} {03} {04}}. It is especially useful in relieving muscle spasms and clonus ^{17}. Studies comparing the efficacy of tizanidine with that of other current treatment agents, such as baclofen and diazepam, found tizanidine to be as effective as the other agents in reducing spasticity ^{{02} {05} {19}}. In addition, clinical studies have demonstrated that tizanidine reduces muscle tone without causing excessive muscle weakness ^{{17} {18}}.

Acceptance not established
Preliminary studies and case reports suggest that tizanidine may be used as an alternative treatment in patients with chronic tension headaches and cluster headaches who are resistant to other types of drug therapy ^{{27} {28}}. However, data are insufficient to establish safety and efficacy of tizanidine for these indications.

A preliminary study suggests tizanidine may be used as an alternative to clonidine as an adjunct in anesthesia ^{26} . Results of a small study in healthy volunteers have shown that the effects of a single 12-mg dose of tizanidine were comparable to those of a 150-mcg dose of oral clonidine ^{26}. However, data are currently insufficient to establish safety and efficacy for this indication.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Imidazoline ^{01}.
Molecular weight—
    290.18 ^{20}

Mechanism of action/Effect:

Tizanidine is an alpha-adrenergic agonist ^{01}. It acts by increasing presynaptic inhibition of motor neurons at the alpha ₂-adrenergic receptor sites ^{01}, possibly by reducing the release of excitatory amino acids ^{{06} {21}} and inhibiting facilitory caeruleospinal pathways ^{15}, resulting in a reduction in spasticity ^{{01} {10}}. Some studies suggest a possible postsynaptic action at the excitatory amino acid receptors ^{15}. In addition, tizanidine may have some activity at the imidazoline receptors. A study in animals found that tizanidine acts mainly on the polysynaptic pathways, thereby reducing facilitation of spinal motor neurons ^{{01} {12}}. Tizanidine may also have minor effects on monosynaptic reflexes, which are associated with the facilitory effect of the caeruleospinal pathways ^{15}. The exact mechanism of action of tizanidine is unknown.


Other actions/effects:

Tizanidine produces antihypertensive effects ^{01}, possibly by binding to the imidazoline receptors ^{{21} {24}}. Pharmacologic studies done in animals found tizanidine to have one fiftieth to one tenth of the potency of clonidine, an alpha ₂-adrenergic agonist, in lowering blood pressure ^{01}. These antihypertensive effects are mild and transitory in relation to its activity as a muscle relaxant ^{15}.

Tizanidine also has antinociceptive effects ^{10}. However, these effects may be mediated through an alpha ₂-adrenergic receptor mechanism rather than a narcotic or endorphin mechanism ^{{10} {21}}. The antinociceptive action has been confirmed at doses lower than those producing a muscle relaxant action ^{{10} {11}}.

In addition, various studies have shown that tizanidine has anticonvulsant, hypothermic, gastrointestinal ^{29}, and sympatholytic ^{26} effects ^{21}.

Absorption:

Well-absorbed following oral administration ^{{01} {09}}. Due to extensive metabolism, bioavailability is low (approximately 40%) ^{01}. The presence of food has no effect on the extent of absorption ^{01}. However, food affects the rate of absorption by decreasing the time to peak concentration and increasing the maximum plasma concentration ^{01}, although these effects are not clinically significant.

Distribution:

Tizanidine is widely distributed ^{01}. The apparent volume of distribution (Vol _D) following intravenous administration is approximately 2.4 L per kg of body weight (L/kg) ^{01}.

Protein binding:

Low (30%) ^{{01} {21}}.

Biotransformation:

Hepatic; 95% metabolized to inactive metabolites ^{01}.

Half-life:

Tizanidine—Approximately 2.5 hours ^{{01} {08}}.

Metabolites—Approximately 20 to 40 hours ^{01}.

Time to peak concentration:

Approximately 1.5 hours ^{{01} {07}}.
Note: Following single doses of up to 8 mg, a linear relationship is observed among the dose, plasma concentration, and antispastic action ^{16}.



Elimination:
    Renal—Approximately 60% ^{01}.
    Fecal—Approximately 20% ^{01}.


Precautions to Consider

Carcinogenicity

No evidence of carcinogenicity was found in rats and mice given tizanidine at doses of up to 16 mg per kg of body weight (mg/kg) (2 times the maximum recommended human dose [MRHD] on a mg per square meter of body surface area [mg/m ²] basis) for 78 weeks and doses of up to 9 mg/kg (2.5 times the MRHD on a mg/m ² basis) for 104 weeks, respectively ^{01}.

Mutagenicity

Tizanidine demonstrated no mutagenic or clastogenic potential in in vitro studies, including the bacterial Ames test, the mammalian gene mutation test, and chromosomal aberration test in Chinese hamster cells ^{01}. In addition, there was no evidence of mutagenic potential in in vivo studies in mice, including the bone marrow micronucleus test, dominant lethal mutagenicity test, and unscheduled DNA synthesis test; or in in vivo Chinese hamster studies, including the bone marrow micronucleus test and cytogenicity test ^{01}.

Pregnancy/Reproduction
Fertility—
Studies in male and female rats given doses of 10 mg/kg (approximately 2.7 times the MRHD) and 3 mg/kg (approximately equal to the MRHD on a mg/m ² basis), respectively, found no evidence of impairment of fertility. However, another study in male and female rats receiving 30 mg/kg (8 times the MRHD on a mg/m ² basis) and 10 mg/kg (2.7 times the MRHD on a mg/m ² basis), respectively, revealed reduced fertility ^{01}. Abnormal maternal behavior, marked sedation, weight loss, and ataxia were also observed with doses used in the latter study ^{01}.

Pregnancy—
Adequate and well-controlled studies have not been done in humans.

Reproduction studies in rats and rabbits given doses of 3 mg/kg (equal to the MRHD) and 30 mg/kg (16 times the MRHD on a mg/m ² basis), respectively, found no evidence of teratogenicity ^{01}. However, a study in rats given doses equal to and up to eight times the MRHD on a mg/m ² basis found an increase in gestation period ^{01}. In addition, prenatal and postnatal pup loss increased and developmental retardation occurred. Another study in rabbits given doses of 1 mg/kg or greater (equal to or greater than 0.5 times the MRHD on a mg/m ² basis) reported an increase in postimplantation loss ^{01}.

FDA Pregnancy Category C ^{01}.


Labor and delivery—

The effect of tizanidine on labor and delivery is unknown ^{01}.

Breast-feeding

It is not known whether tizanidine is distributed into breast milk ^{01}. Since tizanidine is lipid soluble, it may pass into the breast milk ^{01}. However, problems in humans have not been documented ^{01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of tizanidine have not been performed in the pediatric population ^{01}. Safety and efficacy have not been established ^{01}.


Geriatrics


Tizanidine clearance is decreased fourfold in geriatric patients ^{01}. In addition, geriatric patients are more likely to have age-related renal function impairment, which may require dosage adjustment ^{01}.


Dental

Prolonged use of tizanidine may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen    (in clinical trials, concurrent use of acetaminophen and tizanidine resulted in a delay in the time to peak effect of tizanidine by 16 minutes; the delay was not reported to be clinically significant ^{01})


Alcohol or
CNS depression–producing medications, other (see Appendix II )    (concurrent use with tizanidine may enhance the central nervous system [CNS] depressant effects ^{01})


» Hypotension-producing medications, other (see Appendix II )    (concurrent use may potentiate antihypertensive effects; caution is recommended; concurrent use with other alpha ₂-adrenergic agonists is not recommended ^{01})


» Oral contraceptives    (concurrent use may reduce the clearance of tizanidine by approximately 50%; caution and dosage adjustments are recommended ^{01})


» Phenytoin    (in one study, a patient receiving 6 mg of phenytoin per day experienced an increase in the trough serum concentration of phenytoin from a baseline of approximately 75 micromoles per liter to 100 micromoles per liter, after one week of concurrent use with tizanidine ^{{21} {22}}; careful monitoring of serum hydantoin concentrations and dosage adjustments may be necessary)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (in controlled clinical studies, the values have been increased up to three times the upper limit of normal)

^{01}{04}{13}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment or
» Renal function impairment    (studies have shown increased plasma concentrations of tizanidine in patients with hepatic or renal function impairment ^{01}; a study evaluating six patients between 42 and 82 years of age receiving a single 4-mg dose of tizanidine reported an increase in mean maximum plasma concentration, mean elimination half-life, and mean area under the plasma concentration–time curve compared with those patients without renal impairment ^{21}; adjustment of tizanidine dosage may be necessary ^{01})


Sensitivity to tizanidine

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hepatic function determinations    (recommended during the first 6 months of treatment and periodically thereafter ^{01})




Side/Adverse Effects

Note: A study comparing tizanidine (single dose of 3 or 6 mg) with diazepam (10 mg) reported no evidence of psychological dependence associated with tizanidine ^{{21} {23}}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
CNS effects, including nervousness^{01}
and paresthesias^{01} (tingling, burning, or prickling sensations)
    
fever^{01}{13}
    
hepatotoxicity^{01}{14} (loss of appetite; nausea and/or vomiting; yellow eyes or skin)
    
skin ulcers^{01} (sores on the skin)
    
urinary tract infections^{01} (pain or burning while urinating)

Incidence less frequent
    
Arrhythmias^{01} (irregular heartbeat)
    
blood dyscrasias, including anemia^{01} (unusual tiredness or weakness), leukocytosis^{01}
or leukopenia^{01} (chills, fever, or sore throat)
    
gastrointestinal hemorrhage^{01} (black, tarry stools; bloody vomit)
    
hypothyroidism^{01} (coldness; dry, puffy skin; unusual tiredness; weight gain)
    
mood or mental changes, including delusions^{01}
or visual hallucinations^{01}{04} (seeing things that are not there)
    
renal calculi^{01} (kidney stones)
    
seizures^{01}
    
syncope^{01} (fainting)
    
upper respiratory tract infections^{01} (cough, fever, or sore throat)
    
visual disturbances, including amblyopia^{01}{13} (blurred vision), eye pain^{01}
or visual field defects^{01} (blurred vision)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anxiety^{01}
    
asthenia^{{01}{02}{03}{04}} (unusual tiredness and/or weakness)—dose-related
    
back pain^{01}{13}
    
constipation^{01}
    
depression^{01}
    
dizziness^{{01}{03}{04}{13}} —dose-related
    
drowsiness^{{01}{04}{07}{08}{13}} —dose-related
    
dry mouth^{{01}{02}{03}{04}{08}{13}} —dose-related
    
dyskinesia^{01} (uncontrolled movements of the body)
    
dyspepsia^{01}{13} (heartburn)
    
hypotension^{01}{02} (dizziness or lightheadedness, especially when getting up from a lying or sitting position)
    
gastrointestinal effects^{{01}{03}{04}{13}} (diarrhea; stomach pain; vomiting)
    
increased muscle spasms or tone^{01}{02} —dose-related
    
increased sweating^{01}
    
myasthenia^{01} (muscle weakness)
    
pharyngitis^{01}{13} (pain or burning in throat)
    
rhinitis^{01} (runny nose)
    
skin rash^{01}{04}{13}
    
somnolence^{{01}{03}{04}{13}} (sleepiness)—dose-related
    
speech disorder^{01} (difficulty in speaking)

Incidence less frequent
    
Alopecia^{01} (loss of hair)
    
arthritis^{01} (joint or muscle pain or stiffness)
    
cellulitis^{01} (swollen area that feels warm and tender)
    
dry skin^{01}
    
dysphagia^{01} (difficulty swallowing)
    
edema^{01}{13} (swelling of feet or lower legs)
    
migraine headache^{01}{13}
    
mood or mental changes, including agitation^{01}
euphoria^{01} (unusual feeling of well-being), or depersonalization^{01}
    
neck pain^{01}
    
tremor^{01}{04} (trembling or shaking)
    
weight loss^{01}





Overdose
For specific information on the agents used in the management of tizanidine overdose, see:
   • Furosemide in Diuretics, Loop (Systemic) monograph; and/or
   • Mannitol (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
    
Respiratory depression^{01}


Treatment of overdose
To enhance elimination—Gastric lavage and forced diuresis with furosemide and mannitol ^{01}.

Supportive care—May include maintaining an open airway and breathing, maintaining proper fluid and electrolyte balance, correcting hypotension, and controlling seizures. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tizanidine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tizanidine





Breast-feeding—May be distributed into breast milk





Use in the elderly—Clearance may be reduced. Also, elderly people are more likely to have age-related renal function impairment, which may require dosage adjustment
Other medications, especially hypotension-producing medications, oral contraceptives, or phenytoin
Other medical problems, especially hepatic or renal function impairment

Proper use of this medication
Not taking more medication than the amount prescribed to minimize possibility of side effects

» Proper dosing
Missed dose: Taking if remembered within an hour; not taking if not remembered until later; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

» Checking with physician before discontinuing medication; gradual dosage adjustment may be necessary

» Avoiding use of alcohol or other CNS depressants during therapy unless approved by physician

» Caution when driving or doing anything else requiring alertness because of possible drowsiness, dizziness, lightheadedness, impairment of physical or mental abilities, false sense of well-being, or visual disturbances

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

» Caution when getting up suddenly from a lying or sitting position


Side/adverse effects
Signs of potential side effects, especially CNS effects, fever, hepatotoxicity, skin ulcer, urinary tract infections, arrhythmias, blood dyscrasias, gastrointestinal hemorrhage, hypothyroidism, mood or mental changes, renal calculi, seizures, syncope, upper respiratory tract infections, and visual disturbances


Oral Dosage Forms

TIZANIDINE ^† TABLETS

Usual adult dose
Antispastic
Oral, 8 mg every six to eight hours as needed ^{01}.

Note:  Due to the dose-related nature of the side effects ^{01} and the various responses to doses among patients ^{16}, the dose may be started at 4 mg and gradually titrated to optimum effect in 2- to 4-mg increments on an individual basis over a two- to four-week period ^{{01} {25}}.



Usual adult prescribing limits
36 mg per day ^{01}.

Usual pediatric dose
Safety and efficacy have not been established ^{01}.

Usual geriatric dose
See Usual adult dose .

Note: Dosage adjustment may be required ^{01}.


Strength(s) usually available
U.S.—


4 mg (Rx) [Zanaflex (lactose) (microcrystalline cellulose) (silicone dioxide colloidal) (stearic acid)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 ºC (104 ºF), preferably between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by the manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.

Revised: 04/15/1999

References

1. Zanaflex package insert (Athena Neurosciences—US), Rev 12/96, Rec 12/96.
   

2. Stien R, Nordal HJ, Oftedal, et al. The treatment of spasticity in multiple sclerosis: a double-blind clinical trial of a new anti-spastic drug tizanidine compared with baclofen. Acta Neurol Scand 1987; 75(3): 190-4.
   

3. Hoogstraten MC, van der Ploeg RJ, v.d. Burg W, et al. Tizanidine versus baclofen in the treatment of spasticity in multiple sclerosis patients. Acta Neurol Scand 1988; 77(3): 224-30.
   

4. Lapierre Y, Bouchard S, Tansey C. Treatment of spasticity with tizanidine in multiple sclerosis. Can J Neurol Sci 1987; 14(3 Suppl): 513-7.
   

5. Bass B, Weinshenker B, Rice GP, et al. Tizanidine versus baclofen in the treatment of spasticity in patients with multiple sclerosis. Can J Neurol Sci 1988; 15(1): 15-9.
   

6. Coward DM. Selective muscle relaxant properties of tizanidine and an examination of its mode of action. Triangle 1981: 151-8.
   

7. Emre M, Leslie GC, Muir C. Correlations between dose, plasma concentrations, and antispastic action of tizanidine (Siralud ^®). J Neurol Neurosurg Psychiatry 1994; 57: 1355-9.
   

8. 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; 26(4): 9-16.
   

9. Tse FL, Jaffe JM, Bhuta S. Pharmacokinetics of orally administered tizanidine in healthy volunteers. Fundam Clin Pharmacol 1987; 1(6): 479-88.
   

10. Nabeshima T, Yamada S, Sugimoto A, et al. Comparison of tizanidine and morphine with regard to tolerance-developing ability to antinociceptive action. Pharmacol Biochem Behav 1986; 25(4): 835-41.
    

11. Kameyama T, Nabeshima T, Matsuno K, et al. Comparison of alpha-adrenoreceptor involvement in the antinociceptive action of tizanidine and clonidine in the mouse. Eur J Pharmacol 1986; 125(2): 257-64.
    

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

13. Nance PW, Bugaresti J, Shellenberger K, et al. Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. Neurology 1994; 44 Suppl 9: S44-S52.
    

14. Smith C, Birnbaum G, Carter J, et al. Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial. Neurology 1994; 44 Suppl 9: S34-S43.
    

15. Coward DM. Tizanidine: neuropharmacology and mechanism of action. Neurology 1994; 44 Suppl 9: S6-S9.
    

16. Roberts RC, Part NJ, Pokorny R, et al. Pharmacokinetics and pharmacodynamics of tizanidine. Neurology 1994; 44 Suppl 9: S29-S30.
    

17. Lataste X, Emre M, Davis C, et al. Comparative profile of tizanidine in the management of spasticity. Neurology 1994; 44 Suppl 9: S53-S59.
    

18. Milanov I, Georgiev D. Mechanisms of tizanidine action on spasticity. Acta Neurol Scand 1994; 89: 274-9.
    

19. 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.
    

20. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1996. p. 723.
    

21. 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; 53(3): 435-52.
    

22. Ueno K, Miyai K, Mitsuzane K. Phenytoin-tizanidine interaction [letter]. Drug Intell Clin Pharm 1991; 25: 1273.
    

23. Yanagita T, Yamamura H, Igarashi S. Effects of tizanidine in healthy volunteers: double-blind study compared with diazepam and placebo. Int J Clin Pharmacol Res 1988; 8: 75-94.
    

24. Maramatsu I, Kigushi S. Tizanidine may discriminate between imidazoline-receptors and alpha ₂-adrenoreceptors. Jpn J Pharmacol 1992; 59: 457-9.
    

25. Wallace JD. Summary of combined clinical analysis of controlled clinical trials with tizanidine. Neurology 1994; 44 Suppl 9: S60-S69.
    

26. Miettinen TJ, Kanto JH, Markku A, et al. The sedative and sympatholytic effects of oral tizanidine in healthy volunteers. Anesth Analg 1996; 82: 817-20.
    

27. D'Alessandro R. Tizanidine for chronic cluster headache. Arch Neurol 1996; 53(11): 1093.
    

28. Nakashima K, Tumura R, Wang Y, et al. Effects of tizanidine administration on exteroceptive suppression of the temporalis muscle in patients with chronic tension-type headache. Headache 1994; 34: 455-7.
    

29. Takayanagi I, Konno F, Kusunoki M. Some pharmacological effects of tizanidine on smooth muscle organs and alpha ₂-adrenoreceptor. Gen Pharmacol 1985; 16(5): 501-3.
    

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