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TIZANIDINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tizanidine is a centrally acting (alpha2-adrenergic agonist) muscle relaxant.

Specific Substances

    1) AN-021
    2) DS-103-282
    3) DS-103-282-ch
    4) Hidrocloruro de tizanidina
    5) Sirdalud
    6) Ternelin
    7) Tizanidina, hidrocloruro de
    8) 2,1,3-Benzothiadiazole, 5-chloro-4-(2-imidazolin-2-ylamino)-
    9) 2,1,3-Benzothiadiazole-4-amine, 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-
    10) 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiodiazole hydrochloride
    11) Molecular Formula: C9-H8-Cl-N5-S,HCl
    12) CAS 51322-75-9 (tizanidine)
    13) CAS 64461-82-1 (tizanidine hydrochloride)

Available Forms Sources

    A) FORMS
    1) Tizanidine is available in the US as 2 mg and 4 mg tablets and 2 mg, 4 mg, 6 mg capsules for oral administration (Prod Info ZANAFLEX(R) oral tablets, 2013; Prod Info ZANAFLEX Capsules(R) oral capsules, 2013).
    B) USES
    1) Tizanidine is a short-acting drug used to treat spasticity (Prod Info ZANAFLEX(R) oral tablets, 2013; Prod Info ZANAFLEX Capsules(R) oral capsules, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Tizanidine is used in the management of spasticity. It is an imidazole derivative that is structurally related to clonidine, but possesses only 1/10 to 1/50 of clonidine's potency.
    B) PHARMACOLOGY: Tizanidine is a central alpha-2-adrenergic agonist that can reduce spasticity by increasing presynaptic inhibition of motor neurons. The effects appear to be greatest on polysynaptic pathways. Overall, tizanidine reduces facilitation of spinal motor neurons.
    C) TOXICOLOGY: Excessive alpha-2-adrenergic agonism causes bradycardia, hypotension and CNS depression.
    D) EPIDEMIOLOGY: Overdose is infrequent.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: COMMON: Dry mouth, somnolence, asthenia, dizziness and mild hypotension are common adverse effects with therapeutic use. INFREQUENT: Bradycardia, palpitations, ventricular extrasystoles, rash, sweating, skin ulcer, pruritus, nausea/vomiting, dyspepsia, abdominal pain, diarrhea, constipation, elevated liver enzymes, back pain, lethargy, drowsiness, insomnia, headache, anxiety, syncope, tremor, depression, weakness, paresthesia, and visual hallucinations.
    2) PEDIATRIC: In a review of the safety of tizanidine in children receiving tizanidine for tic disorders associated with attention deficit or autism, children were more likely to develop symptoms related to aggression, agitation, anxiety, and insomnia compared to adults. Overall, children had fewer serious adverse events compared to adults. COMMON: Enuresis and aggression. Symptoms that were also likely to occur included constipation, convulsions, respiratory distress and weight increase. INFREQUENT: Somnolence was reported significantly less frequently than adults. Other infrequent events were dry mouth and hypotension. Hallucinations were not reported in children.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: May cause alterations of mental status, lethargy, bradycardia, hypotension, agitation, confusion, drowsiness, vomiting, miosis, coma, or respiratory depression. Sinus bradycardia (HR 34 beats/minute), first degree AV block, and Wenckebach type second degree AV block were reported in a woman who ingested 120 mg tizanidine and 30 mg lorazepam.
    0.2.3) VITAL SIGNS
    A) Hypotension and bradycardia can develop following exposure.
    0.2.20) REPRODUCTIVE
    A) Tizanidine is classified as FDA pregnancy category C. According to the manufacturer, the drug is lipid-soluble and therefore, it may pass into breast milk.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Bradycardia and hypotensions are likely to occur in overdose. Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor respiratory function and monitor patency of airway.
    D) Monitor fluid and electrolyte status in patients with severe vomiting and/or diarrhea.
    E) Monitor liver enzymes following a significant overdose.
    F) Tizanidine concentrations are not widely available or useful to guide treatment.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) There is no specific treatment. Monitor vital signs. Hypotension should be treated with intravenous fluids. Bradycardia is typically mild and usually does not require any treatment. Bradycardia, hypotension and CNS depression often respond to physical stimulation. Children (l6 years of age or less) may develop more anxiety and aggression following exposure; these patients may need a quiet and supportive environment.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe bradycardia associated with hypotension that is not responsive to physical stimulation should be treated with a standard dose of atropine or cardiac pacing. Norepinephrine or dopamine may be beneficial in patients with severe bradycardia and hypotension not responding to physical stimulation, naloxone, intravenous fluids and/or atropine. Patients with significant CNS and/or respiratory depression should be intubated.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is not recommended because of the potential risk of altered mental status.
    2) HOSPITAL: Activated charcoal may be considered if the patient presents early after a significant ingestion, is alert and can protect airway.
    D) AIRWAY MANAGEMENT
    1) Monitor airway and respiratory function. Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS and/or respiratory depression.
    E) ENHANCED ELIMINATION
    1) Tizanidine has a large volume of distribution (2.4 L/kg); therefore, hemodialysis is unlikely to be effective.
    F) PITFALLS
    1) Patients taking tizanidine for muscular pain may also be taking opioids, which can add to the respiratory and CNS depressant effects. Clinical manifestations may be different in children (more agitation) than in adults.
    G) PHARMACOKINETICS
    1) Tizanidine is almost completely absorbed. It has a steady state volume of distribution of 2.4 L/kg following IV administration. It is approximately 30% bound to plasma proteins. Peak plasma concentrations of tizanidine occur 1 hour after dosing and it has a half-life of approximately 2.5 hours. The primary cytochrome P450 isoenzyme for tizanidine metabolism is CYP1A2.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult taking an extra 1 to 2 tablets can be monitored at home. An asymptomatic child that takes an inadvertent dose (single 2 mg tablet) can be monitored at home with adult supervision.
    2) OBSERVATION CRITERIA: Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Any patient with persistent hypotension, bradycardia, conduction disturbances or CNS depression should be admitted. i
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity (CNS depression, respiratory depression) or in whom the diagnosis is not clear.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established. ADULT: An adult developed hypotension and bradycardia after ingesting 360 mg of tizanidine. A woman developed bradycardia, hypotension, respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg of tizanidine. Following supportive therapy, she recovered completely. PEDIATRIC: A 2-year-old developed bradycardia and drowsiness after ingesting 16 mg. In children (less than 6 years old), mild drowsiness has been reported after ingesting a single tablet (2 or 4 mg).
    B) THERAPEUTIC DOSE: ADULT: Initial dose: 2 mg; it may be increased gradually; single doses greater than 16 mg have not been studied; maximum dose: 36 mg/day. PEDIATRIC: Safety and efficacy have not been determined in pediatric patients. Tizanidine has been used for off-labelled treatment of tics associated with attention deficit disorders and autism.

Clinical Effects

Summary Of Exposure

    A) USES: Tizanidine is used in the management of spasticity. It is an imidazole derivative that is structurally related to clonidine, but possesses only 1/10 to 1/50 of clonidine's potency.
    B) PHARMACOLOGY: Tizanidine is a central alpha-2-adrenergic agonist that can reduce spasticity by increasing presynaptic inhibition of motor neurons. The effects appear to be greatest on polysynaptic pathways. Overall, tizanidine reduces facilitation of spinal motor neurons.
    C) TOXICOLOGY: Excessive alpha-2-adrenergic agonism causes bradycardia, hypotension and CNS depression.
    D) EPIDEMIOLOGY: Overdose is infrequent.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: COMMON: Dry mouth, somnolence, asthenia, dizziness and mild hypotension are common adverse effects with therapeutic use. INFREQUENT: Bradycardia, palpitations, ventricular extrasystoles, rash, sweating, skin ulcer, pruritus, nausea/vomiting, dyspepsia, abdominal pain, diarrhea, constipation, elevated liver enzymes, back pain, lethargy, drowsiness, insomnia, headache, anxiety, syncope, tremor, depression, weakness, paresthesia, and visual hallucinations.
    2) PEDIATRIC: In a review of the safety of tizanidine in children receiving tizanidine for tic disorders associated with attention deficit or autism, children were more likely to develop symptoms related to aggression, agitation, anxiety, and insomnia compared to adults. Overall, children had fewer serious adverse events compared to adults. COMMON: Enuresis and aggression. Symptoms that were also likely to occur included constipation, convulsions, respiratory distress and weight increase. INFREQUENT: Somnolence was reported significantly less frequently than adults. Other infrequent events were dry mouth and hypotension. Hallucinations were not reported in children.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: May cause alterations of mental status, lethargy, bradycardia, hypotension, agitation, confusion, drowsiness, vomiting, miosis, coma, or respiratory depression. Sinus bradycardia (HR 34 beats/minute), first degree AV block, and Wenckebach type second degree AV block were reported in a woman who ingested 120 mg tizanidine and 30 mg lorazepam.

Vital Signs

    3.3.1) SUMMARY
    A) Hypotension and bradycardia can develop following exposure.
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension has been reported following tizanidine therapy (Prod Info ZANAFLEX(R) oral tablets, 2013).
    B) WITH POISONING/EXPOSURE
    1) In a retrospective study, hypotension was observed in 8 of 45 patients following tizanidine overdose (mean dose ingested = 72 mg) (Spiller et al, 2004).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Bradycardia has been reported following tizanidine therapy (Prod Info ZANAFLEX CAPSULES(TM) oral capsules, 2006).
    B) WITH POISONING/EXPOSURE
    1) In a retrospective study, bradycardia was observed in 14 of 45 patients following tizanidine overdose (mean dose ingested = 72 mg) (Spiller et al, 2004).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Although dose-related retinal degeneration and corneal opacities have been reported in animal studies at doses equal to approximately the maximum recommended dose on a milligram-per-square-meter basis, no such events have been reported in clinical studies (Prod Info ZANAFLEX CAPSULES(TM) oral capsules, 2006).
    B) WITH POISONING/EXPOSURE
    1) MIOSIS
    a) Miosis has been reported following tizanidine overdose (Spiller et al, 2004; Chu et al, 2001).
    b) CASE REPORT: A 30-year-old woman developed bradycardia (HR in the 30s), hypotension (81/48 mmHg), respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg (30 tablets of either 2 mg or 4 mg) of tizanidine. Following supportive therapy, she recovered completely (Spiller et al, 2004).
    c) CASE REPORT: A 46-year-old man developed hypotension (93/47 mmHg), a heart rate of 50 beats/min, and pinpoint pupils after ingesting 360 mg of tizanidine (Spiller et al, 2004).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia, palpitations, and ventricular extrasystoles have been reported infrequently and have been transitory (Prod Info ZANAFLEX(R) oral tablets, 2013; Coward, 1994; Lang & Riley, 1992; Bes et al, 1988).
    b) CASE REPORT: A 71-year-old woman on hemodialysis for renal failure experienced dizziness and loss of balance while receiving tizanidine 3 mg daily for 33 days for leg cramps. A 24-hour ECG revealed bradycardia at an average of 48 beats/min, which resolved when tizanidine use was discontinued (Kitabata et al, 2005).
    2) WITH POISONING/EXPOSURE
    a) In a retrospective study, bradycardia was observed in 14 of 45 patients (31%) following tizanidine overdose (mean dose ingested = 72 mg) (Spiller et al, 2004).
    b) CASE REPORT/PEDIATRIC: A 2-year-old (weight unknown) developed bradycardia (HR 40 beats/min) and drowsiness after ingesting 16 mg of tizanidine (Spiller et al, 2004).
    c) CASE REPORT: A 30-year-old woman developed bradycardia (heart rate in the 30s), hypotension (81/48 mmHg), respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg (30 tablets of either 2 mg or 4 mg) of tizanidine. Following supportive therapy, she recovered completely (Spiller et al, 2004).
    d) CASE REPORT: Sinus bradycardia (HR 34 beats/min), first degree AV block, and Wenckebach type second degree AV block were reported in a 27-year-old woman who ingested 120 mg tizanidine and 30 mg lorazepam (Luciani et al, 1995).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension, usually mild, has been reported in up to 33% of patients treated with oral tizanidine. Hypotension is dose-related (Prod Info ZANAFLEX(R) oral tablets, 2013; Fogelholm & Murros, 1992; Lang & Riley, 1992; Eyssette et al, 1988; Bes et al, 1988; Stien et al, 1987).
    b) Orthostatic hypotension, light-headedness, dizziness, and rarely syncope have been associated with tizanidine (Prod Info ZANAFLEX(R) oral tablets, 2013).
    c) In a retrospective chart review to evaluate the safety of tizanidine in pediatric (children 16 years of age or less) patients (n=99), hypotension (2% (n=2)) was reported infrequently (Henney & Chez, 2009).
    2) WITH POISONING/EXPOSURE
    a) In a retrospective study, hypotension was observed in 8 of 45 patients (18%) following tizanidine overdose (mean dose ingested = 72 mg) (Spiller et al, 2004).
    b) CASE REPORT: A 46-year-old man developed hypotension (93/47 mmHg), a heart rate of 50 beats/min, and pinpoint pupils after ingesting 360 mg of tizanidine (Spiller et al, 2004).
    c) CASE REPORT: A 47-year-old with a history of spastic paraplegia, unintentionally ingested 16 mg of tizanidine (usual dose 4 mg daily) and became drowsy and developed miosis. Approximately 3 hours after exposure, the patient became hypotensive (74/48 mmHg), which responded to a crystalloid infusion (BP normalized after 4L of normal saline). No other cardiovascular or CNS effects were reported. The patient was discharged to home the following day (Chu et al, 2001).
    d) CASE REPORT: A 30-year-old woman developed bradycardia (HR in the 30s), hypotension (81/48 mmHg), respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg (30 tablets of either 2 mg or 4 mg) of tizanidine. Following supportive therapy, she recovered completely (Spiller et al, 2004).
    e) CASE REPORT: A 63-year-old woman developed hypotension (88/52 mmHg) and a heart rate of 54 beats/min after ingesting 28 mg of tizanidine (Spiller et al, 2004).
    C) ATRIOVENTRICULAR BLOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Sinus bradycardia (HR 34 beats/min), first degree AV block, and Wenckebach type second degree AV block were reported in a 27-year-old woman who ingested 120 mg tizanidine and 30 mg lorazepam (Luciani et al, 1995).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 42-year-old man was found to have an eosinophilic exudative pleural effusion that was temporally related to the administration of tizanidine. The patient had a long history of low back pain and bilateral lower extremity pain that was unresponsive to treatment. Baclofen was added for control of lower extremity cramping, but was replaced after one week by tizanidine 2 mg orally every 8 hours. Six weeks after starting tizanidine, a large right-sided pleural effusion was discovered. One month later, tizanidine was increased to 4 mg every 8 hours and later that same month the patient became symptomatic and complained of shortness of breath, dyspnea on exertion, and pleuritic chest pain. The patient received an extensive workup to discover the cause of the pleural effusion and after ruling out other likely causes a drug reaction was suspected. Tizanidine was discontinued and 4 weeks later chest x-rays and physical examination showed resolution of the pleural effusion (Moufarrege et al, 2003).
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study, respiratory depression was observed in 3 of 45 patients (7%) following tizanidine overdose (mean dose ingested = 72 mg) (Spiller et al, 2004).
    b) CASE REPORT: A 30-year-old woman developed bradycardia (HR in the 30s), hypotension (81/48 mmHg), respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg (30 tablets of either 2 mg or 4 mg) of tizanidine. Following supportive therapy, she recovered completely (Spiller et al, 2004).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) LETHARGY
    1) WITH THERAPEUTIC USE
    a) Sedation has been reported in 48% (n=264) of patients with 10% reporting it as severe. It may interfere with everyday activities; the sedative effects appear to be dose-related (Prod Info ZANAFLEX(R) oral tablets, 2013; Fogelholm & Murros, 1992; Medici et al, 1989; Bes et al, 1988; Bass et al, 1988; Berry & Hutchinson, 1988; Lapierre et al, 1987; Stien et al, 1987). Sedation has tended to occur early, subsiding with continued therapy in some studies (Lapierre et al, 1987); however, drowsiness persists in some patients (Medici et al, 1989; Bass et al, 1988).
    b) PEDIATRIC USE: In a retrospective chart review to evaluate the safety of tizanidine in pediatric (children 16 years of age or less) patients with tic disorders associated with attention deficit or autism (n=99), somnolence developed in 7% of patients compared to 15.6% of adults (Henney & Chez, 2009).
    c) Adverse central nervous system effects of tizanidine other than sedation have included insomnia and fatigue. Headache, nervousness, dizziness or light-headedness, anxiety, syncope, and tremor have occurred less frequently. Depression, weakness, and paresthesia have also been frequently reported (Prod Info ZANAFLEX(R) oral tablets, 2013; Wagstaff & Bryson, 1997; Hutchinson, 1989; Medici et al, 1989; Bes et al, 1988; Eyssette et al, 1988; Bass et al, 1988; Lapierre et al, 1987) .
    d) Daytime drowsiness occurred more frequently with tizanidine compared with baclofen in one study involving multiple sclerosis patients (Bass et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) Lethargy, confusion, agitation, or coma have been reported following tizanidine overdose. In children (less than 6 years old), mild drowsiness has been reported after the ingestion of a single tablet (2 or 4 mg) (Spiller et al, 2004).
    b) CASE REPORT: A 2-year-old developed bradycardia (HR 40 beats/min) and drowsiness after ingesting 16 mg of tizanidine (Spiller et al, 2004).
    c) CASE REPORT: A 30-year-old woman developed bradycardia (HR in the 30s), hypotension (81/48 mmHg), respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg (30 tablets of either 2 mg or 4 mg) of tizanidine. Following supportive therapy, she recovered completely (Spiller et al, 2004).
    d) INCIDENCE: In a series of 45 patients with tizanidine only exposure, 38 (84%) developed lethargy, and 2 (4%) became comatose (Spiller et al, 2004).
    B) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a series of 45 patients with tizanidine only exposure, 7 (16%) developed agitation, and 5 (11%) developed confusion (Spiller et al, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, dyspepsia, abdominal pain, and diarrhea or constipation have been reported occasionally during oral tizanidine therapy (less than 6% of patients; n=264) (Prod Info ZANAFLEX CAPSULES(TM) oral capsules, 2006; Medici et al, 1989; Bass et al, 1988; Berry & Hutchinson, 1988; Bes et al, 1988; Lapierre et al, 1987).
    b) PEDIATRIC USE: In a retrospective chart review to evaluate the safety of tizanidine in pediatric (children 16 years of age or less) patients with tic disorders associated with attention deficit or autism (n=99), constipation was reported in 6% of children compared to 0.9% in adults; vomiting occurred in 3% of children compared to 2.4% of adults (Henney & Chez, 2009).
    c) Dryness of the mouth has been observed relatively frequently during tizanidine therapy, particularly during initiation of therapy (49% to 88% of patients). This effect appears to be dose-dependent (Prod Info ZANAFLEX(R) oral tablets, 2013). Symptoms generally subside with continued administration (Lang & Riley, 1992; Bass et al, 1988; Bes et al, 1988; Stien et al, 1987; Lapierre et al, 1987).
    1) PEDIATRIC USE: In a retrospective chart review to evaluate the safety of tizanidine in pediatric (children 16 years of age or less) patients with tic disorders associated with attention deficit or autism (n=99), dry mouth was not reported in children (Henney & Chez, 2009).
    2) WITH POISONING/EXPOSURE
    a) In a retrospective study, vomiting was observed in 3 of 45 patients following tizanidine overdose (mean dose ingested = 72 mg) (Spiller et al, 2004).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Elevations in liver function tests (bilirubin, transaminases) have been described in some patients during tizanidine therapy, resolving after dose reduction or drug withdrawal. Occasionally, nausea, vomiting, anorexia, and jaundice have been reported in symptomatic cases (Prod Info ZANAFLEX(R) oral tablets, 2013; de Graaf et al, 1996; Lang & Riley, 1992; Eyssette et al, 1988; Lapierre et al, 1987).
    b) PEDIATRIC USE: In a retrospective chart review to evaluate the safety of tizanidine in pediatric (children 16 years of age or less) patients with tic disorders associated with attention deficit or autism, increases in liver enzymes or hepatobiliary disorders were less likely to occur compared to adults (Henney & Chez, 2009).
    c) CASE SERIES: Three tizanidine-treated patients have experienced liver failure and died. One patient developed jaundice and liver enlargement after using tizanidine (6 mg three times daily) for 2 months. A liver biopsy revealed multilobular necrosis without eosinophilic infiltration. Ten days later, he died in hepatic coma. There was no explanation for the liver injury other than a reaction to tizanidine. The two other patients were taking carbamazepine and dantrolene, respectively, in addition to tizanidine (Prod Info ZANAFLEX CAPSULES(TM) oral capsules, 2006).
    d) CASE REPORT: Tizanidine-induced hepatic injury was described in a case report. A 55-year-old woman with multiple sclerosis was administered tizanidine (maximum of 36 mg/day after 2 weeks) for 4 months to treat spastic paraparesis. She developed jaundice, fatigue, nausea, anorexia, elevated serum liver enzymes, decreased clotting factors, and prolonged clotting times. She was also taking baclofen, chlormezanone, diazepam, flurazepam, diclofenac, and 10 days later all other drugs were discontinued. She was treated with a low protein diet, lactulose, neomycin, and phytomenadione. Baclofen was reinstituted after 5 days because of severe leg spasticity. Her condition improved after 2 weeks and, by 2 months following tizanidine discontinuation, her serum liver enzymes were normal. A single tizanidine 4 mg dose was given accidentally resulting in increases in serum aspartate aminotransferase (AST) (13 to 154 Units/L) and alanine aminotransferase (ALT) (14 to 155 Units/L) within 6 days. These values normalized within 1 week. Gamma-GT was slightly elevated for several months. Other causes of liver injury were ruled out (de Graaf et al, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Skin rash, sweating, skin ulcer, and pruritus have been reported occasionally during tizanidine therapy (Prod Info ZANAFLEX(R) oral tablets, 2013; Prod Info ZANAFLEX CAPSULES(TM) oral capsules, 2006; Lang & Riley, 1992; Lapierre et al, 1987).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain and myasthenia have frequently been reported by patients in clinical trials. In trials, increased spasm or tone lead to 2% (n=264) of patients withdrawal (Prod Info ZANAFLEX CAPSULES(TM) oral capsules, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Tizanidine is classified as FDA pregnancy category C. According to the manufacturer, the drug is lipid-soluble and therefore, it may pass into breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: In reproduction studies, no evidence of teratogenicity was observed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m(2) basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m(2) basis (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans(Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013).
    B) PREGNANCY CATEGORY
    1) FDA pregnancy category C (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013)
    C) ANIMAL STUDIES
    1) RATS, RABBITS: Tizanidine increased gestation duration in rats at doses up to 8 times the maximum recommended human dose on a mg/m(2) basis. In addition, prenatal and postnatal pup loss was increased and developmental retardation was observed. In rabbits, postimplantation loss was increased at doses of 1 mg/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m(2) basis (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether tizanidine is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown . Until additional data are available, caution should be exercised with its use in women who are nursing (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013). According to the manufacturer, the drug is lipid-soluble and therefore, may pass into breast milk (Prod Info ZANAFLEX(R) oral tablets, 2006).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on human fertility from exposure to tizanidine (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013).
    B) ANIMAL STUDIES
    1) RATS: In male rats, tizanidine, at doses of 10 mg/kg (approximately 8 times the maximum recommended human dose on a mg/m(2) basis), did not affect fertility. However, tizanidine, at doses 30 mg/kg (8 times the maximum recommended human dose on a mg/m(2) basis), reduced fertility (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013).
    2) RATS: In female rats, tizanidine, at doses 3 mg/kg/day (approximately 3 times the maximum recommended human dose on a mg/m(2) basis), did not affect fertility. However tizanidine, at doses of 10 mg/kg/day, reduced fertility (Prod Info ZANAFLEX Capsules(R) oral capsules, 2013; Prod Info ZANAFLEX(R) oral tablets, 2013).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS51322-75-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS64461-82-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Bradycardia and hypotensions are likely to occur in overdose. Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor respiratory function and monitor patency of airway.
    D) Monitor fluid and electrolyte status in patients with severe vomiting and/or diarrhea.
    E) Monitor liver enzymes following a significant overdose.
    F) Tizanidine concentrations are not widely available or useful to guide treatment.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Any patient with persistent hypotension, bradycardia, conduction disturbances or CNS depression should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult taking an extra 1 to 2 tablets can be monitored at home. An asymptomatic child that takes an inadvertent dose (single 2 mg tablet) can be monitored at home with adult supervision.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity (CNS depression, respiratory depression) or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility.

Monitoring

    A) Monitor vital signs and mental status.
    B) Bradycardia and hypotensions are likely to occur in overdose. Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor respiratory function and monitor patency of airway.
    D) Monitor fluid and electrolyte status in patients with severe vomiting and/or diarrhea.
    E) Monitor liver enzymes following a significant overdose.
    F) Tizanidine concentrations are not widely available or useful to guide treatment.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) GI decontamination is not recommended because of the potential risk of altered mental status.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of a tizanidine overdose, treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Bradycardia and hypotensions are likely to occur in overdose. Institute continuous cardiac monitoring and obtain an ECG.
    3) Monitor respiratory function and monitor patency of airway.
    4) Monitor fluid and electrolyte status in patients with severe vomiting and/or diarrhea.
    5) Monitor liver enzymes following a significant overdose.
    6) Tizanidine concentrations are not widely available or useful to guide treatment.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) NALOXONE
    1) Seven patients have received naloxone following tizanidine overdose; arousal was observed in only one patient. Five patients had no response and one had a poor response (Spiller et al, 2004).
    E) AGGRESSIVE BEHAVIOR
    1) PEDIATRIC USE
    a) Children may develop more aggression/agitation and less CNS depression than adults.
    b) RETROSPECTIVE CHART REVIEW: In a retrospective chart review to evaluate the safety of tizanidine for off-labeled (ie, most commonly used as an adjunctive treatment for attention deficit disorders and autism) use in pediatric (children 16 years of age or less) patients, psychiatric disturbances were the most common disorders reported in this age group. Aggression was one of the most common adverse events. Other events occurring in greater than 2% or more of children in this age group included: anxiety, mood swings, mania, psychomotor hyperactivity, depression, irritability, impulsive behavior, obsessive thoughts, agitation, panic attack, sleep terror and tic. These events were either not observed or occurred with minor frequency (less than 1%) in adults. In this study, children were also less likely to develop CNS depression (ie, somnolence) compared to adults; insomnia was frequently observed. Severe hypotension was also not observed. The authors noted that the differences in adverse effect profile between children an adults may be related to the underlying disorders for which tizanidine is used (off label) in children (autism, ADD) (Henney & Chez, 2009).

Enhanced Elimination

    A) SUMMARY
    1) Tizanidine is also extensively distributed throughout the body and has a large volume of distribution (2.4 L/kg) (Prod Info ZANAFLEX(R) oral tablets, 2013). It is anticipated that hemodialysis and hemoperfusion would not be effective in removal of tizanidine from plasma.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established. ADULT: An adult developed hypotension and bradycardia after ingesting 360 mg of tizanidine. A woman developed bradycardia, hypotension, respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg of tizanidine. Following supportive therapy, she recovered completely. PEDIATRIC: A 2-year-old developed bradycardia and drowsiness after ingesting 16 mg. In children (less than 6 years old), mild drowsiness has been reported after ingesting a single tablet (2 or 4 mg).
    B) THERAPEUTIC DOSE: ADULT: Initial dose: 2 mg; it may be increased gradually; single doses greater than 16 mg have not been studied; maximum dose: 36 mg/day. PEDIATRIC: Safety and efficacy have not been determined in pediatric patients. Tizanidine has been used for off-labelled treatment of tics associated with attention deficit disorders and autism.

Therapeutic Dose

    7.2.1) ADULT
    A) INITIAL DOSE: 2 mg every 6 to 8 hours as needed; may be increased by 2 to 4 mg at each dose allowing 1 to 4 days between each increase; MAX: 36 mg/day (Prod Info ZANAFLEX(R) oral tablets, 2013)
    B) PREMEDICATION: The effect of the tizanidine 12 mg dose was equivalent to clonidine 150 mcg in quality and magnitude (sedative and sympatholytic effects) but had a shorter duration of action which may make it useful in premedication (Miettinen et al, 1996). The small size of this study makes any conclusion questionable; further study with a larger sample size is needed.
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info ZANAFLEX(R) oral tablets, 2013).
    B) OFF-LABELLED USE: In children less than 10 years of age with attention deficit disorders and autism: 1 mg orally of tizanidine has been administered at bedtime to control tics, and in children 10 years of age and older 2 mg orally is given at bedtime (Henney & Chez, 2009).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT
    a) In a small retrospective study, clinically significant toxic effects (hypotension, bradycardia, significant CNS depression) did not develop in adults at doses below 28 milligrams (7 to 14 tablets). It was reported that tizanidine may have a shorter duration of effects following an overdose compared to clonidine (mean duration, 9 to 16 hours) (Spiller et al, 2004).
    b) CASE REPORT: A 46-year-old man developed hypotension (93/47 mmHg) and a heart rate of 50 beats/min after ingesting 360 mg of tizanidine (Spiller et al, 2004).
    c) CASE REPORT: A 47-year-old with a history of spastic paraplegia, unintentionally ingested 16 mg of tizanidine (usual dose 4 mg daily) and became drowsy and developed miosis. Approximately 3 hours after exposure, the patient became hypotensive (74/48 mmHg), which responded to a crystalloid infusion (BP normalized after 4L of normal saline). No other cardiovascular or CNS effects were reported. The patient was discharged to home the following day (Chu et al, 2001).
    d) CASE REPORT: Sinus bradycardia (HR 34 beats/min), first degree AV block, and Wenckebach type second degree AV block were reported in a 27-year-old woman who ingested 120 mg of tizanidine and 30 mg of lorazepam (Luciani et al, 1995).
    e) CASE REPORT: A 30-year-old woman developed bradycardia (HR in the 30s), hypotension (81/48 mmHg), respiratory depression, pinpoint pupils, and coma after ingesting 60 mg to 120 mg (30 tablets of either 2 mg or 4 mg) of tizanidine. Following supportive therapy, she recovered completely (Spiller et al, 2004).
    2) PEDIATRIC
    a) CASE REPORT: A 2-year-old developed bradycardia (HR 40 beats/min) and drowsiness after ingesting 16 mg of tizanidine (Spiller et al, 2004).
    b) In children (less than 6 years old), mild drowsiness has been reported after the ingestion of a single tablet (2 or 4 mg) (Spiller et al, 2004).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ORAL
    a) CAPSULE: 15.6 ng/mL (Hutchinson, 1989).
    2) ONSET
    a) INITIAL RESPONSE: Spasticity, oral: 2 weeks (Eyssette et al, 1988).
    b) PEAK RESPONSE: Spasticity, oral: 8 weeks (Eyssette et al, 1988).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 57-year-old woman was found dead following a mixed ingestion including tizanidine, alcohol, and diazepam. Postmortem tizanidine concentrations were as follows:
    1) Heart blood: 2.34 mg/L
    2) Urine: 0.055 mg/L
    3) Liver: 9.19 mg/kg
    4) Bile: 3.37 mg/L
    5) Gastric: 10 mg

Workplace Standards

    A) ACGIH TLV Values for CAS51322-75-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS64461-82-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS51322-75-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS64461-82-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS51322-75-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS64461-82-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS51322-75-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS64461-82-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 235 milligrams/kilogram (RTECS, 2004)
    B) LD50- (ORAL)RAT:
    1) 600 milligrams/kilogram (RTECS, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tizanidine, an imidazole derivative, is a centrally acting muscle relaxant. It is an agonist at alpha-2 adrenergic receptor and imidazoline receptor sites. It presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. Tizanidine has been shown to reduce polysynaptic excitation of spinal cord interneurons, preventing release of excitatory amino acids, an effect that may be mediated by a presynaptic alpha-2 adrenergic agonist. It has no direct effect on skeletal muscle fibers or the neuromuscular junction, and no major effect on monosynaptic spinal reflexes. Tizanidine is structurally related to clonidine, but possesses only 1/10 to 1/50 of clonidine's potency. It has been reported that tizanidine 12 mg has sedative and sympatholytic effects comparable with clonidine 150 micrograms.(Prod Info ZANAFLEX(R) oral tablets, 2013; Miettinen et al, 1996; Bass et al, 1988; Bes et al, 1988; Eyssette et al, 1988; Muramatsu & Kigoshi, 1992).

Physicochemical

Physical Characteristics

    A) White to off-white, fine crystalline powder, odorless or with a faint characteristic odor, slightly soluble in water and methanol (Prod Info Zanaflex(R), 2000).

Molecular Weight

    A) 290.2 (Prod Info Zanaflex(R), 2000)

References

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