Tizanidine (Page 2 of 6)

5.6 Hypersensitivity Reactions

Tizanidine hydrochloride can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue tizanidine hydrochloride and seek immediate medical care should these signs and symptoms occur. [see Contraindications ( 4) ]

5.7 Increased Risk of Adverse Reactions in Patients with Renal Impairment

Tizanidine hydrochloride should be used with caution in patients with renal insufficiency (creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. [see Dosage and Administration ( 2.2) and Use in Specific Populations ( 8.6)]

5.8 Withdrawal Adverse Reactions

Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 to 4 mg per day). [see Dosage and Administration ( 2.2) ]


The following adverse reactions are described elsewhere in other sections of the prescribing information:

  • Hypotension [see Warnings and Precautions ( 5.1) ]
  • Liver Injury [see Warnings and Precautions ( 5.2) ]
  • Sedation [see Warnings and Precautions ( 5.3) ]
  • Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions ( 5.4) ]
  • Hypersensitivity Reactions [see Warnings and Precautions ( 5.6) ]

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Three double-blind, randomized, placebo controlled -clinical studies were conducted to evaluate the effect of tizanidine on spasticity control. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1- week dose tapering. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies patient ages ranged from 15 to 69 years and 51.4 percent were women. The median dose during the plateau phase ranged from 20 to 28 mg/day.

The most frequent adverse reactions reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness) and dizziness. Three-quarters of the patients rated the events as mild to moderate and one-quarter of the patients rated the events as being severe. These events appeared to be dose related.

Table 1 lists signs and symptoms that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine hydrochloride where the frequency in the tizanidine hydrochloride group was greater than the placebo group. For comparison purposes, the corresponding frequency of the event (per 100 patients) among placebo treated patients is also provided.

Table 1: Multiple Dose, Placebo-Controlled Studies—Frequent (>2%) Adverse Reactions Reported for Which Tizanidine Tablets Incidence is Greater than Placebo

Event Placebo N = 261 % Tizanidine Tablet N = 264 %
Dry mouth 10 49
Somnolence 10 48
Asthenia* 16 41
Dizziness 4 16
UTI 7 10
Infection 5 6
Constipation 1 4
Liver test abnormality 2 6
Vomiting 0 3
Speech disorder 0 3
Amblyopia (blurred vision) <1 3
Urinary frequency 2 3
Flu syndrome 2 3
Dyskinesia 0 3
Nervousness <1 3
Pharyngitis 1 3
Rhinitis 2 3

*(weakness, fatigue, and/or tiredness)

In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies ( 14) ], the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less.

Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported

Event Placebo N = 48 % Tizanidine Tablet, 8mg , N = 45 % Tizanidine Tablet,16 mg, N = 49 %
Somnolence 31 78 92
Dry mouth 35 76 88
Asthenia* 40 67 78
Dizziness 4 22 45
Hypotension 0 16 33
Bradycardia 0 2 10

*(weakness, fatigue, and/or tiredness)

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of tizanidine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Certain events, such as somnolence, dry mouth, hypotension, decreased blood pressure, bradycardia, dizziness, weakness or asthenia, muscle spasms, hallucinations, fatigue, liver function test abnormality and hepatotoxicity, have been observed in post marketing and clinical trials and are discussed in previous sections of this document.

The following adverse reactions have been identified as occurring in the post marketing experience of tizanidine hydrochloride. Based on the information provided regarding these reactions, a causal relationship with tizanidine hydrochloride cannot be entirely excluded. The events are listed in order of decreasing clinical significance; severity in the post marketing setting is not reported.

  • Stevens Johnson Syndrome
  • Anaphylactic Reaction
  • Exfoliative Dermatitis
  • Ventricular
  • Tachycardia
  • Hepatitis
  • Convulsion
  • Depression
  • Arthralgia
  • Paresthesia
  • Rash
  • Tremor
    To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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