Adverse Reactions Section
6 ADVERSE REACTIONS
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 where the frequency in the tizanidine 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 Tablets
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,
8 mg, 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. 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. Based on the information provided regarding these reactions, a causal relationship with tizanidine 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
