TIZANIDINE HYDROCHLORIDE (Page 3 of 4)

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No evidence for carcinogenicity was seen in two dietary studies in rodents. Tizanidine was administered to mice for 78 weeks at doses up to 16 mg/kg, which is equivalent to 2 times the maximum recommended human dose on a mg/m2 basis. Tizanidine was also administered to rats for 104 weeks at doses up to 9 mg/kg, which is equivalent to 2.5 times the maximum recommended human dose on a mg/m2 basis. There was no statistically significant increase in tumors in either species.

Tizanidine was not mutagenic or clastogenic in the following in vitro assays: the bacterial Ames test and the mammalian gene mutation test and chromosomal aberration test in Chinese hamster cells. It was also negative in the following in vivo assays: the bone marrow micronucleus test in mice, the bone marrow micronucleus and cytogenicity test in Chinese hamsters, the dominant lethal mutagenicity test in mice, and the unscheduled DNA synthesis (UDS) test in mice.

Tizanidine did not affect fertility in male rats at doses of 10 mg/kg, approximately 2.7 times the maximum recommended human dose on a mg/m2 basis, and in females at doses of 3 mg/kg, approximately equal to the maximum recommended human dose on a mg/m2 basis; fertility was reduced in males receiving 30 mg/kg (8 times the maximum recommended human dose on a mg/m2 basis) and in females receiving 10 mg/kg (2.7 times the maximum recommended human dose on a mg/m2 basis). At these doses, maternal behavioral effects and clinical signs were observed including marked sedation, weight loss, and ataxia.

Pregnancy

Pregnancy Category C
Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m2 basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m basis, did not show evidence of teratogenicity. Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m2 basis increased gestation duration in rats. Prenatal and postnatal pup loss was increased and developmental retardation occurred. Post-implantation loss was increased in rabbits at doses of 1 mg/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m2 basis. Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if clearly needed.

Labor and Delivery
The effect of tizanidine on labor and delivery in humans is unknown.

Nursing Mothers
It is not known whether tizanidine is excreted in human milk, although as a lipid soluble drug, it might be expected to pass into breast milk.

Geriatric Use
Tizanidine should be used with caution in elderly patients because clearance is decreased four-fold.

Pediatric Use
There are no adequate and well-controlled studies to document the safety and efficacy of tizanidine in children.

ADVERSE REACTIONS

In multiple dose, placebo-controlled clinical studies, 264 patients were treated with tizanidine and 261 with placebo. Adverse events, including severe adverse events, were more frequently reported with tizanidine than with placebo.

Common Adverse Events Leading to Discontinuation
Forty-five of 264 (17%) patients receiving tizanidine and 13 of 261 (5%) of patients receiving placebo in three multiple dose, placebo-controlled clinical studies discontinued treatment for adverse events. When patients withdrew from the study, they frequently had more than one reason for discontinuing. The adverse events most frequently leading to withdrawal of tizanidine treated patients in the controlled clinical studies were asthenia (weakness, fatigue and/or tiredness) (3%), somnolence (3%), dry mouth (3%), increased spasm or tone (2%) and dizziness (2%).

Most Frequent Adverse Clinical Events Seen in Association with the Use of Tizanidine
In multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity, the most frequent adverse effects 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.

Adverse Events Reported in Controlled Studies The events cited reflect experience gained under closely monitored conditions of clinical studies in a highly selected patient population. In actual clinical practice or in other clinical studies, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 1 lists treatment emergent 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 at least as common as in the placebo group. These events are not necessarily related to tizanidine treatment. 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 Events Reported for Which Tizanidine Incidence is Greater Than Placebo

Event PlaceboN=261% Tizanidine TabletN=264%
*
(weakness, fatigue, and/or tiredness)
Dry Mouth 10 49
Somnolence 10 48
Asthenia * 16 41
Dizziness 4 16
UTI 7 10
Infection 5 6
Constipation 1 4
Liver function tests abnormal <1 3
Vomiting 0 3
Speech disorder 0 3
Amblyopia (blurred vision) <1 3
Urinary frequency 2 3
Flu syndrome 2 3
SGPT/ALT increased <1 3
Dyskinesia 0 3
Nervousness <1 3
Pharyngitis 1 3
Rhinitis 2 3

In the single dose, placebo-controlled study involving 142 patients with spasticity, the patients were specifically asked if they had experienced any of the four most common adverse events: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these adverse events are 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 Events Reported

Event PlaceboN = 48% Tizanidine Tablet8 mg, N = 45% Tizanidine Tablet16 mg, N = 49%
*
(weakness, fatigue and/or tiredness)
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

Other Adverse Events Observed During the Evaluation of Tizanidine
Tizanidine was administered to 1385 patients in additional clinical studies where adverse event information was available. The conditions and duration of exposure varied greatly, and included (in overlapping categories) double-blind and open-label studies, uncontrolled and controlled studies, inpatient and outpatient studies, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 1385 patients exposed to tizanidine who experienced an event of the type cited on at least one occasion while receiving tizanidine. All reported events are included except those already listed in Table 1. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with tizanidine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients.

Body as a Whole
Frequent: Fever
Infrequent: Allergic reaction, moniliasis, malaise, abscess, neck pain, sepsis, cellulites, death, overdose
Rare: Carcinoma, congenital anomaly, suicide attempt

Cardiovascular System
Infrequent: Vasodilatation postural hypotension, syncope, migraine, arrhythmia
Rare: Angina pectoris, coronary artery disorder, heart failure, myocardial infarct, phlebitis, pulmonary embolus, ventricular extrasystoles, ventricular tachycardia

Digestive System
Frequent: Abdomen pain, diarrhea, dyspepsia
Infrequent: Dysphagia, cholelithiasis, fecal impaction, flatulence, gastrointestinal hemorrhage, hepatitis, melena
Rare: Gastroenteritis, hematemesis, hepatoma, intestinal obstruction, liver damage

Hemic and Lymphatic System
Infrequent: Ecchymosis, hypercholesteremia, anemia, hyperlipemia, leukopenia, leukocytosis, sepsis
Rare: Petechia, purpura, thrombocythemia, thrombocytopenia

Metabolic and Nutritional System
Infrequent: Edema, hypothyroidism, weight loss
Rare: Adrenal cortex insufficiency, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, respiratory acidosis

Musculoskeletal System
Frequent: Myasthenia, back pain
Infrequent: Pathological fracture, arthralgia, arthritis, bursitis

Nervous System
Frequent: Depression, anxiety, paresthesia
Infrequent: Tremor, emotional lability, convulsion, paralysis, thinking abnormal, vertigo, abnormal dreams, agitation, depersonalization, euphoria, migraine, stupor, dysautonomia, neuralgia
Rare: Dementia, hemiplegia, neuropathy

Respiratory System
Infrequent: Sinusitis, pneumonia, bronchitis
Rare: Asthma

Skin and Appendages
Frequent: Rash, sweating, skin ulcer
Infrequent: Pruritus, dry skin, acne, alopecia, urticaria
Rare: Exfoliative dermatitis, herpes simplex, herpes zoster, skin carcinoma

Special Senses
Infrequent: Ear pain, tinnitus, deafness, glaucoma, conjunctivitis, eye pain, optic neuritis, otitis media, retinal hemorrhage, visual field defect
Rare: Iritis, keratitis, optic atrophy

Urogential System
Infrequent: Urinary urgency, cystitis, menorrhagia, pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged, vaginal moniliasis, vaginitis
Rare: Albuminuria, glycosuria, hematuria, metrorrhagia

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