Tizanidine Hydrochloride

SECTION 2: Hazards identification

Dose and A single dose of 8 mg of tizanidine reduces muscle tone in patients Administration with spasticity for a period of several hours. The effect peaks at Approximately 1 to 2 hours and dissipates between 3 to 6 hours. Effects are dose-related. Although single doses of less than 8 mg have not been demonstrated to be effective in controlled clinical studies, the dose-related nature of tizanidine's common adverse events make it prudent to begin treatment with single oral doses of 4 mg. Increase the dose gradually (2 to 4 mg steps) to optimum effect (satisfactory reduction of muscle tone at a tolerated dose). The dose can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours. The total daily dose should not exceed 36 mg. Experience with single doses exceeding 8 mg and daily doses exceeding 24 mg is limited. There is essentially no experience with repeated, single, daytime doses greater than 12 mg or total daily doses greater than 36 mg Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. These pharmacokinetic differences may result in clinically significant differences when [1] switching administration of the capsule between the fed or fasted state, [2] switching between the tablet and capsule in the fed state, or [3] switching between the intact capsule and sprinkling the contents of the capsule on applesauce. These changes may result in increased adverse events or delayed/more rapid onset of activity, depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions Adverse Effects 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%). 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. 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. 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; rare adverse events are those occurring in fewer than 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, hyperglycaemia, hypokalaemia, hypernatremia, hypoproteinemia, respiratory acidosis MUSCULOSKELETAL SYSTEM Frequent: Myasthenia, back pain Infrequent: Pathological fracture, arthralgia, arthritis, bursitis NERVOUS SYSTEM Frequent: Depression, anxiety, paresthesia Infrequent: Tremor, emotional liability, 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 UROGENITAL SYSTEM Infrequent: Urinary urgency, cystitis, menorrhagia, pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged, vaginal moniliasis, vaginitis Rare: Albuminuria, glycosuria, hematuria, metrorrhagia Review of the safety surveillance database revealed cases of Over Dose Effect intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function are also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to those following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center. Contraindications Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. Significantalterations of pharmacokinetic parameters of tizanidine including increased AUC, t1/2, Cmax, increased oral bioavailability and decreased plasma clearance have been observed with concomitant administration of either fluvoxamine or ciprofloxacin. This pharmacokinetic interaction can result in potentially serious adverse events. Pregnancy Comments 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/m2 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. Pregnancy Category Pregnancy Category C