Product Elements:
Tizanidine tizanidine anhydrous lactose cellulose, microcrystalline silicon dioxide stearic acid tizanidine hydrochloride tizanidine white to off white u;168
Indications and Usage:
Tizanidine tablet is a short-acting drug for the management of spasticity. because of the short duration of effect, treatment with tizanidine should be reserved for those daily activities and times when relief of spasticity is most important (see dosage and administration).
Warnings:
Limited data base for chronic use of single doses above 8 mg and multiple doses above 24 mg per day clinical experience with long-term use of tizanidine at doses of 8 to 16 mg single doses or total daily doses of 24 to 36 mg (see dosage and administration) is limited. in safety studies, approximately 75 patients have been exposed to individual doses of 12 mg or more for at least one year or more and approximately 80 patients have been exposed to total daily doses of 30 to 36 mg/day for at least one year or more. there is essentially no long-term experience with single, daytime doses of 16 mg. because long-term clinical study experience at high doses is limited, only those adverse events with a relatively high incidence are likely to have been identified (see warnings, precautions and adverse reactions). hypotension tizanidine is a α 2 -adrenergic agonist (like clonidine) and can produce hypotension. in a single dose study where blood pressure was monitored closely after dosing, two-
Read more...thirds of patients treated with 8 mg of tizanidine had a 20% reduction in either the diastolic or systolic bp. the reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing and was associated, at times, with bradycardia, orthostatic hypotension, lightheadedness/dizziness and rarely syncope. the hypotensive effect is dose related and has been measured following single doses of ⥠2 mg.the chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. in addition, patients moving from a supine to a fixed upright position may be at increased risk for hypotension and orthostatic effects. caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy and should not be used with other α 2 -adrenergic agonists. clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg of tizanidine. therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of cyp1a2, is contraindicated (see contraindications and clinical pharmacology: drug interactions). risk of liver injury tizanidine occasionally causes liver injury, most often hepatocellular in type. in controlled clinical studies, approximately 5% of patients treated with tizanidine had elevations of liver function tests (alt/sgpt, ast/sgot) to greater than 3 times the upper limit of normal (or 2 times if baseline levels were elevated) compared to 0.4% in the control patients. most cases resolved rapidly upon drug withdrawal with no reported residual problems. in occasional symptomatic cases, nausea, vomiting, anorexia and jaundice have been reported. based upon postmarketing experience, death associated with liver failure has been a rare occurrence reported in patients treated with tizanidine.monitoring of aminotransferase levels is recommended during the first 6 months of treatment (e.g., baseline, 1, 3 and 6 months) and periodically thereafter, based on clinical status. because of the potential toxic hepatic effect of tizanidine, the drug should ordinarily be avoided or used with extreme caution in patients with impaired hepatic function. sedation in the multiple doses, controlled clinical studies, 48% of patients receiving any dose of tizanidine reported sedation as an adverse event. in 10% of these cases, the sedation was rated as severe compared to < 1% in the placebo treated patients. sedation may interfere with everyday activity.the effect appears to be dose related. in a single dose study, 92% of the patients receiving 16 mg, when asked, reported that they were drowsy during the 6 hour study. this compares to 76% of the patients on 8 mg and 35% of the patients on placebo. patients began noting this effect 30 minutes following dosing. the effect peaked 1.5 hours following dosing. of the patients who received a single dose of 16 mg, 51% continued to report drowsiness 6 hours following dosing compared to 13% in the patients receiving placebo or 8 mg of tizanidine. in the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study. hallucinosis/psychotic-like symptoms tizanidine use has been associated with hallucinations. formed, visual hallucinations or delusions have been reported in 5 of 170 patients (3%) in two north american controlled clinical studies. these 5 cases occurred within the first 6 weeks. most of the patients were aware that the events were unreal. one patient developed psychoses in association with the hallucinations. one patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. use in patients with hepatic impairment the influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on the pharmacokinetics of tizanidine. tizanidine should ordinarily be avoided or used with extreme caution in patients with hepatic impairment (see also risk of liver injury) potential interaction with fluvoxamine or ciprofloxacin in a pharmacokinetic study, tizanidine serum concentration was significantly increased (c max 12-fold, auc 33-fold) when the drug was given concomitantly with fluvoxamine. potentiated hypotensive and sedative effects were observed. fluvoxamine and tizanidine should not be used together. (see contraindications and clinical pharmacology: drug interactions).in a pharmacokinetic study, tizanidine serum concentration was significantly increased (c max 7-fold, auc 10-fold) when the drug was given concomitantly with ciprofloxacin. potentiated hypotensive and sedative effects were observed. ciprofloxacin and tizanidine should not be used together (see contraindications and clinical pharmacology: drug interactions). possible interaction with other cyp1a2 inhibitors because of potential drug interactions, concomitant use of tizanidine with other cyp1a2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine (see clinical pharmacology: drug interactions) should ordinarily be avoided. if their use is clinically necessary, they should be used with caution.
Warnings and Cautions:
Pharmacokinetic differences between tizanidine capsules and tizanidine tablets: tizanidine capsules are not bioequivalent to tizanidine tablets in the fed state. the prescriber should be thoroughly familiar with the complex effects of food on tizanidine pharmacokinetics (see pharmacokinetics and dosage and administration).
Dosage and Administration:
A single dose of 8 mg of tizanidine reduces muscle tone in patients 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 (see warnings). food has complex effect
Read more...s on tizanidine pharmacokinetics, which differ with the different formulations. these pharmacokinetic differences may result in clinically significant differences when [1] switching administration of the tablet between the fed or fasted state, [2] switching administration of the capsule between the fed or fasted state, [3] switching between the tablet and capsule in the fed state, or [4] 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 (see clinical pharmacology: pharmacokinetics).
Contraindications:
Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of cyp1a2, is contraindicated. significant alterations of pharmacokinetic parameters of tizanidine including increased auc, t1/2, c max , 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 (see warnings and clinical pharmacology: drug interactions). tizanidine tablets is contraindicated in patients with known hypersensitivity to tizanidine tablets or its ingredients.
Adverse Reactions:
In multiple doses, placebo-controlled clinical studies, 264 patients were treated with tizanidine and 261 with placebo. adverse events, including asevere 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 involvin
Read more...g 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. advrse 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 studiesâfrequent (> 2%) adverse events 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 function tests abnormal <1 3 vomiting 0 3 speech disorder 0 3 amblyopia (blurred vision) <1 3 urinary frequency 2 3 flu symptom 2 3 sgpt/alt increased <1 3 dyskinesia 0 3 nervousness <1 3 pharyngitis 1 3 rhinitis 2 3 *(weakness, fatigue, and/or tiredness)
Adverse Reactions Table:
Table 1: Multiple Dose, Placebo-Controlled Studies—Frequent (> 2%) Adverse Events Reported for Which Tizanidine Tablets Incidence is Greater than Placebo | Event | PlaceboN = 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 function tests abnormal | <1 | 3 |
| Vomiting | 0 | 3 |
| Speech disorder | 0 | 3 |
| Amblyopia (blurred vision) | <1 | 3 |
| Urinary frequency | 2 | 3 |
| Flu Symptom | 2 | 3 |
| SGPT/ALT increased | <1 | 3 |
| Dyskinesia | 0 | 3 |
| Nervousness | <1 | 3 |
| Pharyngitis | 1 | 3 |
| Rhinitis | 2 | 3 |
| *(weakness, fatigue, and/or tiredness) |
Overdosage:
A review of the safety surveillance database revealed cases of 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.
Description:
Description tizanidine hydrochloride is a centrally acting α 2 -adrenergic agonist. tizanidine hcl (tizanidine) is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. tizanidine is slightly soluble in water and methanol; solubility in water decreases as the ph increases. its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiodiazole hydrochloride. tizanidine's molecular formula is c 9 h 8 cin 5 s-hcl, its molecular weight is 290.2 and its structural formula is: tizanidine tablets usp are supplied as 2 and 4 mg tablets for oral administration. tizanidine tablets usp are composed of the active ingredient, tizanidine hydrochloride usp (2.288 mg equivalent to 2 mg tizanidine base and 4.576 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, colloidal silicon dioxide, stearic acid, microcrystalline cellulose and anhydrous lactose. tizanidine hydrochloride
Clinical Pharmacology:
Clinical pharmacology mechanism of action tizanidine is an agonist at α 2 -adrenergic receptor sites and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. in animal models, tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction, and no major effect on monosynaptic spinal reflexes. the effects of tizanidine are greatest on polysynaptic pathways. the overall effect of these actions is thought to reduce facilitation of spinal motor neurons. the imidazoline chemical structure of tizanidine is related to that of the anti-hypertensive drug clonidine and other α 2 -adrenergic agonists. pharmacological studies in animals show similarities between the two compounds, but tizanidine was found to have one-tenth to one-fiftieth (1/50) of the potency of clonidine in lowering blood pressure. pharmacokinetics absorption and distributionfollowing oral administration, tizanidine is essentially completely absorbed. the absolute ora
Read more...l bioavailability of tizanidine is approximately 40% (cv = 24%), due to extensive first-pass hepatic metabolism. tizanidine is extensively distributed throughout the body with a mean steady state volume of distribution of 2.4 l/kg (cv = 21%) following intravenous administration in healthy adult volunteers. tizanidine is approximately 30% bound to plasma proteins. pharmacokinetics, metabolism and excretion tizanidine has linear pharmacokinetics over a dose of 1 to 20 mg. tizanidine has a half-life of approximately 2.5 hours (cv=33%). approximately 95% of an administered dose is metabolized. the primary cytochrome p450 isoenzyme involved in tizanidine metabolism is cyp1a2. tizanidine metabolites are not known to be active; their half-lives range from 20 to 40 hours. following single and multiple oral dosing of 14 c-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. pharmacokinetic differences between tizanidine capsules and tizanidine tablets tizanidine capsules and tizanidine tablets are bioequivalent to each other under fasted conditions, but not under fed conditions. a single dose of either two 4 mg tablets or two 4 mg capsules was administered under fed and fasting conditions in an open label, four period, randomized crossover study in 96 human volunteers, of whom 81 were eligible for the statistical analysis. following oral administration of either the tablet or capsule (in the fasted state), tizanidine has peak plasma concentrations occurring 1.0 hours after dosing with a half-life of approximately 2 hours. when two 4 mg tablets are administered with food the mean maximal plasma concentration is increased by approximately 30%, and the median time to peak plasma concentration is increased by 25 minutes, to 1 hour and 25 minutes. in contrast, when two 4 mg capsules are administered with food the mean maximal plasma concentration is decreased by 20%, the median time to peak plasma concentration is increased by 2 hours to 3 hours. consequently, the mean c max for the capsule when administered with food is approximately 2/3's the c max for the tablet when administered with food. food also increases the extent of absorption for both the tablets and capsules. the increase with the tablet (~30%) is significantly greater than with the capsule (~10%). consequently when each is administered with food, the amount absorbed from the capsule is about 80% of the amount absorbed from the tablet (see figure 1). administration of the capsule contents sprinkled on applesauce is not bioequivalent to administration of an intact capsule under fasting conditions. administration of the capsule contents on applesauce results in a 15% - 20% increase in c max and auc of tizanidine compared to administration of an intact capsule while fasting, and a 15 minute decrease in the median lag time and time to peak concentration. figure 1 : mean tizanidine concentration vs. time profiles for tizanidine tablets and capsules (2 4 mg) under fasted and fed conditions figure 1 special populations age effectsno specific pharmacokinetic study was conducted to investigate age effects. cross study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. tizanidine has not been evaluated in children (see precautions). hepatic impairment the influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. tizanidine should ordinarily be avoided or used with extreme caution in this patient population (see warnings). renal impairment tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 ml/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. tizanidine should be used with caution in renally impaired patients (see precautions). gender effects no specific pharmacokinetic study was conducted to investigate gender effects. retrospective analysis of pharmacokinetic data, however, following single and multiple dose administration of 4 mg tizanidine showed that gender had no effect on the pharmacokinetics of tizanidine. race effects pharmacokinetic differences due to race have not been studied. drug interactions fluvoxaminethe effect of fluvoxamine on the pharmacokinetics of tizanidine was studied in 10 healthy subjects. the cmax, auc, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold respectively. these changes resulted in significant decreases in blood pressure, increased drowsiness, and psychomotor impairment. (see contraindications and warnings) ciprofloxacin the effect of ciprofloxacin on the pharmacokinetics of tizanidine was studied in 10 healthy subjects. the c max and auc of tizanidine increased by 7-fold and 10-fold respectively. these changes resulted in significant decreases in blood pressure, increased drowsiness, and psychomotor impairment. (see contraindications and warnings) cyp1a2 inhibitors the interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of cyp1a2 by fluvoxamine or ciprofloxacin. although there have been no clinical studies evaluating the effects of other cyp1a2 inhibitors on tizanidine, other cyp1a2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone and verapamil), cimetidine, famotidine oral contraceptives, acyclovir and ticlopidine, may also lead to substantial increases in tizanidine blood concentrations. (see warnings) oral contraceptives no specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine. retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives (see precautions).
How Supplied:
Tizanidine tablets usp are available as white to off-white, round, flat, beveledged uncoated tablets containing 2 mg or 4 mg of tizanidine.tizanidine tablets usp 2 mg are debossed with "u" and "168" on one side and bisecting score on other side. ndc 60760-782-04 bottles of 4 60760-782-15 bottles of 15 60760-782-30 bottles of 30 60760-782-90 bottles of 90 dispense in tight, light-resistant container [see usp]. rx only
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