Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3817
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TIZANIDINE HYDROCHLORIDE (Tablet)
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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 . 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 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 .
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Tizanidine hydrochloride is a centrally acting��-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 CHCINS���HCl, its molecular weight is 290.2 and its structural formula is: Tizanidine hydrochloride is supplied as 2 and 4 mg tablets for oral administration. Tizanidine hydrochloride tablets are composed of the active ingredient, tizanidine hydrochloride (2.288 mg equivalent to 2 mg tizanidine base and 4.576 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, microcrystalline cellulose, anhydrous lactose, colloidal silicon dioxide, pregelatinized starch and stearic acid.
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Mechanism of ActionTizanidine is an agonist at��-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��-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.<br/>Pharmacokinetics: Absorption and DistributionFollowing oral administration, tizanidine is essentially completely absorbed. The absolute oral 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 ExcretionTizanidine 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 tizandine 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 ofC-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. Pharmacokinetic differences between tizanidine hydrochloride capsules and tizanidine hydrochloride tabletsTizandine hydrochloride capsules and tizanidine hydrochloride 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 occurring1.0 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 Cfor the capsule when administered with food is approximately 2/3's the Cfor 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% to 20% increase in Cand 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 hydrochloride tablets and capsules (2 x 4 mg) Under Fasted and Fed Conditions<br/>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 . Hepatic ImpairmentThe 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 . Renal ImpairmentTizanidine 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 . Gender EffectsNo 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 EffectsPharmacokinetic differences due to race have not been studied.<br/>Drug Interactions: FluvoxamineThe effect of fluvoxamine on the pharmacokinetics of tizanidine was studied in 10 healthy subjects. The C, AUC, and half-life of tizandine increased by 12-fold, 33-fold, and 3-fold, respectively. These changes resulted in significant decreases in blood pressure, increased drowsiness, and psychomotor impairment. . CiprofloxacinThe effect of ciprofloxacin on the pharmacokinetics of tizanidine was studied in 10 healthy subjects. The Cand 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. . CYP1A2 InhibitorsThe 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. . Oral ContraceptivesNo 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 .<br/>CLINICAL STUDIES: Tizanidine's capacity to reduce increased muscle tone associated with spasticity was demonstrated in two adequate and well controlled studies in patients with multiple sclerosis or spinal cord injury. In one study, patients with multiple sclerosis were randomized to receive single oral doses of drug or placebo. Patients and assessors were blind to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). In all, 140 patients received either placebo, 8 mg or 16 mg of tizanidine. Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score), with a score of 0 used to describe normal muscle tone. A score of 1 indicated a slight spastic catch while a score of 2 indicated more marked muscle resistance. A score of 3 was used to describe considerable increase in tone, making passive movement difficult. A muscle immobilized by spasticity was given a score of 4. Spasm counts were also collected. Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 and 16 mg tizanidine groups was indistinguishable from muscle tone in placebo treated patients. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group. FIGURE 2: Single Dose Study - Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale��95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) In a multiple dose study, 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding. Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg daily given in three unequal doses (e.g., 10 mg given in the morning and afternoon and 16 mg given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients. At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. FIGURE 3: Multiple Dose Study - Mean Change in Muscle Tone 0.5-2.5 Hours After Dosing as Measured by the Ashworth Scale��95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline)
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Tizanidine hydrochloride tablets 2 mg are supplied as white, round compressed tablets; debossed���cor���above the bisect and���106���below the bisect on one side and the other side is plain. They are supplied as follows:Bottles of 150 (NDC 64720-106-15)Bottles of 500 (NDC 64720-106-50)Bottles of 1000 (NDC 64720-106-11) Tizanidine hydrochloride tablets 4 mg are supplied as white, round compressed tablets; debossed���cor���over���138���on one side and���quadrisect���on the other side. They are supplied as follows:Bottles of 150 (NDC 64720-138-15)Bottles of 500 (NDC 64720-138-50)Bottles of 1000 (NDC 64720-138-11) Store at controlled room temperature 15��-30��C (59��-86��F) (see USP). Dispense in containers with child resistant closure. Keep this and all drugs out of the reach of children. Manufactured and Distributed by:Corepharma, LLC.Middlesex, NJ 08846 MF # 203-01March 2007
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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 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.
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TIZANIDINE HYDROCHLORIDE
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TIZANIDINE HYDROCHLORIDE (Tablet)
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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 DiscontinuationForty-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 TizanidineIn 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 StudiesThe 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 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 Other Adverse Events Observed During the Evaluation of TizanidineTizanidine 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; rare adverse events are those occurring in fewer than 1/1000 patients. Body as a WholeFrequent: FeverInfrequent: Allergic reaction, moniliasis, malaise, abscess, neck pain, sepsis, cellulites, death, overdoseRare: Carcinoma, congenital anomaly, suicide attempt Cardiovascular SystemInfrequent: Vasodilatation postural hypotension, syncope, migraine, arrhythmiaRare: Angina pectoris, coronary artery disorder, heart failure, myocardial infarct, phlebitis, pulmonary embolus, ventricular extrasystoles, ventricular tachycardia Digestive SystemFrequent: Abdomen pain, diarrhea, dyspepsiaInfrequent: Dysphagia, cholelithiasis, fecal impaction, flatulence, gastrointestinal hemorrhage, hepatitis, melenaRare: Gastroenteritis, hematemesis, hepatoma, intestinal obstruction, liver damage Hemic and Lymphatic SystemInfrequent: Ecchymosis, hypercholesteremia, anemia, hyperlipemia, leukopenia, leukocytosis, sepsisRare: Petechia, purpura, thrombocythemia, thrombocytopenia Metabolic and Nutritional SystemInfrequent: Edema, hypothyroidism, weight lossRare: Adrenal cortex insufficiency, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, respiratory acidosis Musculoskeletal SystemFrequent: Myasthenia, back painInfrequent: Pathological fracture, arthralgia, arthritis, bursitis Nervous SystemFrequent: Depression, anxiety, paresthesiaInfrequent: Tremor, emotional lability, convulsion, paralysis, thinking abnormal, vertigo, abnormal dreams, agitation, depersonalization, euphoria, migraine, stupor, dysautonomia, neuralgiaRare: Dementia, hemiplegia, neuropathy Respiratory SystemInfrequent: Sinusitis, pneumonia, bronchitisRare: Asthma Skin and AppendagesFrequent: Rash, sweating, skin ulcerInfrequent: Pruritus, dry skin, acne, alopecia, urticariaRare: Exfoliative dermatitis, herpes simplex, herpes zoster, skin carcinoma Special SensesInfrequent: Ear pain, tinnitus, deafness, glaucoma, conjunctivitis, eye pain, optic neuritis, otitis media, retinal hemorrhage, visual field defectRare: Iritis, keratitis, optic atrophy Urogential SystemInfrequent: Urinary urgency, cystitis, menorrhagia, pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged, vaginal moniliasis, vaginitisRare: Albuminuria, glycosuria, hematuria, metrorrhagia
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Tizanidine 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 .
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TIZANIDINE HYDROCHLORIDE
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