TIZANIDINE HYDROCHLORIDE — tizanidine hydrochloride tablet
PHARMACOKINETIC DIFFERENCES BETWEEN TIZANIDINE HYDROCHLORIDE CAPSULES AND TIZANIDINE HYDROCHLORIDE TABLETS:
TIZANIDINE HYDROCHLORIDE CAPSULES ARE NOT BIOEQUIVALENT TO TIZANIDINE HYDROCHLORIDE 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).
Tizanidine hydrochloride is a centrally acting α2 -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 C9 H8 CIN5 S•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.
Mechanism of Action
Tizanidine is an agonist at α2 -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 α2 -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.
Absorption and Distribution
Following oral administration, tizanidine is essentially completely absorbed and has a half-life of approximately 2.5 hours (coefficient of variation [CV] = 33%). Following administration of tizanidine, peak plasma concentrations occurred at 1.5 hours(CV = 40%) after dosing. Food increases Cmax by approximately one-third and shortens time to peak concentration by approximately 40 minutes, but the extent of tizanidine absorption is not affected. Tizanidine has linear pharmacokinetics over a dose of 1 to 20 mg. The absolute oral bioavailability of tizanidine is approximately 40% (CV = 24%), due to extensive first-pass metabolism in the liver; approximately 95% of an administered dose is metabolized. Tizanidine metabolites are not known to be active; their half-lives range from 20 to 40 hours. 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, independent of concentration over the therapeutic range.
Pharmacokinetics, Metabolism and Excretion
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.
No 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).
Pharmacokinetic differences due to hepatic impairment have not been studied (see WARNINGS).
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).
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.
Pharmacokinetic differences due to race have not been studied.
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 (see PRECAUTIONS).
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 1 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 1: 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 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.
FIGURE 2: 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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