Tizanidine (Page 4 of 6)
9 DRUG ABUSE AND DEPENDENCE
Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine.
Tizanidine is closely related to clonidine, which is often abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. Three cases of rebound symptoms on sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. Withdrawal symptoms are more likely to occur in cases where high doses are used, especially for prolonged periods, or with concomitant use of narcotics. If therapy needs to be discontinued, the dose should be decreased slowly to minimizethe risk of withdrawal symptoms [see Dosage and Administration ( 2.2) ].
Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m 2 basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.
A review of the safety surveillance database revealed cases of intentional and accidental tizanidine hydrochloride 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 is 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. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. 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 that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.
Tizanidine hydrochloride USP, is a central α 2 -adrenergic agonist. Tizanidine hydrochloride USP is almost white to slightly yellow crystalline powder, which is slightly soluble in water and methanol. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiodiazole monohydrochloride. Tizanidine’s molecular formula is C 9 H 8 ClN 5 S.HCl, its molecular weight is 290.2 and its structural formula is:
Tizanidine tablets USP, are supplied as 2 mg and 4 mg tablets for oral administration. Tizanidine tablets USP, contain 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, anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide and stearic acid.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons.
Absorption and Distribution
Following 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.
Differences between Tizanidine Capsules and Tizanidine Tablets
Tizanidine capsules and tizanidine tablets are bioequivalent to each other under fasting 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), peak plasma concentrations of tizanidine occurred 1 hours after dosing with a half-life of approximately 2 hours. When two 4 mg tablets were administered with food, the mean maximal plasma concentration was increased by approximately 30%, and the median time to peak plasma concentration was increased by 25 minutes, to 1 hour and 25 minutes. In contrast, when two 4 mg capsules were administered with food, the mean maximal plasma concentration was decreased by 20%, the median time to peak plasma concentration was increased 2 to 3 hours.
Consequently, the mean C max for the capsule when administered with food is approximately 66% the C max for the tablet when administered with food.
Food also increased the extent of absorption for both the tablets and capsules. The increase with the tablet (~30%) was significantly greater than with the capsule (~10%). Consequently when each was administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. Administration of the capsule contents sprinkled on applesauce was not bioequivalent to administration of an intact capsule under fasting conditions. Administration of the capsule contents on applesauce resulted in a 15% to 20% increase in C max and AUC of tizanidine and a 15 minute decrease in the median lag time and time to peak concentration compared to administration of an intact capsule while fasting.
Figure 1: Mean Tizanidine Concentration vs. Time Profiles For Tizanidine Tablets and Capsules (2 × 4 mg) Under Fasted and Fed Conditions
Metabolism and Excretion
Tizanidine has linear pharmacokinetics over the doses studied in clinical development (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.
No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine hydrochloride showed that younger subjects cleared the drug four times faster than the elderly subjects. Tizanidine hydrochloride has not been evaluated in children. [see Use in Specific Populations ( 8.4, 8.5) ]
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 hydrochloride is not recommended in this patient population [see Use in Specific Populations (8.7)]
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 hydrochloride should be used with caution in renally impaired patients [see Warnings and Precautions ( 5.7) and Use in Specific Populations ( 8.6)].
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 hydrochloride showed that gender had no effect on the pharmacokinetics of tizanidine. Race Effects Pharmacokinetic differences due to race have not been studied.
The interaction between tizanidine hydrochloride and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. The effect of fluvoxamine on the pharmacokinetics of a single 4 mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The C max , AUC, and half-life of tizanidine increased by 12- fold, 33-fold, and 3-fold, respectively. The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The C max and AUC of tizanidine increased by 7-fold and 10-fold, respectively. [see Contraindications ( 4) ]
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 and Precautions ( 5.5) ].
In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes.
No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine hydrochloride. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine hydrochloride, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives [see Warnings and Precautions ( 5.5) ].
Tizanidine delayed the T max of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine.
Alcohol increased the AUC of tizanidine by approximately 20%, while also increasing its C max by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.
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