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.
12.3 Pharmaco*kinetics
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 Cmax for the capsule when administered with food is approximately 66% the Cmax 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 Cmax 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 pharmaco*kinetics 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 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively.
Special Populations
Age Effects
No specific pharmaco*kinetic study was conducted to investigate age effects. Cross study comparison of pharmaco*kinetic 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)]
Hepatic Impairment
The influence of hepatic impairment on the pharmaco*kinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmaco*kinetics of tizanidine. Tizanidine hydrochloride is not recommended in this patient population [see Use in Specific Populations (8.7)]
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 hydrochloride should be used with caution in renally impaired patients [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6)].
Gender Effects
No specific pharmaco*kinetic study was conducted to investigate gender effects. Retrospective analysis of pharmaco*kinetic data, however, following single and multiple dose administration of 4 mg tizanidine hydrochloride showed that gender had no effect on the pharmaco*kinetics of tizanidine.Race Effects Pharmaco*kinetic differences due to race have not been studied.
Drug Interactions
CYP1A2 Inhibitors
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 pharmaco*kinetics of a single 4 mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12- fold, 33-fold, and 3-fold, respectively. The effect of ciprofloxacin on the pharmaco*kinetics of a single 4 mg dose of tizanidine hydrochloride was studied in 10 healthy subjects. The Cmax 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.
Oral Contraceptives
No specific pharmaco*kinetic study was conducted to investigate interaction between oral contraceptives and tizanidine hydrochloride. Retrospective analysis of population pharmaco*kinetic 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)].
Acetaminophen
Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmaco*kinetics of tizanidine.
Alcohol
Alcohol increased the AUC of tizanidine by approximately 20%, while also increasing its Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.
