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 Zanaflex Capsules® and Zanaflex®
Zanaflex Capsules® and Zanaflex® 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
1.0 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%–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 Zanaflex Tablets and Capsules (2 Ã 4 mg) Under Fasted and Fed
Metabolism and Excretion
Tizanidine has linear
pharmacokinetics over the doses studied in clinical development (1–20 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.
No specific pharmacokinetic
study was conducted to investigate age effects. Cross study comparison of
pharmacokinetic data following single dose administration of 6 mg Zanaflex
showed that younger subjects cleared the drug four times faster than the
elderly subjects. Zanaflex has not been evaluated in children. [see Use in
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. Zanaflex is not recommended in this patient population [see Use
in Specific Populations]
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. Zanaflex should be
used with caution in renally impaired patients [see WARNINGS AND
PRECAUTIONS and Use In Specific Populations].
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 Zanaflex showed that gender had no effect on the
pharmacokinetics of tizanidine.
Pharmacokinetic differences due
to race have not been studied.
The interaction between Zanaflex
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 Zanaflex 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
pharmacokinetics of a single 4 mg dose of Zanaflex was studied in 10 healthy
subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold,
respectively. [see CONTRAINDICATIONS]
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
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
Zanaflex. Retrospective analysis of population pharmacokinetic data following
single and multiple dose administration of 4 mg Zanaflex, however, showed that
women concurrently taking oral contraceptives had 50% lower clearance of
tizanidine compared to women not on oral contraceptives [see WARNINGS
Tizanidine delayed the Tmax of
acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics
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.
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 (Studies 1 and 2).
Single-Dose Study in Patients
with Multiple Sclerosis with Spasticity
In Study 1, 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 placebo, 8 mg or 16 mg of Zanaflex.
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 Zanaflex 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 Zanaflex
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)
Seven-Week Study in Patients with Spinal Cord Injury
In a 7-week study (Study 2),
118 patients with spasticity secondary to spinal cord injury were randomized to
either placebo or Zanaflex. 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 Zanaflex 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
Zanaflex 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: Seven Week 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)