CLINICAL PHARMACOLOGY
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.
PHARMACOKINETICS
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% - 20% increase in Cmax and 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 Zanaflex Tablets and Capsules (2 × 4 mg) Under Fasted and Fed
Conditions
SPECIAL POPULATIONS
Age Effects
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).
Hepatic Impairment
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 should ordinarily be avoided or
used with extreme caution in this patient population (see WARNINGS).
Renal Impairment
Tizanidine clearance is reduced by more than 50% in elderly
patients with renal insufficiency (creatinine clearance less than 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).
Gender Effects
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.
Race Effects
Pharmacokinetic differences due to race have not been studied.
DRUG INTERACTIONS
CONTRAINDICATIONS
and WARNINGS.)
CONTRAINDICATIONS and WARNINGS.)
WARNINGS).
PRECAUTIONS).
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 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 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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