TIZANIDINE HYDROCHLORIDE
DESCRIPTION:
SIRDALUD (tizanidine hydrochloride) is a centrally acting (alpha)2-adrenergic
agonist. Tizanidine HCl (tizanidine) is a white to off- white, fine crystalline
powder, 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 C9H8CIN5S*HCl,
its molecular weight is 290.2.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Tizanidine is an agonist at (alpha)2-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 (alpha)2-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
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 widely distributed throughout
the body; mean steady state volume of distribution is 2.4 L/kg (CV = 21%)
following intravenous administration in healthy adult volunteers.
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.
Tizanidine is approximately 30% bound to plasma proteins, independent of
concentration over the therapeutic range.
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: Pharmacokinetic differences due to hepatic impairment have
not been studied (see Warnings).
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 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--ORAL CONTRACEPTIVES: No 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).
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.
Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically
significant reduction of the Ashworth score for Sirdalud 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.
Click here for illustration(s).
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.
At endpoint (the protocol-specified time of outcome assessment), there was a
statistically significant reduction in muscle tone 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.
Click here for illustration(s).
INDICATIONS AND USAGE:
Tizanidine is a short-acting drug for the acute and intermittent management of
increased muscle tone associated with spasticity. The reduction of muscle tone
that follows the oral administration of a single dose of tizanidine has its peak
effect 1 to 2 hours after dosing, and the effect dissipates between 3 to 6
hours. Use must therefore be individualized, directed to those activities and
times when relief of spasticity is most important and titrated to avoid
intolerance. Evidence demonstrating the effectiveness of tizanidine is derived
from a single dose study and from a seven week multiple dose study conducted in
patients with multiple sclerosis and spinal cord injury, respectively.
CONTRAINDICATIONS:
Sirdalud is contraindicated in patients with known hypersensitivity to Sirdalud
or its ingredients.
WARNINGS:
LIMITED DATA BASE FOR CHRONIC USE OF SINGLE DOSES ABOVE 8 MG AND MULTIPLE DOSES
ABOVE 24 MG PER DAY
Clinical experience with long-term use of tizanidine at doses of 8 to 16 mg
single doses or total daily doses of 24 to 36 mg (see Dosage and Administration)
is limited. Approximately 75 patients have been exposed to individual doses of
12 mg or more for at least one year or more and approximately 80 patients have
been exposed to total daily doses of 30 to 36 mg/day for at least one year or
more. There is essentially no long- term experience with single, daytime doses
of 16 mg. Because long-term clinical study experience at high doses is limited,
only those adverse events with a relatively high incidence are likely to have
been identified (see Warnings, Precautions and Adverse Reactions).
HYPOTENSION
Tizanidine is an (alpha)2-adrenergic agonist (like clonidine) and can produce
hypotension. In a single dose study where blood pressure was monitored closely
after dosing, two-thirds of patients treated with 8 mg of tizanidine had a 20%
reduction in either the diastolic or systolic BP. The reduction was seen within
1 hour after dosing, peaked 2 to 3 hours after dosing and was associated, at
times, with bradycardia, orthostatic hypotension, lightheadedness/dizziness and
rarely syncope. The hypotensive effect is dose related and has been measured
following single doses of (>/=) 2 mg.
The chance of significant hypotension may possibly be minimized by titration of
the dose and by focusing attention on signs and symptoms of hypotension prior to
dose advancement. In addition, patients moving from a supine to a fixed upright
position may be at increased risk for hypotension and orthostatic effects.
Caution is advised when tizanidine is to be used in patients receiving
concurrent antihypertensive therapy and should not be used with other (alpha)2-
adrenergic agonists.
RISK OF LIVER INJURY
Tizanidine occasionally causes liver injury, most often hepatocellular in type.
In controlled clinical studies, approximately 5% of patients treated with
tizanidine had elevations of liver function tests (ALT/SGPT, AST/SGOT) to
greater than 3 times the upper limit of normal (or 2 times if baseline levels
were elevated) compared to 0.4% in the control patients. Most cases resolved
rapidly upon drug withdrawal with no reported residual problems. In occasional
symptomatic cases, nausea, vomiting, anorexia and jaundice have been reported.
In postmarketing experience, three deaths associated with liver failure have
been reported in patients treated with tizanidine. In one case, a 49 year-old
male developed jaundice and liver enlargement following 2 months of tizanidine
treatment, primarily at 6 mg tid. A liver biopsy showed multilobular necrosis
without eosinophilic infiltration. Treatment was discontinued and the patient
died in hepatic coma 10 days later. There was no evidence of hepatitis B and C
in this patient and other therapy included only oxezepam and ranitidine. There
was thus no explanation, other than a reaction to tizanidine, to explain the
liver injury. In the two other cases, patients were taking other drugs with
known potential for liver toxicity. One patient, treated with tizanidine at a
dose of 4 mg/day, was also on carbamazepine when he developed cholestatic
jaundice after 2 months of treatment; this patient died with pneumonia about 20
days later. Another patient, treated with tizanidine for 11 days, was also
treated with dantrolene for about 2 weeks prior to developing fatal fulminant
hepatic failure.
Monitoring of aminotransferase levels is recommended during the first 6 months
of treatment (e.g., baseline, 1, 3 and 6 months) and periodically thereafter,
based on clinical status. Because of the potential toxic hepatic effect of
tizanidine, the drug should be used only with extreme caution in patients with
impaired hepatic function.
SEDATION
In the multiple dose, controlled clinical studies, 48% of patients receiving any
dose of tizanidine reported sedation as an adverse event. In 10% of these cases,
the sedation was rated as severe compared to <1% in the placebo treated
patients. Sedation may interfere with every day activity.
The effect appears to be dose related. In a single dose study, 92% of the
patients receiving 16 mg, when asked, reported that they were drowsy during the
6 hour study. This compares to 76% of the patients on 8 mg and 35% of the
patients on placebo. Patients began noting this effect 30 minutes following
dosing. The effect peaked 1.5 hours following dosing. Of the patients who
received a single dose of 16 mg, 51% continued to report drowsiness 6 hours
following dosing compared to 13% in the patients receiving placebo or 8 mg of
tizanidine.
In the multiple dose studies, the prevalence of patients with sedation peaked
following the first week of titration and then remained stable for the duration
of the maintenance phase of the study.
HALLUCINOSIS/PSYCHOTIC-LIKE SYMPTOMS
Tizanidine use has been associated with hallucinations. Formed, visual
hallucinations or delusions have been reported in 5 of 170 patients (3%) in two
North American controlled clinical studies. These 5 cases occurred within the
first 6 weeks. Most of the patients were aware that the events were unreal. One
patient developed psychoses in association with the hallucinations. One patient
among these 5 continued to have problems for at least 2 weeks following
discontinuation of tizanidine.
PRECAUTIONS:
CARDIOVASCULAR
Prolongation of the QT interval and bradycardia were noted in chronic toxicity
studies in dogs at doses equal to the maximum human dose on a mg/m(squared)
basis. ECG evaluation was not performed in the controlled clinical studies.
Reduction in pulse rate has been noted in association with decreases in blood
pressure in the single dose controlled study (see Warnings).
OPHTHALMIC
Dose-related retinal degeneration and corneal opacities have been found in
animal studies at doses equivalent to approximately the maximum recommended dose
on a mg/m(squared) basis. There have been no reports of corneal opacities or
retinal degeneration in the clinical studies.
USE IN RENALLY IMPAIRED PATIENTS
Tizanidine should be used with caution in patients with renal insufficiency
(creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%. In
these patients, during titration, the individual doses should be reduced. If
higher doses are required, individual doses rather than dosing frequency should
be increased. These patients should be monitored closely for the onset or
increase in severity of the common adverse events (dry mouth, somnolence,
asthenia and dizziness) as indicators of potential overdose.
USE IN WOMEN TAKING ORAL CONTRACEPTIVES
Tizanidine should be used with caution in women taking oral contraceptives, as
clearance of tizanidine is reduced by approximately 50% in such patients. In
these patients, during titration, the individual doses should be reduced.
INFORMATION FOR PATIENTS
Patients should be advised of the limited clinical experience with tizanidine
both in regard to duration of use and the higher doses required to reduce muscle
tone (see Warnings).
Because of the possibility of tizanidine lowering blood pressure, patients
should be warned about the risk of clinically significant orthostatic
hypotension (see Warnings).
Because of the possibility of sedation, patients should be warned about
performing activities requiring alertness, such as driving a vehicle or
operating machinery (see Warnings). Patients should also be instructed that the
sedation may be additive when Sirdalud is taken in conjunction with drugs
(baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS
depressants.
DRUG INTERACTIONS
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.
ACETAMINOPHEN: Tizanidine delayed the Tmax of acetaminophen by 16 minutes.
Acetaminophen did not affect the pharmacokinetics 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.
ORAL CONTRACEPTIVES: No specific pharmacokinetic study was conducted to
investigate interaction between oral contraceptives and tizanidine, but
retrospective analysis of population pharmacokinetic data following single and
multiple dose administration of 4 mg tizanidine showed that women concurrently
taking oral contraceptives had 50% lower clearance of tizanidine than women not
on oral contraceptives.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
No evidence for carcinogenicity was seen in two dietary studies in rodents.
Tizanidine was administered to mice for 78 weeks at doses up to 16 mg/kg, which
is equivalent to 2 times the maximum recommended human dose on a mg/m(squared)
basis. Tizanidine was also administered to rats for 104 weeks at doses up to 9
mg/kg, which is equivalent to 2.5 times the maximum recommended human dose on a
mg/m(squared) basis. There was no statistically significant increase in tumors
in either species.
Tizanidine was not mutagenic or clastogenic in the following In Vitro assays:
the bacterial Ames test and the mammalian gene mutation test and chromosomal
aberration test in Chinese hamster cells. It was also negative in the following
In Vivo assays: the bone marrow micronucleus test in mice, the bone marrow
micronucleus and cytogenicity test in Chinese hamsters, the dominant lethal
mutagenicity test in mice, and the unscheduled DNA synthesis (UDS) test in mice.
Tizanidine did not affect fertility in male rats at doses of 10 mg/kg,
approximately 2.7 times the maximum recommended human dose on a mg/m(squared)
basis, and in females at doses of 3 mg/kg, approximately equal to the maximum
recommended human dose on a mg/m(squared) basis; fertility was reduced in males
receiving 30 mg/kg (8 times the maximum recommended human dose on a
mg/m(squared) basis) and in females receiving 10 mg/kg (2.7 times the maximum
recommended human dose on a mg/m(squared) basis). At these doses, maternal
behavioral effects and clinical signs were observed including marked sedation,
weight loss, and ataxia.
PREGNANCY
Pregnancy Category C: Reproduction studies performed in rats at a dose of 3
mg/kg, equal to the maximum recommended human dose on a mg/m(squared) basis,
and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a
mg/m(squared) basis, did not show evidence of teratogenicity. Tizanidine at
doses that are equal to and up to 8 times the maximum recommended human dose
on a mg/m(squared) basis increased gestation duration in rats. Prenatal and
postnatal pup loss was increased and developmental retardation occurred.
Postimplantation loss was increased in rabbits at doses of 1 mg/kg or greater,
equal to or greater than 0.5 times the maximum recommended human dose on a
mg/m(squared) basis. Tizanidine has not been studied in pregnant women.
Tizanidine should be given to pregnant women only if clearly needed.
LABOR AND DELIVERY
The effect of tizanidine on labor and delivery in humans is unknown.
NURSING MOTHERS
It is not known whether tizanidine is excreted in human milk, although as a
lipid soluble drug, it might be expected to pass into breast milk.
GERIATRIC USE
Tizanidine should be used with caution in elderly patients because clearance is
decreased four- fold.
PEDIATRIC USE
There are no adequate and well-controlled studies to document the safety and
efficacy of tizanidine in children.
DRUG INTERACTIONS:
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.
ACETAMINOPHEN: Tizanidine delayed the Tmax of acetaminophen by 16 minutes.
Acetaminophen did not affect the pharmacokinetics 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.
ORAL CONTRACEPTIVES: No specific pharmacokinetic study was conducted to
investigate interaction between oral contraceptives and tizanidine, but
retrospective analysis of population pharmacokinetic data following single and
multiple dose administration of 4 mg tizanidine showed that women concurrently
taking oral contraceptives had 50% lower clearance of tizanidine than women not
on oral contraceptives.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
In multiple dose, placebo-controlled clinical studies, 264 patients were treated
with tizanidine and 261 with placebo. Adverse events, including severe adverse
events, were more frequently reported with tizanidine than with placebo.
COMMON ADVERSE EVENTS LEADING TO DISCONTINUATION
Forty-five of 264 (17%) patients receiving tizanidine and 13 of 261 (5%)
patients receiving placebo in three multiple dose, placebo- controlled clinical
studies discontinued treatment for adverse events. When patients withdrew from
the study, they frequently had more than one reason for discontinuing. The
adverse events most frequently leading to withdrawal of tizanidine treated
patients in the controlled clinical studies were asthenia (3%), somnolence (3%),
dry mouth (3%), increased spasm or tone (2%) and dizziness (2%).
MOST FREQUENT ADVERSE CLINICAL EVENTS SEEN IN ASSOCIATION WITH THE USE OF
TIZANIDINE
In multiple dose, placebo-controlled clinical studies involving 264 patients
with spasticity, the most frequent adverse events were dry mouth,
somnolence/sedation, asthenia, and dizziness. Three-quarters of the patients
rated the events as mild to moderate and one-quarter of the patients rated the
events as being severe. These events appeared to be dose related.
ADVERSE EVENTS REPORTED IN CONTROLLED STUDIES
The events cited reflect experience gained under closely monitored conditions of
clinical studies in a highly selected patient population. In actual clinical
practice or in other clinical studies, these frequency estimates may not apply,
as the conditions of use, reporting behavior, and the kinds of patients treated
may differ. Table 1 lists treatment emergent signs and symptoms that were
reported in greater than 2% of patients in three multiple dose, placebo-
controlled studies who received tizanidine where the frequency in the tizanidine
group was at least as common as in the placebo group. These events are not
necessarily related to tizanidine treatment. For comparison purposes, the
corresponding frequency of the event (per 100 patients) among placebo treated
patients is also provided.
TABLE 1: MULTIPLE DOSE, PLACEBO-CONTROLLED STUDIES -
FREQUENT (> 2%) ADVERSE EVENTS REPORTED FOR WHICH
SIRDALUD INCIDENCE IS GREATER THAN PLACEBO
-------------------------------------------------------------------------------------------------------------------------
EVENT PLACEBO N = 261 % SIRDALUD N = 264 %
-------------------------------------------------------------------------------------------------------------------------
Dry mouth 10 49
Somnolence 10 48
Asthenia (tiredness) 16 41
Dizziness 4 16
UTI 7 10
Infection 5 6
Constipation 1 4
Liver function tests
abnormal <1 3
Vomiting 0 3
Speech disorder 0 3
Amblyopia (blurred vision) <1 3
Urinary frequency 2 3
Flu syndrome 2 3
SGPT/ALT increased <1 3
Dyskinesia 0 3
Nervousness <1 3
Pharyngitis 1 3
Rhinitis 2 3
In the single dose, placebo-controlled study involving 142 patients with
spasticity, the patients were specifically asked if they had experienced any of
the four most common adverse events: dry mouth, somnolence (drowsiness),
asthenia (tiredness), and dizziness. In addition, hypotension and bradycardia
were observed. The occurrence of these adverse events are summarized in Table
2. Other events were, in general, reported at a rate of 2% or less.
TABLE 2: SINGLE DOSE, PLACEBO-CONTROLLED STUDY-
COMMON ADVERSE EVENTS REPORTED
----------------------------------------------------------------------------------------------------------------------
EVENT PLACEBO SIRDALUD 8 MG SIRDALUD 16 MG
N = 48 % N = 45 % N = 49 %
----------------------------------------------------------------------------------------------------------------------
Somnolence 31 78 92
Dry mouth 35 76 88
Asthenia 40 67 78
Dizziness 4 22 45
Hypotension 0 16 33
Bradycardia 0 2 10
OTHER ADVERSE EVENTS OBSERVED DURING THE EVALUATION OF TIZANIDINE
Tizanidine was administered to 1187 patients in additional clinical studies
where adverse event information was available. The conditions and duration of
exposure varied greatly, and included (in overlapping categories) double-blind
and open-label studies, uncontrolled and controlled studies, inpatient and
outpatient studies, and titration studies. Untoward events associated with this
exposure were recorded by clinical investigators using terminology of their own
choosing. Consequently, it is not possible to provide a meaningful estimate of
the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event
categories.
In the tabulations that follow, reported adverse events were classified using a
standard COSTART- based dictionary terminology. The frequencies presented,
therefore, represent the proportion of the 1187 patients exposed to tizanidine
who experienced an event of the type cited on at least one occasion while
receiving tizanidine. All reported events are included except those already
listed in Table 1. If the COSTART term for an event was so general as to be
uninformative, it was replaced with a more informative term. It is important to
emphasize that, although the events reported occurred during treatment with
tizanidine, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are
those occurring on one or more occasions in at least 1/100 patients (only those
not already listed in the tabulated results from placebo-controlled studies
appear in this listing); infrequent adverse events are those occurring in 1/100
to 1/1000 patients.
Body as a Whole: FREQUENT: fever; INFREQUENT: allergic reaction, moniliasis,
malaise, abscess, neck pain, sepsis, cellulitis, death, overdose; RARE:
carcinoma, congenital anomaly, suicide attempt.
Cardiovascular System: INFREQUENT: vasodilatation, postural hypotension,
syncope, migraine, arrhythmia; RARE: angina pectoris, coronary artery disorder,
heart failure, myocardial infarct, phlebitis, pulmonary embolus, ventricular
extrasystoles, ventricular tachycardia.
Digestive System: FREQUENT: abdomen pain, diarrhea, dyspepsia; INFREQUENT:
dysphagia, cholelithiasis, fecal impaction, flatulence, gastrointestinal
hemorrhage, hepatitis, melena; RARE: gastroenteritis, hematemesis, hepatoma,
intestinal obstruction, liver damage.
Hemic and Lymphatic System: INFREQUENT: ecchymosis, hypercholesteremia, anemia,
hyperlipemia, leukopenia, leukocytosis, sepsis; RARE: petechia, purpura,
thrombocythemia, thrombocytopenia.
Metabolic and Nutritional System: INFREQUENT: edema, hypothyroidism, weight
loss; RARE: adrenal cortex insufficiency, hyperglycemia, hypokalemia,
hyponatremia, hypoproteinemia, respiratory acidosis.
Musculoskeletal System: FREQUENT: myasthenia, back pain; INFREQUENT:
pathological fracture, arthralgia, arthritis, bursitis.
Nervous System: FREQUENT: depression, anxiety, paresthesia; INFREQUENT:
tremor, emotional lability, convulsion, paralysis, thinking abnormal, vertigo,
abnormal dreams, agitation, depersonalization, euphoria, migraine, stupor,
dysautonomia, neuralgia; RARE: dementia, hemiplegia, neuropathy.
Respiratory System: INFREQUENT: sinusitis, pneumonia, bronchitis; RARE: asthma.
Skin and Appendages: FREQUENT: rash, sweating, skin ulcer; INFREQUENT:
pruritus, dry skin, acne, alopecia, urticaria; RARE: exfoliative dermatitis,
herpes simplex, herpes zoster, skin carcinoma.
Special Senses: INFREQUENT: ear pain, tinnitus, deafness, glaucoma,
conjunctivitis, eye pain, optic neuritis, otitis media, retinal hemorrhage,
visual field defect; RARE: iritis, keratitis, optic atrophy.
Urogenital System: INFREQUENT: urinary urgency, cystitis, menorrhagia,
pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged,
vaginal moniliasis, vaginitis; RARE: albuminuria, glycosuria, hematuria,
metrorrhagia.
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. 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(squared) basis. These transient withdrawal signs (increased locomotion,
body twitching, and aversive behavior toward the observer) were not reversed by
naloxone administration.
OVERDOSAGE:
One significant overdosage of tizanidine has been reported. Attempted suicide
by a 46 year-old male with multiple sclerosis resulted in coma very shortly
after the ingestion of one-hundred 4mg tizanidine tablets. Pupils were not
dilated and nystagmus was not present. The patient had marked respiratory
depression with Cheyne-Stokes respiration. Gastric lavage and forced diuresis
with furosemide and mannitol were instituted. The patient recovered several
hours later without sequelae. Laboratory findings were normal.
Should overdosage occur, basic steps to ensure the adequacy of an airway and the
monitoring of cardiovascular and respiratory systems should be undertaken. For
the most recent information concerning the management of overdose, contact a
poison control center.
DOSAGE AND ADMINISTRATION:
A single oral dose of 8 mg of tizanidine reduces muscle tone in patients with
spasticity for a period of several hours. The effect peaks at approximately 1
to 2 hours and dissipates between 3 to 6 hours. Effects are dose-related.
Although single doses of less than 8 mg have not been demonstrated to be
effective in controlled clinical studies, the dose-related nature of
tizanidine's common adverse events make it prudent to begin treatment with
single oral doses of 4 mg. Increase the dose gradually (2 to 4 mg steps) to
optimum effect (satisfactory reduction of muscle tone at a tolerated dose).
The dose can be repeated at 6 to 8 hour intervals, as needed, to a maximum of
three doses in 24 hours. The total daily dose should not exceed 36 mg.
Experience with single doses exceeding 8 mg and daily doses exceeding 24 mg is
limited. There is essentially no experience with repeated, single, daytime
doses greater than 12 mg or total daily doses greater than 36 mg (see Warnings).
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