MULTIPLE SCLEROSIS
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TIZANIDINE DESCRIPTION Zanaflex
is a centrally acting alpha2-adrenergic agonist. Tizanidine HCl 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 C9H8ClN5S·HCl,
its molecular weight is 290.2. Zanaflex
is supplied as 4 mg tablets for oral administration. Zanaflex tablets are
composed of the active ingredient tizanidine hydrochloride (4.576 mg equivalent
to 4 mg tizanidine base), and the inactive ingredients, silicon dioxide
colloidal, stearic acid, microcrystalline cellulose and anhydrous lactose. CATEGORIES, BRAND NAMES CATEGORIES:
Spasticity; Pregnancy Category C; FDA
Approved 1996 Dec; Orphan Drugs BRAND
NAMES: Sirdalud; Sirdalud MR; Sirdalud
Retard; Ternelax; Ternelin; Zanaflex CLINICAL PHARMACOLOGY Mechanism
of Action
Tizanidine
is an agonist at alpha2-agonist 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 alpha2-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. 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. Assignments
were made at 1, 2, 3, and 6 hours after treatment. A statistically significant reduction
of the Ashworth score
for tizanidine compared to placebo was detected at 1, 2, and 3 hours after
treatment. 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. 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. INDICATIONS 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. 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). HOW SUPPLIED Tizanidine
HCl is available as 4 mg white
tablets, embossed with the Athena logo and "594" on one side
and cross-scored on the other. Storage:
Store at 15-30°C (59-86°F). Dispense in containers with child
resistant closure 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 Tizanidine Incidence is Greater than Placebo
TABLE
2 - Single
Dose, Placebo-COntrolled Study - Common Adverse Events Reported
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,
monillasis, malaise,
abscess,
neck
pain,
sepsis,
cellulitis, death, overdose; Rare: carcinoma,
congenital
anomaly, suicide
attempt. Cardiovascular
System: Infrequent: vasodilation,
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,
hemoplagia, 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/m2 basis. These transient
withdrawal signs (increased locomotion, body twitching, and aversive behavior
toward the observer) were not reversed by naloxone administration. 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. 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). WARNINGS 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 PRECAUTIONS,
and ADVERSE
REACTIONS). Hypotension
Tizanidine
is an alpha2-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
of 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, light-headedness/dizziness and rarely, syncope. The
hypotensive effect is dose
related and has been measured following single doses of ³2 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 alpha2-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 3 times daily. A liver
biopsy
showed multiobular 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 oxazepam
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 aminotranferase 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 a 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. Hallucinations/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/m2 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/m2 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 the Patient
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 tizanidine is taken in conjunction with drugs (baclofen, benzodiazepines)
or substances (e.g., alcohol) that act
as CNS
depressants. Carcinogenesis,
Mutagenesis, and 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/m2 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/m2 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 cytogenecity 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/m2 basis, and in females at doses of 3 mg/kg, approximately
equal to the maximum recommended human
dose
on a mg/m2 basis; fertility
was reduced in males receiving 30 mg/kg (8 times the maximum
recommended human
dose on a mg/m2 basis) and in females receiving 10 mg/kg (2.7 times
the maximum
recommended human
dose
on a mg/m2 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/m2 basis, and in rabbits at 30 mg/kg, 16 times the
recommended human
dose
on a mg/m2 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/m2 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/m2 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
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. 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 4 mg 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. CONTRAINDICATIONS Tizanidine
is contraindicated in patients with know hypersensitivity to tizanidine or its
ingredients. PATIENT INFORMATION Tizanidine
is used for treatment
of increased muscle
tone
associated with spasticity. Inform
your physician
if you are pregnant
or nursing. Inform
your physician
if you have kidney
disease
or liver
impairment. May
cause
significant
hypotension; Do not rapidly arise from a prone position. Inform
your physician
if you are taking concurrent antihypertensive medication. May
cause
sedation; use caution while driving or operating hazardous machinery. Hallucinations
have been reported; be aware of this possibility. Inform
your physician
if you are taking any other medications, including over-the-counter drugs (e.g.
acetaminophen). Do
not drink alcohol
with tizanidine. Oral
contraceptives can prolong the effect
of tizanidine. May
cause
dry mouth,
sleepiness, slowed heart
rate, weakness, and dizziness. May
be taken with or without food. |