TIZANDINE tablet

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Active ingredient:
TIZANIDINE HYDROCHLORIDE (UNII: B53E3NMY5C) (TIZANIDINE - UNII:6AI06C00GW)
Available from:
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Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Tizanidine is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with tizanidine should be reserved for those daily activities and times when relief of spasticity is most important [see Dosage and Administration (2.1)]. Tizanidine is contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin [see Drug Interactions (7.1, 7.2)]. 8.1 Pregnancy Pregnancy Category C Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus. 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 maximum 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 increas
Product summary:
16.2 Tizanidine Tablets Tizanidine (tizanidine hydrochloride) tablets, USP are available as white to off-white, round, flat, bevel edged uncoated tablets containing 2 mg or 4 mg of tizanidine. Tizanidine tablets USP, 2 mg are debossed with "U" and "168" on one side and bisecting score on other side. Bottles of 150: Bottles of 500: Bottles of 1,000: Tizanidine tablets USP, 4 mg are debossed with "U" and "169" on one side and quadrisecting score on other side. Bottles of 150: Bottles of 300: Bottles of 500: Bottles of 1,000: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container [see USP].
Authorization status:
Abbreviated New Drug Application
Authorization number:
61919-811-72

TIZANDINE- tizandine tablet

Direct_Rx

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TIZANIDINE

Tizanidine is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because

of the short duration of therapeutic effect, treatment with tizanidine should be reserved for those daily

activities and times when relief of spasticity is most important [see Dosage and Administration (2.1)].

2.1 Dosing Information

Tizanidine tablets may be prescribed with or without food. Once the formulation has been selected and

the decision to take with or without food has been made, this regimen should not be altered.

Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations.

Tizanidine Capsules and tizanidine tablets are bioequivalent to each other under fasting conditions (more

than 3 hours after a meal), but not under fed conditions (within 30 minutes of a meal). These

pharmacokinetic differences may result in clinically significant differences when switching

administration of tablet and capsules and when switching administration between the fed or fasted state.

These changes may result in increased adverse events, or delayed or more rapid onset of activity,

depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar

with the changes in kinetics associated with these different conditions [see Clinical Pharmacology

(12.3)].

The recommended starting dose is 2 mg. Because the effect of tizanidine peaks at approximately 1 to 2

hours post-dose and dissipates between 3 to 6 hours post-dose, treatment can be repeated at 6 to 8 hour

intervals, as needed, to a maximum of three doses in 24 hours.

Dosage can be gradually increased by 2 mg to 4 mg at each dose, with 1 to 4 days between dosage

increases, until a satisfactory reduction of muscle tone is achieved. The total daily dose should not

exceed 36 mg. Single doses greater than 16 mg have not been studied.

2.2 Dosing in Patients with Renal Impairment

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 [see Warnings and Precautions (5.7)].

2.3 Dosing in Patients with Hepatic Impairment

Tizanidine should be used with caution in patients with any hepatic impairment. 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. Monitoring of aminotransferase levels is recommended for

baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. [see Use in

Specific Populations (8.7)]

2.4 Drug Discontinuation

If therapy needs to be discontinued, particularly in patients who have been receiving high doses (20 mg

to 36 mg daily) for long periods (9 weeks or more) or who may be on concomitant treatment with

narcotics, the dose should be decreased slowly (2 mg to 4 mg per day) to minimize the risk of

withdrawal and rebound hypertension, tachycardia, and hypertonia [see Drug Abuse and Dependence

(9.3)].

Tablets

Tizanidine tablets USP, 2 mg are white to off-white, round, flat, bevel edged uncoated tablets debossed

with "U" and "168" on one side and bisecting score on other.

Tizanidine tablets USP, 4 mg are white to off-white, round, flat, bevel edged uncoated tablets debossed

with "U" and "169" on one side and quadrisecting score on other.

Tizanidine is contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or

ciprofloxacin [see Drug Interactions (7.1, 7.2)].

5.1 Hypotension

Tizanidine is an α2-adrenergic agonist that can produce hypotension. Syncope has been reported in the

post marketing setting. 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 fixed upright position may be at increased risk for

hypotension and orthostatic effects.

Monitor for hypotension when tizanidine is used in patients receiving concurrent antihypertensive

therapy. It is not recommended that tizanidine be used with other α2-adrenergic agonists. Clinically

significant hypotension (decreases in both systolic and diastolic pressure) has been reported with

concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg of

tizanidine. Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent

inhibitors of CYP1A2, is contraindicated [see Contraindications (4) and Drug Interactions (7.1, 7.2)].

5.2 Risk of Liver Injury

Tizanidine may cause hepatocellular liver injury. Tizanidine should be used with caution in patients with

any hepatic impairment. Monitoring of aminotransferase levels is recommended for baseline and 1 month

after maximum dose is achieved, or if hepatic injury is suspected. [see Dosage and Administration (2.3)

and Use in Specific Populations (8.7)]

5.3 Sedation

Tizanidine can cause sedation, which may interfere with everyday activity. 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. The CNS depressant effects of tizanidine

with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may

be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess

sedation. [see Drug Interactions (7.5, 7.6)]

5.4 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. Most of the

patients were aware that the events were unreal. One patient developed psychosis in association with the

hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following

discontinuation of tizanidine. Consider discontinuing tizanidine in patients who develop hallucinations.

5.5 Interaction with CYP1A2 Inhibitors

Because of potential drug interactions, tizanidine is contraindicated in patients taking potent CYP1A2

inhibitors, such as fluvoxamine or ciprofloxacin. Adverse reactions such as hypotension, bradycardia,

or excessive drowsiness can occur when tizanidine is taken with other CYP1A2 inhibitors, such as

zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrythmics

(amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and

ticlopidine ). Concomitant use should be avoided unless the necessity for tizanidine therapy is clinically

evident. In such a case, use with caution. [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)]

5.6 Hypersensitivity Reactions

Tizanidine can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and

angioedema of the throat and tongue have been reported. Patients should be informed of the signs and

symptoms of severe allergic reactions and instructed to discontinue tizanidine and seek immediate

medical care should these signs and symptoms occur. [see Contraindications (4)]

5.7 Increased Risk of Adverse Reactions in Patients with Renal Impairment

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. [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]

5.8 Withdrawal Adverse Reactions

Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimize

the risk of these reactions, particularly in patients who have been receiving high doses (20 to 28 mg

daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with

narcotics, the dose should be decreased slowly (2 to 4 mg per day). [see Dosage and Administration

(2.2)]

The following adverse reactions are described elsewhere in other sections of the prescribing

information:

Hypotension [see Warnings and Precautions (5.1)]

Liver Injury [see Warnings and Precautions (5.2)]

Sedation [see Warnings and Precautions (5.3)]

Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions (5.4)]

Hypersensitivity Reactions [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in clinical practice.

Three double-blind, randomized, placebo controlled -clinical studies were conducted to evaluate the

effect of tizanidine on spasticity control. Two studies were conducted in patients with multiple

sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period

which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided

doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose

tapering. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three

studies patient ages ranged from 15–69 years and 51.4 percent were women. The median dose during

the plateau phase ranged from 20–28 mg/day.

The most frequent adverse reactions reported in multiple dose, placebo-controlled clinical studies

involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue

and/or tiredness) 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.

Table 1 lists 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 greater than the placebo group. 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 Reactions Reported for

Which Tizanidine Tablets Incidence is Greater than Placebo

*(weakness, fatigue, and/or tiredness)

Event

Placebo

N = 261

Tizanidine Tablet

N = 264

Dry mouth

Somnolence

Asthenia*

Dizziness

Infection

Constipation

Liver test abnormality

Vomiting

Speech disorder

Amblyopia (blurred vision)

<1

Urinary frequency

Flu symptom

Dyskinesia

Nervousness

<1

Pharyngitis

Rhinitis

In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple

sclerosis (Study 1) [see Clinical Studies (14)], the patients were specifically asked if they had

experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness),

asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia

were observed. The occurrence of these reactions is 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 Reactions Reported

*(weakness, fatigue, and/or tiredness)

Event

Placebo

N = 48

Tizanidine Tablet,8 mg,

N = 45

Tizanidine Tablet,16 mg,

N = 49

Somnolence

Dry mouth

Asthenia*

Dizziness

Hypotension

Bradycardia

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of tizanidine. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Certain events, such as somnolence, dry mouth, hypotension, decreased blood pressure, bradycardia,

dizziness, weakness or asthenia, muscle spasms, hallucinations, fatigue, liver function test abnormality

and hepatotoxicity, have been observed in post marketing and clinical trials and are discussed in

previous sections of this document.

The following adverse reactions have been identified as occurring in the post marketing experience of

tizanidine. Based on the information provided regarding these reactions, a causal relationship with

tizanidine cannot be entirely excluded. The events are listed in order of decreasing clinical

significance; severity in the post marketing setting is not reported.

Stevens Johnson Syndrome

Anaphylactic Reaction

Exfoliative Dermatitis

Ventricular Tachycardia

Hepatitis

Convulsion

Depression

Arthralgia

Paresthesia

Rash

Tremor

7.1 Fluvoxamine

Concomitant use of fluvoxamine and tizanidine is contraindicated. Changes in pharmacokinetics of

tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure,

increased drowsiness, and increased psychomotor impairment. [see Contraindications (4) and Clinical

Pharmacology (12.3)]

7.2 Ciprofloxacin

Concomitant use of ciprofoxacin and tizanidine is contraindicated. Changes in pharmacokinetics of

tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure,

increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical

Pharmacology (12.3)]

7.3 CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin

Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors,

such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated),

antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral

contraceptives, acyclovir, and ticlopidine) should be avoided. If their use is clinically necessary,

therapy should be initiated with 2 mg dose and increased in 2–4 mg steps daily based on patient response

to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur,

reduce or discontinue tizanidine therapy. [see Warnings and Precautions (5.5) and Clinical

Pharmacology (12.3)]

7.4 Oral Contraceptives

Concomitant use of tizanidine with oral contraceptives is not recommended. However, if concomitant

use is clinically necessary, initiate tizanidine with a single 2 mg dose and increase in 2–4 mg steps daily

based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or

excessive drowsiness occur, reduce or discontinue tizanidine therapy. [see Clinical Pharmacology

(12.3)]

7.5 Alcohol

Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine. This was

associated with an increase in adverse reactions of tizanidine. The CNS depressant effects of tizanidine

and alcohol are additive. [see Clinical Pharmacology (12.3)]

7.6 Other CNS Depressants

The sedative effects of tizanidine with CNS depressants (e.g., benzodiazepines, opioids, tricyclic

antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for

symptoms of excess sedation. [see Clinical Pharmacology (12.3)]

7.7 a2-adrenergic agonists

Because hypotensive effects may be cumulative, it is not recommended that tizanidine be used with

other α2-adrenergic agonists. [see Warnings and Precautions (5.1)]

8.1 Pregnancy

Pregnancy Category C

Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only

if the benefit outweighs the risk to the unborn fetus. 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 maximum 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. Post-implantation 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.

8.3 Nursing mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human

milk, caution should be exercised when tizanidine is administered to a nursing woman.

8.4 Pediatric use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric use

Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this

drug may be greater in patients with impaired renal function. Because elderly patients are more likely to

have decreased renal function, care should be taken in dose selection, and it may be useful to monitor

renal function. Clinical studies of tizanidine did not include sufficient numbers of subjects aged 65 and

over to determine whether they respond differently than younger subjects. 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. In elderly patients with renal

insufficiency (creatinine clearance <25 mL/min), tizanidine clearance is reduced by more than 50%

compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical

effect. During titration, the individual doses should be reduced. If higher doses are required, individual

doses rather than dosing frequency should be increased. Monitor elderly patients because they may

have an increased risk for adverse reactions associated with tizanidine.

8.6 Impaired Renal Function

Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this

drug may be greater in patients with impaired renal function. In patients with renal insufficiency

(creatinine clearance < 25 mL/min) clearance was 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. [see Dosage and Administration (2.2), Warnings and Precautions (5.7)

and Clinical Pharmacology (12.3)]

8.7 Impaired Hepatic Function

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. [see Dosing and Administration (2.3),

Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].

9.2 Abuse

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.

9.3 Dependence

Tizanidine is closely related to clonidine, which is often abused in combination with narcotics and is

known to cause symptoms of rebound upon abrupt withdrawal. Three cases of rebound symptoms on

sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were

also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor,

and anxiety. Withdrawal symptoms are more likely to occur in cases where high doses are used,

especially for prolonged periods, or with concomitant use of narcotics. If therapy needs to be

discontinued, the dose should be decreased slowly to minimize the risk of withdrawal symptoms [see

Dosage and Administration (2.2)].

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.

9.2 Abuse

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.

9.3 Dependence

Tizanidine is closely related to clonidine, which is often abused in combination with narcotics and is

known to cause symptoms of rebound upon abrupt withdrawal. Three cases of rebound symptoms on

sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were

also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor,

and anxiety. Withdrawal symptoms are more likely to occur in cases where high doses are used,

especially for prolonged periods, or with concomitant use of narcotics. If therapy needs to be

discontinued, the dose should be decreased slowly to minimize the risk of withdrawal symptoms [see

Dosage and Administration (2.2)].

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.

Tizanidine hydrochloride is a central alpha2-adrenergic agonist. Tizanidine hydrochloride, USP is a

white to off-white, fine crystalline powder, which is 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-benzothiadiazole monohydrochloride.

Tizanidine's molecular formula is C9H8ClN5S-HCl, its molecular weight is 290.2 and its structural

formula is:

[molecular structure]

Tizanidine tablets, USP are supplied as 2 mg and 4 mg tablets for oral administration. Tizanidine tablets,

USP contain the active ingredient, tizanidine hydrochloride (2.288 mg equivalent to 2 mg tizanidine base

and 4.576 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, colloidal silicon dioxide,

stearic acid, microcrystalline cellulose and anhydrous lactose.

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 Pharmacokinetics

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 1.0 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 Tizanidine Tablets and Capsules (2 × 4

mg) Under Fasted and Fed Conditions

[Figure-1]

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.

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 Use in Specific Populations (8.4, 8.5)]

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 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 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 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

CYP1A2 Inhibitors

The interaction between tizanidine 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 tizanidine 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 tizanidine 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 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 Warnings and Precautions (5.5)].

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.

13.1 Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the

maximum recommended human dose (MRHD) on a mg/m2 basis. Tizanidine was administered to rats for

104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m2 basis. There was

no increase in tumors in either species.

Mutagenesis

Tizanidine was negative in in vitro (bacterial reverse mutation [Ames], mammalian gene mutation, and

chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and

cytogenetics) assay.

Impairment of fertility

Oral administration of tizanidine resulted in reduced fertility in male and female rats following doses of

30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3

(female) mg/kg/day, which are approximately 8 and 3 times, respectively, the MRHD on a mg/m2 basis).

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 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 tizanidine 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)

[Figure 3]

Seven-Week Study in Patients with Spinal Cord Injury with Spasticity

In a 7-week study (Study 2), 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: 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)

[Figure 4]

16.2 Tizanidine Tablets

Tizanidine (tizanidine hydrochloride) tablets, USP are available as white to off-white, round, flat, bevel

edged uncoated tablets containing 2 mg or 4 mg of tizanidine.

Tizanidine tablets USP, 2 mg are debossed with "U" and "168" on one side and bisecting score on other

side.

Bottles of 150:

Bottles of 500:

Bottles of 1,000:

Tizanidine tablets USP, 4 mg are debossed with "U" and "169" on one side and quadrisecting score on

other side.

Bottles of 150:

Bottles of 300:

Bottles of 500:

Bottles of 1,000:

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in tight, light-resistant container [see USP].

Serious Drug Interactions

Advise patients they should not take tizanidine if they are taking fluvoxamine or ciprofloxacin because

of the increased risk of serious adverse reactions including severe lowering of blood pressure and

sedation. Instruct patients to inform their physicians or pharmacists when they start or stop taking any

medication because of the risks associated with interaction between tizanidine and other medicines.

Tizanidine Dosing

Tell patients to take tizanidine exactly as prescribed (consistently either with or without food) and not to

switch between tablets and capsules. Inform patients that they should not take more tizanidine than

prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses

greater than 36 mg. Tell patients that they should not suddenly discontinue tizanidine, because rebound

hypertension and tachycardia may occur.

Effects of tizanidine

Warn patients that they may experience hypotension and to be careful when changing from a lying or

sitting to a standing position. Tell patients that tizanidine may cause them to become sedated or

somnolent and they should be careful when performing activities that require alertness, such as driving

a vehicle or operating machinery. Tell patients 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. Remind patients that if they depend on their spasticity to sustain posture and balance in

locomotion, or whenever spasticity is utilized to obtain increased function, that tizanidine decreases

spasticity and caution should be used.

Manufactured by:

UNICHEM LABORATORIES LTD.

Pilerne Ind. Estate,

Pilerne, Bardez, Goa 403511, India

Manufactured for:

[logo]

Hasbrouck Heights, NJ 07604

06-R-11/2017

13009861

TIZANDINE

tizandine tablet

Product Information

Dire ct_Rx

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 19 -8 11(NDC:29 30 0 -16 8 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TIZANIDINE HYDRO CHLO RIDE (UNII: B53E3NMY5C) (TIZANIDINE - UNII:6 AI0 6 C0 0 GW)

TIZANIDINE

2 mg

Inactive Ingredients

Ingredient Name

Stre ng th

STEARIC ACID (UNII: 4ELV7Z6 5AP)

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

Product Characteristics

Color

white ((White to o ff white))

S core

2 pieces

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

U;16 8

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -8 11-72

120 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /19 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 128 3

0 8 /19 /20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re la be l(6 19 19 -8 11)

Revised: 8/2019

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