Tizanidine: Package Insert and Label Information (Page 2 of 3)

6.2 Post-Marketing 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 DRUG INTERACTIONS

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 to 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 to 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 α2-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 USE IN SPECIFIC POPULATIONS

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 DRUG ABUSE AND DEPENDENCE

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.

10 OVERDOSAGE

A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose.

Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.

11 DESCRIPTION

Tizanidine hydrochloride is a centrally acting α₂ -adrenergic agonist. Tizanidine HCl (tizanidine) 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 hydrochloride. Tizanidine’s molecular formula is C₉ H₈ ClN₅ S-HCl, its molecular weight is 290.2 and its structural formula is:

Tizanidine Tablets, USP are supplied as 2, and 4 mg tablets for oral administration. Tizanidine Tablets, USP are composed of 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, anhydrous lactose, colloidal silicon dioxide, microcrystalline cellulose and stearic acid.

Meets USP Dissolution Test 2

12 CLINICAL PHARMACOLOGY

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 C_max for the capsule when administered with food is approximately 66% the C_max 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% to 20% increase in C_max 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.

Metabolism and Excretion
Tizanidine has linear pharmacokinetics over the doses studied in clinical development (1 to 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 ¹⁴ C-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 C_max , 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 C_max 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 T_max 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 C_max by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.