Tizanidin: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

Tablets

Tizanidine Tablets USP, 2 mg are white to off white, oval, flat, beveled edged tablets debossed with “R179” on one side and “bisecting score” on other side.

Tizanidine Tablets USP, 4 mg are white to off white, oval, flat, beveled edged tablets debossed with “R180” on one side and “quadrisecting score” on other side.

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 to 69 years and 51.4 percent were women. The median dose during the plateau phase ranged from 20 to 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 hydrochloride where the frequency in the tizanidine hydrochloride 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

Event | Placebo N = 261 % | Tizanidine Tablet N = 264 %
Dry mouth | 10 | 49
Somnolence | 10 | 48
Asthenia* | 16 | 41
Dizziness | 4 | 16
UTI | 7 | 10
Infection | 5 | 6
Constipation | 1 | 4
Liver test abnormality | 2 | 6
Vomiting | 0 | 3
Speech disorder | 0 | 3
Amblyopia (blurred vision) | <1 | 3
Urinary frequency | 2 | 3
Flu syndrome | 2 | 3
Dyskinesia | 0 | 3
Nervousness | <1 | 3
Pharyngitis | 1 | 3
Rhinitis | 2 | 3

*(weakness, fatigue, and/or tiredness)

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

Event | Placebo N = 48 % | Tizanidine Tablet, 8mg, N = 45 % | Tizanidine Tablet,16 mg, 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

*(weakness, fatigue, and/or tiredness)

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of tizanidine hydrochloride. 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 hydrochloride. Based on the information provided regarding these reactions, a causal relationship with tizanidine hydrochloride 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 To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

5.1 Hypotension

Tizanidine is an α ₂-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 hydrochloride is used in patients receiving concurrent antihypertensive therapy. It is not recommended that tizanidine hydrochloride be used with other α ₂-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 hydrochloride. Therefore, concomitant use of tizanidine hydrochloride 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 hydrochloride may cause hepatocellular liver injury. Tizanidine hydrochloride 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 hydrochloride 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 hydrochloride with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine hydrochloride with another CNS depressant for symptoms of excess sedation. [see Drug Interactions ( 7.5, 7.6 )]

5.4 Hallucinosis/Psychotic-Like Symptoms

Tizanidine hydrochloride 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 hydrochloride in patients who develop hallucinations.

5.5 Interaction with CYP1A2 Inhibitors

Because of potential drug interactions, tizanidine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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) ]

7.1 Fluvoxamine

Concomitant use of fluvoxamine and tizanidine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride therapy. [see Warnings and Precautions ( 5.5) and Clinical Pharmacology ( 12.3) ]

7.4 Oral Contraceptives

Concomitant use of tizanidine hydrochloride with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine hydrochloride 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 hydrochloride therapy. [see Clinical Pharmacology ( 12.3) ]

7.5 Alcohol

Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine hydrochloride. This was associated with an increase in adverse reactions of tizanidine hydrochloride. The CNS depressant effects of tizanidine hydrochloride and alcohol are additive. [see Clinical Pharmacology ( 12.3) ]

7.6 Other CNS Depressants

The sedative effects of tizanidine hydrochloride with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine hydrochloride with another CNS depressant for symptoms of excess sedation. [see Clinical Pharmacology ( 12.3) ]

7.7 α ₂-adrenergic agonists

Because hypotensive effects may be cumulative, it is not recommended that tizanidine hydrochloride be used with other α ₂-adrenergic agonists. [see Warnings and Precautions ( 5.1) ]

8.1 Pregnancy

Pregnancy Category C

Tizanidine hydrochloride has not been studied in pregnant women. Tizanidine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride.

8.6 Impaired Renal Function

Tizanidine hydrochloride 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) ].

A review of the safety surveillance database revealed cases of intentional and accidental tizanidine hydrochloride 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.

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 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.

Figure 1: Mean Tizanidine Concentration vs. Time Profiles For Tizanidine Tablets and Capsules (2 × 4 mg) Under Fasted and Fed Conditions

Metabolism and Excretion