Zanaflex

Administering tizanidine with food increases the C_max, the time to peak concentration, and the extent of absorption of tizanidine (see Action and Clinical Pharmacology). These pharmacokinetic differences may result in clinically significant differences when switching between fed or fasted states, such as changed incidence of adverse events or delayed/more rapid onset of activity, depending on the nature of the switch (see Dosage and Administration).

No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and Zanaflex, but retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg Zanaflex showed that women concurrently taking oral contraceptives had 50% lower clearance of Zanaflex than women not on oral contraceptives.

Alcohol increased the AUC of Zanaflex by approximately 20% while also increasing its C_max by approximately 15%. This was associated with an increase in side effects of Zanaflex. The CNS depressant effects of Zanaflex and alcohol are additive.

Zanaflex should not be used together with moderate and potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin (see Contraindications). Concomitant use of tizanidine with fluvoxamine, a potent CYP450 1A2 inhibitor in man, resulted in a 33-fold increase in the tizanidine AUC by fluvoxamine in 10 healthy male subjects. Concomitant use of tizanidine with ciprofloxacin resulted in a 10-fold increase in tizanidine AUC in 10 healthy male subjects. In both studies, clinically significant hypotension resulted along with somnolence, dizziness and decreased psychomotor performance. Coadministration of tizanidine with other inhibitors of CYP1A2 such as antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, other fluoroquinolones (norfloxacin, moxifloxacin), oral contraceptives, and ticlopidine should be avoided or used in caution (see also Warnings and Precautions, Drug Interaction with CYP1A2 Inhibitors).

Zanaflex delayed the T_max of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of Zanaflex.

In placebo-controlled clinical trials, Zanaflex has been administered concomitantly with antihypertensive medications in 30 patients. The addition of Zanaflex to antihypertensive therapy was associated with a 20-30% increase in the incidence of clinically significant decreases in systolic or diastolic blood pressure compared with both placebo plus antihypertensive (N=36) and Zanaflex alone (N=226).

Concurrent use of antihypertensive and Zanaflex therapy also resulted in an increase in reports of orthostatic hypotension. Lower initial doses and cautious dose titration should be considered when Zanaflex is to be administered to patients receiving antihypertensive therapy or if antihypertensive therapy is to be initiated in a patient receiving Zanaflex.

In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor its major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. There are reports of drug interaction of tizanidine and CYP1A2 inhibitors, such as oral contraceptives, fluvoxamine, fluoroquinolones, and others.

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. There have been post-market reports of QT prolongation and a small number of reports of torsades de pointes, none of them fatal, during Zanaflex treatment. Zanaflex should be used with caution in patients taking drugs known to prolong the QT interval.

Administration of tizanidine with food increases the C_max, the time to peak concentration, and the extent of absorption of tizanidine. These pharmacokinetic differences may result in clinically significant differences when switching between fed or fasted states, such as changed incidence of adverse events or delayed/more rapid onset of activity, depending on the nature of the switch. For this reason, the prescriber should recommend patients to always take tizanidine the same way with regard to fed and fasted state (see Action and Clinical Pharmacology).

A single oral dose of 8 mg of Zanaflex (tizanidine HCl) 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. Zanaflex dosing should be scheduled such that the peak effect coincides with activities for which relief of spasticity is most desirable. 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 Zanaflex's common adverse events, particularly blood pressure reduction, make it prudent to begin treatment with single oral doses of 2 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 and Precautions).

Frequent: abdomen pain, diarrhea, dyspepsia; Infrequent: dysphagia, cholelithiasis, fecal impaction, flatulence, gastrointestinal hemorrhage, hepatitis, melena; Rare: gastroenteritis, hematemesis, hepatoma, intestinal obstruction, liver damage.

Infrequent: edema, hypothyroidism, weight loss; Rare: adrenal cortex insufficiency, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, respiratory acidosis.

Infrequent: ear pain, tinnitus, deafness, glaucoma, conjunctivitis, eye pain, optic neuritis, otitis media, retinal hemorrhage, visual field defect; Rare: iritis, keratitis, optic atrophy.

Frequent: rash, sweating, skin ulcer; Infrequent: pruritus, dry skin, acne, alopecia, urticaria; Rare: exfoliative dermatitis, herpes simplex, herpes zoster, skin carcinoma.

Frequent: myasthenia, back pain; Infrequent: pathological fracture, arthralgia, arthritis, bursitis.

Frequent: fever; Infrequent: allergic reaction, moniliasis, malaise, abscess, neck pain, sepsis, cellulitis, death, overdose; Rare: carcinoma, congenital anomaly, suicide attempt.

x

Single Dose, Placebo-Controlled Study (Common Adverse Events Reported)

Infrequent: vasodilatation, postural hypotension, syncope, migraine, arrhythmia; Rare: angina pectoris, coronary artery disorder, heart failure, myocardial infarct, phlebitis, pulmonary embolus, ventricular extrasystoles, ventricular tachycardia.

In post-marketing experience, nausea has also been reported at a frequency of <0.1% and ≥0.01%.

Zanaflex was administered to 1187 patients in additional clinical studies where adverse event information was available. The conditions and duration of exposure varied greatly, and included (in overlapping categories) double-blind and open-label studies, uncontrolled and controlled studies, inpatient and outpatient studies, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 1187 patients exposed to Zanaflex 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 Zanaflex, 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.

Frequent: depression, anxiety, paresthesia; Infrequent: tremor, emotional lability, convulsion, paralysis, thinking abnormal, vertigo, abnormal dreams, agitation, depersonalization, euphoria, migraine, stupor, dysautonomia, neuralgia; Rare: dementia, hemiplegia, neuropathy.

Infrequent: urinary urgency, cystitis, menorrhagia, pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged, vaginal moniliasis, vaginitis; Rare: albuminuria, glycosuria, hematuria, metrorrhagia.

In multiple dose, placebo-controlled clinical studies, 264 patients were treated with Zanaflex (tizanidine HCl) and 261 with placebo. Adverse events, including severe adverse events, were more frequently reported with Zanaflex than with placebo.

Infrequent: sinusitis, pneumonia, bronchitis; Rare: asthma.

Infrequent: ecchymosis, hypercholesteremia, anemia, hyperlipemia, leukopenia, leukocytosis, sepsis; Rare: petechia, purpura, thrombocythemia, thrombocytopenia.

Evidence from clinical studies and experience suggests that use in the geriatric population may be associated with differences in safety or effectiveness and a brief discussion can be found in the appropriate sections (Warnings and Precautions and Action and Clinical Pharmacology).

No data are available.

Zanaflex (tizanidine HCl) is a short-acting drug for the management of spasticity.

Zanaflex should be used with caution in patients with renal insufficiency (Clcr <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 onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose.

Only animal carcinogenesis data and mutagenesis data from in vitro and in vivo assays are available.

Tizanidine HCl is an α₂-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 Zanaflex had a 20% reduction in either the diastolic or systolic BP. The reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing and was associated, at times, with bradycardia, orthostatic hypotension, lightheadedness/dizziness and rarely syncope. The hypotensive effect is dose related and has been measured following single doses of ≥2 mg.

The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. In addition, patients moving from a supine to a fixed upright position may be at increased risk for hypotensive and orthostatic effects.

Caution is advised when Zanaflex is to be used in patients who have a history of orthostatic hypotension or labile blood pressure or who are receiving concurrent antihypertensive therapy. Zanaflex should not be used with other α₂-adrenergic agonists.

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.

The effect of Zanaflex on labor and delivery in humans is unknown.

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 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. Zanaflex has not been studied in pregnant women. Zanaflex should be given to pregnant women only if the potential benefit clearly outweighs the potential risk to mother and child.

In the multiple dose, controlled clinical studies, 48% of patients receiving any dose of Zanaflex reported sedation as an adverse event. In 10% of these cases, the sedation was rated as severe compared to <1% in the placebo treated patients. Sedation may interfere with every day activity.

The effect appears to be dose related. In a single dose study, 92% of the patients receiving 16 mg, when asked, reported that they were drowsy during the 6-hour study. This compares to 76% of the patients on 8 mg and 35% of the patients on placebo. Patients began noting this effect 30 minutes following dosing. The effect peaked 1.5 hours following dosing. Of the patients who received a single dose of 16 mg, 51% continued to report drowsiness 6 hours following dosing compared to 13% in the patients receiving placebo or 8 mg of Zanaflex.

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.

Zanaflex should be used with caution in elderly patients because clearance is decreased four-fold.

Zanaflex use occasionally causes drug induced liver injury, most often hepatocellular in type (see Warnings and Precautions, General).

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 is closely related to clonidine, which is often abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. There have been cases of rebound symptoms reported on sudden withdrawal of tizanidine. Some of the case reports suggest that these patients were also misusing opioids. Withdrawal symptoms included but were not limited to: hypertension, tachycardia, hypertonia, convulsions, tremor, and anxiety. As with clonidine, withdrawal is expected to be more likely in cases where high doses are used, especially for prolonged periods. There have been also reports of tizanidine abuse and dependence, most of them with concomitant use of opioids, benzodiazepines, other hypnotics or multiple analgesics. The potential for tizanidine abuse should be monitored, especially in patients simultaneously using opioids or benzodiazepines.

Zanaflex use has been associated with sedation (see Warnings and Precautions, General).

Zanaflex use has been associated with hallucinations (see Warnings and Precautions, General).

If therapy needs to be discontinued, especially in patients who have been receiving high doses for long periods, the dose should be decreased slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia.

The following additional precautions are listed alphabetically.

There are no adequate and well-controlled studies to document the safety and efficacy of Zanaflex in children under 18 years in age.

Zanaflex use occasionally causes drug induced liver injury, most often hepatocellular in type. In controlled clinical studies, approximately 5% of patients treated with Zanaflex had elevations of liver function tests (ALT, AST) to greater than 3 times the upper limit of normal (or 2 times if baseline levels were elevated). The patients usually remain asymptomatic despite increased aminotransferases. In occasional symptomatic cases, nausea, vomiting, anorexia and jaundice have been reported. The onset of the elevated liver enzymes typically occurred within the first 6 months of treatment with Zanaflex and most resolved rapidly upon drug withdrawal with no reported residual problems. In postmarketing experience, three deaths associated with liver failure have been reported in patients treated with tizanidine, including one case of fatal fulminant hepatitis.

Monitoring of aminotransferase levels is recommended during the first 6 months of treatment (e.g., baseline, 1, 3 and 6 months) and periodically thereafter, based on clinical status. Because of the potential toxic hepatic effect of tizanidine, the drug should be used only with extreme caution in patients with impaired hepatic function.

Concomitant use of tizanidine and moderate or potent CYP450 1A2 inhibitors is contraindicated (see Contraindications). Concomitant use of tizanidine with fluvoxamine, a potent CYP450 1A2 inhibitor in man, resulted in a 33-fold increase in the tizanidine AUC by fluvoxamine; concomitant use of tizanidine with ciprofloxacin, another CYP1A2 inhibitor, resulted in a 10-fold increase in tizanidine AUC; in both studies, clinically significant hypotension resulted along with somnolence, dizziness and decreased psychomotor performance (see Drug Interactions). Coadministration of tizanidine with other inhibitors of CYP1A2 such as antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, other fluoroquinolones (norfloxacin, moxifloxacin), and ticlopidine should be avoided or used with caution.

Zanaflex 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.

It is not known whether Zanaflex is excreted in human milk, although as a lipid soluble drug, it might be expected to pass into breast milk.

Patients should be advised of the limited clinical experience with Zanaflex both in regard to duration of use and the higher doses required to reduce muscle tone (see Warnings and Precautions, General).

Because of the possibility of Zanaflex lowering blood pressure, patients should be warned about the risk of clinically significant orthostatic hypotension (see Warnings and Precautions, General).

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 and Precautions, General). Patients should also be instructed that the sedation may be additive when Zanaflex is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants.

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. There have been post-market reports of QT prolongation and a small number of reports of torsades de pointes, none of them fatal, during Zanaflex treatment.

Caution should be exercised when Zanaflex is prescribed with drugs known to prolong the QT interval.

Tizanidine HCl can produce hypotension associated, at times, with bradycardia and orthostatic hypotension, dizziness and rarely syncope (see Warnings and Precautions, General).

Pharmacokinetic differences due to hepatic impairment have not been studied (see Warnings and Precautions).

Tizanidine is widely distributed throughout the body; mean steady state volume of distribution is 2.4 L/kg following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins, independent of concentration over the therapeutic range.

Following oral administration, tizanidine is essentially completely absorbed and has a half-life of approximately 2 hours. Following administration of tizanidine peak plasma concentrations occurred at approximately 1 hour after dosing. Food increases the mean C_max by approximately 30% and increases the median time to peak concentration by approximately 25 minutes, from 1 hour to 1 hour and 25 minutes. Food increases the extent of absorption of tizanidine by approximately 30%. Tizanidine has linear pharmacokinetics over a dose of 1 to 20 mg.

Tizanidine is an agonist at α₂-adrenergic receptor sites and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. In animal models, tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction, and no major effect on monosynaptic spinal reflexes. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons.

The imidazoline chemical structure of tizanidine is related to that of the anti-hypertensive drug clonidine and other α₂-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.

No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data, following single dose administration of 6 mg Zanaflex showed that younger subjects cleared the drug four times faster than the elderly subjects. Zanaflex has not been evaluated in children (see Warnings and Precautions).

Pharmacokinetic differences due to race have not been studied.

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.

Zanaflex 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. Zanaflex should be used with caution in renally impaired patients (see Warnings and Precautions).

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 Zanaflex showed that gender had no effect on the pharmacokinetics of Zanaflex.

The absolute oral bioavailability of tizanidine is approximately 40%, 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.