Comfort pac w/tizanidine

Overdose

Clinical experience is limited. In one case, where an adult patient ingested 400mg Comfort Pac w/Tizanidine, recovery was uneventful. This patient received mannitol and furosemide

Symptoms

Nausea, vomiting, hypotension, bradycardia, QT prolongation, dizziness, miosis, respiratory distress, coma, restlessness, somnolence.

Treatment

General supportive measures are indicated and an attempt should be made to remove ingested substance from the gastro-intestinal tract using gastric lavage or by repeated administration of high doses of activated charcoal. The patient should be well hydrated as forced diuresis is expected to accelerate the elimination of Comfort Pac w/Tizanidine. Further treatment should be symptomatic.

A review of the safety surveillance database revealed cases of intentional and accidental Comfort Pac w/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.

Contraindications

Comfort Pac w/Tizanidine is contraindicated in patientstaking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin.

Incompatibilities

Not applicable.

Undesirable effects

The adverse effects are classified below by system organ class according to the following convention:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to ≤1/100)

Rare (>1/10,000 to ≤1/1,000)

Very rare, including isolated reports (<1/10,000)

Not known (cannot be estimated from the available data)

* The hallucinations are self-limiting, without evidence of psychosis, and have invariably occurred in patients concurrently taking potentially hallucinogenic substances, e.g. anti-depressants.

With low doses, such as those recommended for the relief of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, blood pressure decrease, nausea, gastrointestinal disorder and transaminase increase have been reported, usually as mild and transient adverse reactions..

With the higher doses recommended for the treatment of spasticity, the adverse reactions reported with low doses are more frequent and more pronounced, but seldom severe enough to require discontinuation of treatment.

In addition, the following adverse reactions may occur: confusional state, hypotension, bradycardia, muscular weakness, insomnia, sleep disorder, hallucination, hepatitis.

Withdrawal syndrome

Rebound hypertension and tachycardia have been observed after sudden withdrawal of Comfort Pac w/Tizanidine, when it had been used chronically, and/or in high daily dosages, and/or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard

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

• Hypotension
• Liver Injury
• Sedation
• Hallucinosis/Psychotic-Like Symptoms
• Hypersensitivity Reactions

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 Comfort Pac w/Tizanidine where the frequency in the Comfort Pac w/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 Comfort Pac w/Tizanidine Tablets Incidence is Greater than Placebo

In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) , 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

The following adverse reactions have been identified during post approval use of Comfort Pac w/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 Comfort Pac w/Tizanidine. Based on the information provided regarding these reactions, a causal relationship with Comfort Pac w/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

Preclinical safety data

Acute toxicity

Comfort Pac w/Tizanidine possesses a low order of acute toxicity. Signs of overdose were seen after single doses > 40mg/kg in animals and are related to the pharmacological action of the substance.

Repeat dose toxicity

The toxic effects of Comfort Pac w/Tizanidine are mainly related to its pharmacological action. At doses of 24 and 40mg/kg per day in subchronic and chronic rodent studies, the α2-agonist effects resulted in central nervous system stimulation, e.g. motor excitation, aggressiveness, tremor and convulsions.

Signs related to centrally mediated muscle relaxation, e.g. sedation and ataxia, were frequently observed at lower dose levels in subchronic and chronic oral studies with dogs. Such signs, related to the myotonolytic activity of the substance, were noted at 1 to 4mg/kg per day in a 13 week dog study, and at 1.5mg/kg per day in a 52-week dog study.

Prolongation of the QT interval and bradycardia were noted in chronic toxicity studies in dogs at doses of 1.0mg/kg per day and above.

Retinal atrophy and corneal opacity have been observed in chronic toxicity studies in the rat. The no observed adverse effect load in the rat was below 1mg/kg/day.

Slight increases in hepatic serum transaminases were observed in a number of toxicity studies at higher dose levels. They were not consistently associated with histopathological changes in the liver.

Mutagenicity

Various in vitro assays as well as in vivo assays produced no evidence of mutagenic potential of Comfort Pac w/Tizanidine.

Carcinogenicity

No evidence for carcinogenicity was demonstrated in two long-term dietary studies in mice (78 weeks) and rats (104 weeks), at dose levels up to 9mg/kg per day in rats and up to 16mg/kg per day in mice. At these dose levels, corresponding to the maximum tolerated dose, based on reductions in growth rate, no neoplastic or pre-neoplastic pathology, attributable to treatment, was observed.

Reproductive toxicity

No embryotoxicity or teratogenicity occurred in pregnant rats and rabbits at dose levels up to 30mg/kg per day of Comfort Pac w/Tizanidine. However, doses of 10-100mg/kg per day in rats were maternally toxic and resulted in developmental retardation of foetuses as seen by lower foetal body weights and retarded skeletal ossification.

In female rats, treated prior to mating through lactation or during late pregnancy until weaning of the young, a dose-dependent (10 and 30mg/kg per day) prolongation of gestation time and dystocia occurred, resulting in an increased foetal mortality and delayed development. These effects were attributed to the pharmacological effect of Comfort Pac w/Tizanidine. No developmental effects occurred at 3mg/kg per day although sedation was induced in the treated dams.

Passage of Comfort Pac w/Tizanidine and/or its metabolites into milk of rodents is known to occur.

Therapeutic indications

Treatment of spasticity associated with multiple sclerosis or with spinal cord injury or disease.

Comfort Pac w/Tizanidine is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with Comfort Pac w/Tizanidine should be reserved for those daily activities and times when relief of spasticity is most important.

Pharmacodynamic properties

Pharmacotherapeutic group: Musculo-skeletal system; muscle relaxants; centrally acting agents; other centrally acting agents

ATC code: M03B X02

Comfort Pac w/Tizanidine is a centrally acting skeletal muscle relaxant. Its principal site of action is the spinal cord, where the evidence suggests that, by stimulating presynaptic alpha2-receptors, it inhibits the release of excitatory aminoacids that stimulate N-methyl-D-aspartate (NMDA) receptors. Polysynaptic signal transmission at spinal interneuron level, which is responsible for excessive muscle tone, is thus inhibited and muscle tone reduced. Comfort Pac w/Tizanidine has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic spinal reflexes. In addition to its muscle-relaxant properties, Comfort Pac w/Tizanidine also exerts a moderate central analgesic effect.

In humans, Comfort Pac w/Tizanidine reduces pathologically increased muscle tone, including resistance to passive movements and alleviates painful spasms and clonus.

Pharmacokinetic properties

Absorption

Comfort Pac w/Tizanidine is rapidly absorbed, reaching peak plasma concentration in approximately 1 hour after dosing.

Distribution

Comfort Pac w/Tizanidine is only about 30% bound to plasma proteins and, in animal studies, was found to readily cross the bloodbrain barrier. Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg.

Biotransformation

Although Comfort Pac w/Tizanidine is well absorbed, first pass metabolism limits plasma availability to 34% of that of an intravenous dose. Comfort Pac w/Tizanidine undergoes rapid and extensive metabolism in the liver. Comfort Pac w/Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro.

Elimination

The metabolites are primarily excreted via the renal route (approximately 70% of the administered dose) and appear to be inactive. Renal excretion of the parent compound is approximately 53% after a single 5 mg dose and 66% after dosing with 4 mg three times daily. The elimination half-life of Comfort Pac w/Tizanidine from plasma is 2-4 hours in patients.

Linearity

Comfort Pac w/Tizanidine has linear pharmacokinetics over the dose range 4 to 20 mg. The low intraindividual variation in pharmacokinetic parameters (Cmax and AUC) enables reliable prediction of plasma levels following oral administration.

Characteristics in special patient populations

The pharmacokinetic parameters of Comfort Pac w/Tizanidine are not affected by gender.

In patients with renal insufficiency (creatinine clearance < 25 mL/min), maximal mean plasma levels were found to be twice as high as in normal volunteers, and the terminal half-life was prolonged to approximately 14 hours, resulting in much higher (approximately 6-fold on average) AUC values.

Effect of food

Concomitant food intake has no clinically significant influence on the pharmacokinetic profile of Comfort Pac w/Tizanidine tablets.

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 Comfort Pac w/Tizanidine Capsules® and Comfort Pac w/Tizanidine® Tablets

Comfort Pac w/Tizanidine Capsules® and Comfort Pac w/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 Comfort Pac w/Tizanidine Tablets and Capsules (2 × 4 mg) Under Fasted and Fed Conditions

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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

CYP inhibitors

Concomitant use of Comfort Pac w/Tizanidine with CYP1A2 inhibitors is not recommended.

Hypotension

Hypotension may occur during treatment with Comfort Pac w/Tizanidine and also as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive drugs. Severe manifestations of hypotension such as loss of consciousness and circulatory collapse have also been observed.

Withdrawal syndrome

Rebound hypertension and tachycardia have been observed after sudden withdrawal of Comfort Pac w/Tizanidine, when it had been used chronically, and/or in high daily dosages, and/or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident. Comfort Pac w/Tizanidine should not be stopped abruptly, but rather gradually.

Renal insufficiency

In patients with renal insufficiency (creatinine clearance < 25 mL/min), it is recommended to start treatment at 2 mg once daily. Dosage increases should be done in small steps according to tolerability and efficacy. If efficacy has to be improved, it is advisable to increase first the once daily dose before increasing the frequency of administration.

Cardiovascular, hepatic or renal disorders

Caution is required in patients with cardiovascular disorders, coronary artery disease or renal or hepatic disorders. Regular clinical laboratory and ECG monitoring is recommended during treatment with Comfort Pac w/Tizanidine.

Hepatic dysfunction

Since hepatic dysfunction has been reported in association with Comfort Pac w/Tizanidine but rarely at daily doses up to 12mg, it is recommended that liver function tests should be monitored monthly for the first four months in patients receiving doses of 12mg and higher and in patients who develop clinical symptoms suggestive of hepatic dysfunction, such as unexplained nausea, anorexia or tiredness. Treatment with Comfort Pac w/Tizanidine should be discontinued if serum levels of SGPT (serum glutamic-pyruvic transaminase) and/or SGOT (serum glutamic-oxaloacetic transaminase) are persistently above three times the upper limit of the normal range. Comfort Pac w/Tizanidine should be discontinued in patients with symptoms compatible with hepatitis or where jaundice occurs.

This medicinal product contains lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Included as part of the PRECAUTIONS section.

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 Comfort Pac w/Tizanidine is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Comfort Pac w/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 Comfort Pac w/Tizanidine. Therefore, concomitant use of Comfort Pac w/Tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated.

Comfort Pac w/Tizanidine may cause hepatocellular liver injury. Comfort Pac w/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.

Comfort Pac w/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 Comfort Pac w/Tizanidine with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Comfort Pac w/Tizanidine with another CNS depressant for symptoms of excess sedation.

Comfort Pac w/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 Comfort Pac w/Tizanidine in patients who develop hallucinations.

Because of potential drug interactions, Comfort Pac w/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 Comfort Pac w/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 Comfort Pac w/Tizanidine therapy is clinically evident. In such a case, use with caution.

Comfort Pac w/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 Comfort Pac w/Tizanidine and seek immediate medical care should these signs and symptoms occur.

Comfort Pac w/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.

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).

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.

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.

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).

Comfort Pac w/Tizanidine has not been studied in pregnant women. Comfort Pac w/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.

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 Comfort Pac w/Tizanidine is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established.

Comfort Pac w/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 Comfort Pac w/Tizanidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Crossstudy comparison of pharmacokinetic data following single dose administration of 6 mg Comfort Pac w/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 Comfort Pac w/Tizanidine.

Comfort Pac w/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.

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..

Effects on ability to drive and use machines

Patients experiencing somnolence, dizziness or any signs or symptoms of hypotension should refrain from activities requiring a high degree of alertness, e.g. driving a vehicle or operating machines.

Dosage (Posology) and method of administration

Posology

The effect of Comfort Pac w/Tizanidine on spasticity is maximal within 2-3 hours of dosing and it has a relatively short duration of action. The timing and frequency of dosing should therefore be tailored to the individual, and Comfort Pac w/Tizanidine should be given in divided doses, up to 3-4 times daily, depending on the patient's needs. There is considerable variation in response between patients so careful titration is necessary. Care should be taken not to exceed the dose producing the desired therapeutic effect.

It is usual to start with a single dose of 2mg increasing by 2mg increments at no less than half-weekly intervals. The optimum therapeutic response is generally achieved with a daily dose of between 12 and 24mg, administered in 3 or 4 equally spaced doses. Single doses should not exceed 12mg. The total daily dose should not exceed 36mg.

Adverse events may occur at therapeutic doses but these can be minimised by slow titration so that in the large majority of patients they are not a limiting factor.

Discontinuing therapy

If therapy needs to be discontinued, particularly in patients who have been receiving high doses for long periods, the dose should be decreased slowly.

Elderly

Experience in the elderly is limited and use of Comfort Pac w/Tizanidine is not recommended unless the benefit of treatment clearly outweighs the risk. Pharmacokinetic data suggest that renal clearance in the elderly may in some cases be significantly decreased. Caution is therefore indicated when using Comfort Pac w/Tizanidine in elderly patients.

Paediatric population

Experience with Comfort Pac w/Tizanidine in patients under the age of 18 years is limited. Comfort Pac w/Tizanidine is not recommended for use in this population.

Renal impairment

In patients with renal insufficiency (creatinine clearance < 25 ml/min) treatment should be started with 2mg once daily with slow titration to achieve the effective dose. Dosage increases should be in increments of no more than 2mg according to tolerability and effectiveness. If efficacy has to be improved, it is advisable to slowly increase the once-daily dose before increasing the frequency of administration. Renal function should be monitored as appropriate in these patients.

Hepatic impairment

Comfort Pac w/Tizanidine is contraindicated in patients with significantly impaired hepatic function.

Method of administration

For oral use

Comfort Pac w/Tizanidine Capsules® or Comfort Pac w/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. Comfort Pac w/Tizanidine Capsules and Comfort Pac w/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.

The recommended starting dose is 2 mg. Because the effect of Comfort Pac w/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.

Comfort Pac w/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.

Comfort Pac w/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.

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.

Special precautions for disposal and other handling

No special requirements.