Tizagelan 2 mg tablets

Tizagelan 4 mg tablets

Tizagelan 2 mg tablets

Each tablet contains 2 mg tizanidine (as 2.29 mg tizanidine hydrochloride).

Excipients with known effect:

Each tablet contains 106.79 mg lactose monohydrate and 11.76 mg sucrose.

Tizagelan 4 mg tablets

Each tablet contains 4 mg tizanidine (as 4.57 mg tizanidine hydrochloride).

Excipients with known effect:

Each tablet contains 104.51 mg lactose monohydrate and 11.76 mg sucrose.

For the full list of excipients, see section 6.1.

Tablet

Tizagelan 2 mg tablets

White to yellowish coloured, round and biconvex tablet, with a break score on one side and with a diameter of about 8 mm.

The tablet can be divided into equal doses.

Tizagelan 4 mg tablets

White to yellowish coloured, round and biconvex tablet, with a cross break score on one side and with a diameter of about 8 mm.

The tablet can be divided into equal doses, either halves or quarts.

Spasms of the skeletal muscles

- associated with static and functional disorders of the spine (cervical and lumbar syndromes)

- after surgical interventions on the musculoskeletal system, e.g. herniated disc or joint disorders of the hip.

Spasticity due to neurological disorders, such as

- multiple sclerosis, chronic myelopathy, degenerative spinal cord disease, cerebrovascular accidents and cerebral palsy.

Tizagelan has a narrow therapeutic index and a high inter-patient variability in tizanidine plasma concentrations. Therefore, it is important to adjust the dose individually.

A low starting dose of 2 mg three times daily can reduce the risk of side effects. The dose should be increased gradually and with caution according to the individual patient's need and the therapeutic response.

Posology

Spasms of the skeletal muscles

The recommended dose is 2-4 mg 3 times daily.

In severe cases, an extra dose of 2-4 mg may be given, preferably late in the evening to reduce the sedative effect.

Spasticity due to neurological disorders

The initial daily dose should not exceed 6 mg in 3 divided doses. This dose may be increased in steps by 2-4 mg at intervals of half or full week.

The optimum therapeutic response is usually achieved with a daily dose of between 12 and 24 mg, divided into 3-4 equal doses throughout the day.

The total daily dose should not exceed 36 mg.

Special populations

Paediatric population

The safety and efficacy of tizanidine in children and adolescents under 18 years have not been established. Limited data are available. Tizanidine cannot be recommended for the use in children and adolescents (see section 4.8).

Elderly

Experience with tizanidine in the elderly is limited.

In this patient group the starting dose should be as low as possible and it should be increased in small increments, according to tolerability and efficacy.

Renal impairment

In patients with renal impairment (CL_CR < 25 mL/min) treatment should be started with 2 mg once daily with slow titration to achieve the effective dose. Dosage increases should be in increments of no more than 2 mg 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 (see sections 4.4 and 5.2).

Hepatic impairment

Tizanidine is contraindicated in patients with severe hepatic impairment (see section 4.3).

Only limited data are available in this patient group. Tizanidine is mainly metabolised in the liver (see section 5.2). Its use is associated with reversible abnormalities in liver function (see sections 4.4 and 4.8). Tizanidine should be used with caution in patients with mild and moderate hepatic impairment. The starting dose should be as low as possible and it should be increased in small increments, according to tolerability and efficacy.

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. This is to prevent or reduce the risk of rebound hypertension and tachycardia (see section 4.4).

Method of administration

Oral use.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Severe hepatic impairment

- Concomitant use of tizanidine with potent CYP1A2 inhibitors such as fluvoxamine or ciprofloxacin (see section 4.5)

CYP1A2 inhibitors

Because of potential drug interactions, tizanidine is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin (see section 4.3).

Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when tizanidine is taken with other CYP1A2 inhibitors (see section 4.5). Concomitant use should be avoided unless the necessity for tizanidine therapy is clinically evident. In such a case, tizanidine should be used with caution.

Hypotension

Tizanidine is an α₂-adrenergic agonist that can produce hypotension. Syncope has been reported in the post marketing setting. The chance of significant hypotension may possibly be minimised 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 (see section 4.5).

Withdrawal syndrome

Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimise the risk of these reactions, particularly in patients who have been receiving high doses (20 to 28 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 to 4 mg per day).

Hepatic impairment

Since hepatic dysfunction has been reported in association with tizanidine, but rarely at daily doses up to 12 mg, it is recommended that liver function tests should be monitored monthly for the first four months in patients receiving doses of 12 mg and higher and in patients who develop clinical symptoms suggestive of hepatic dysfunction, such as unexplained nausea, anorexia or tiredness. Treatment with 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. Tizanidine should be discontinued in patients with symptoms compatible with hepatitis or where jaundice occurs.

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 tizanidine.

Renal impairment

Tizanidine should be used with caution in patients with renal insufficiency (creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia, and dizziness) as indicators of potential overdose (see section 4.2).

Sedation

Tizanidine can cause sedation, which may interfere with everyday activity. In 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.

Hallucinosis/Psychotic-like symptoms

Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions have been reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Discontinuing should be considered in patients who develop hallucinations.

Hypersensitivity reactions

Tizanidine can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue tizanidine and seek immediate medical care if they occur.

Tizagelan contains lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Tizagelan contains sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

CYP1A2 inhibitors

The concomitant use of tizanidine with potent CYP1A2 inhibitors such as fluvoxamine or ciprofloxacin is contraindicated (see section 4.3). Fluvoxamine or ciprofloxacin increases the exposure to tizanidine by a mean of 10- to 33-fold, respectively. The hypotensive and sedative effects of tizanidine can increase markedly.

The concomitant use of tizanidine with other CYP1A2 inhibitors may lead to a marked increase in tizanidine serum levels (see sections 4.4 and 5.2). Therefore, the concomitant use of tizanidine with other CYP1A2 inhibitors such as some antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, acyclovir, and ticlopidine should be avoided. If their use is clinically necessary, the patients should be closely monitored. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, tizanidine therapy should be reduced or discontinued.

Oral contraceptives

Combined hormonal contraceptives moderately increase tizanidine Ievels and might increase its adverse effects. If concomitant use is clinically necessary, and if adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, tizanidine therapy should be reduced or discontinued.

CYP1A2 inducers

In the contrary to CYP1A2 inhibitors, CYP1A2 inducers may lead to a decrease in tizanidine serum levels.

Rifampicin

Rifampicin appears to be only a weak to moderate inducer of CYP1A2. The clinical relevance is unclear. A small increase in dose might be required if rifampicin is given to those taking established doses of tizanidine.

Drugs that prolong the QT interval

The concurrent use of more than one drug that prolongs the QT interval increases the risk of torsade de pointes. Therefore, caution is advised when tizanidine is used concurrently.

Antihypertensives

As tizanidine may induce hypotension it may potentiate the effect of antihypertensive products, including diuretics, and caution should therefore be exercised in patients receiving blood pressure lowering products.

Caution should also be exercised when tizanidine is used concurrently with ß-adrenoceptor blocking substances or digoxin as the combination may potentiate hypotension or bradycardia (see section 4.4).

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.

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.

Smoking

Smoking decreases the plasma levels of tizanidine.

Pregnancy

The safety of tizanidine in pregnancy has not been established.

Therefore, tizanidine should not be used in pregnant women unless the benefit clearly outweighs the risk.

Breast-feeding

The safety of tizanidine in breast-fed infants of mothers receiving tizanidine is not known. Tizanidine and/or its metabolites have been found in the milk of rodents (see section 5.3). Therefore, tizanidine should not be used in nursing mothers unless the benefit clearly outweighs the risk.

Fertility

Reproductive studies in rats and rabbits indicate that tizanidine does not have embryonic or teratogenic potential but at maternally toxic doses of 10-100 mg/kg per day tizanidine can retard foetal development due to its pharmacodynamic effects.

Tizanidine has minor or moderate influence on the ability to drive and use machines. Patients experiencing drowsiness or dizziness should be advised against activities requiring a high degree of alertness.

a. Summary of the safety profile

Many adverse effects have been found to be dose related and slow titration of doses appears to reduce the frequency of occurrence.

With low doses, such as those recommended for the relief of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, decreased blood pressure, nausea, gastrointestinal disturbances, and increased hepatic enzymes 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.

b. Tabulated list of adverse reactions

The table below shows the frequencies of adverse reactions which have been reported in clinical trials and post-marketing experience. The frequencies are defined as follows: 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 (< 1/10,000), and not known (frequency cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

c. Description of selected adverse reactions

Hallucinations

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

Withdrawal syndrome

Rebound hypertension and tachycardia have been observed after sudden withdrawal of 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 (see sections 4.4 and 4.5).

d. Paediatric population

Spontaneous adverse event reports were compared in a clinical adverse event database for children (≤ 16 years; n = 99) and adults (> 16 years; n = 1,153). The overall safety of tizanidine in the paediatric group appeared good; however, the adverse event profile differed from that in adults. The most common adverse event classes in children were psychiatric disorders (52.5%) followed by nervous system disorders (29.3%), and gastrointestinal disorders (16.2%), whereas the most common adverse event classes in adults were nervous system disorders (42.4%), general disorders and administration site conditions (28.6%), and gastrointestinal disorders (21.3%). Serious adverse events were substantially less frequent in children than adults (19.2% vs 45.9%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 national reporting system:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Clinical experience is limited. In one case, where an adult patient ingested 400 mg tizanidine, recovery was uneventful.

Symptoms

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

Management

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 tizanidine. Further treatment should be symptomatic.

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

ATC code: M03BX02

The exact mechanism of action of tizanidine has not been fully clarified. It is believed that the pharmacodynamic effects of tizanidine are primarily linked to its α₂-adrenergic agonist properties, although its imidazoline receptor binding may play a role. The predominant effect of tizanidine appears to occur presynaptically in the spinal cord by reducing release of the excitatory amino acids glutamate and aspartate from the presynaptic terminal of spinal interneurons. There is some evidence of postsynaptic action on excitatory amino acid receptors.

In humans, tizanidine reduces pathologically increased muscle tone, including resistance to passive movements and alleviates painful spasms and clonus.

Absorption

Tizanidine is rapidly and almost completely absorbed. The maximum plasma concentration is reached approximately 1 hour after administration. The mean absolute bioavailability is approximately 34% because of the strong first-pass metabolism. The average maximum plasma concentration (C_max) of tizanidine is 12.3 ng/mL after a single administration and 15.6 ng/mL after repeated administration of 4 mg tizanidine. Concomitant use of food has no relevant influence on the pharmacokinetic profile of tizanidine. Food increases C_max by about one third, but has no effect on the extent of absorption (AUC). The increase in C_max is not considered clinically relevant.

Distribution

Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg. Tizanidine is 30% bound to plasma proteins. Tizanidine has linear pharmacokinetics in the dose range of 1-20 mg.

Biotransformation

Tizanidine undergoes rapid and extensive metabolism in the liver (about 95%). Tizanidine is mainly metabolised in vitro by CYP1A2. The metabolites appear to be inactive.

Elimination

The elimination half-life of tizanidine from plasma is 2 to 4 hours. The metabolites are primarily excreted via the renal route (approx. 70% of the dose). Only a small part of the active substance is excreted unchanged via the urine (approx. 4.5%).

Special patient groups

Renal impairment

In patients with renal insufficiency (creatinine clearance < 25 mL/min), maximum mean plasma levels were found to be two times higher than in healthy volunteers. Also the terminal half-life was extended to approximately 14 hours, resulting in a significant (mean approximately 6-fold) increase in bioavailability (AUC).

Hepatic impairment

No specific studies have been conducted with this population. Because tizanidine is metabolised mainly in the liver by CYP1A2, hepatic impairment can lead to increased systemic exposure. Tizanidine is contraindicated in patients with significant hepatic impairment (see section 4.3).

The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolised in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine.

Paediatric population

Tizanidine has not been evaluated in the paediatric population.

Elderly (over 65 years of age)

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 4-times faster than the elderly subjects.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential.

Tizanidine has been found to pass into the milk of nursing rats with a milk to blood concentration ratio of 1.8:1.

Lactose monohydrate

Starch, pregelatinised (maize)

Macrogol 4000

Stearic acid

Sucrose

Magnesium stearate

Not applicable.

30 months

No special storage conditions.

Opaque PVC/PVdC/PVC-aluminium blister packs with 10, 30, 60, 90, 100 or 120 tablets.

Not all pack sizes may be marketed.

No special requirements.

G.L. Pharma GmbH., Schlossplatz 1, 8502 Lannach, Austria

PL 21597/0083

PL 21597/0084

25/10/2021

25/10/2021