Tizanidine 4mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tizanidine 4mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 4 mg of tizanidine (as hydrochloride).
Excipient with known effect:
Each tablet contains 48.024 mg lactose anhydrous.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM Tablet
White, 9 mm flat bevel edged tablet marked with “TI” and “4” on one side and a quadrasecting score line on the other.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Tizanidine is indicated in adults for the treatment of spasticity associated with multiple sclerosis, or with spinal cord injury or disease.
4.2 Posology and method of administration
Posology
The effect of 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 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 2 mg increasing by 2 mg increments at no less than halfweekly intervals.
The total daily dose should not exceed 36 mg, although it is usually not necessary to exceed 24 mg daily. Secondary pharmacological effects (see section 4.8) 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.
Elderly patients
Experience with the use of tizanidine in the elderly is limited, therefore use is not recommended in elderly patients unless the benefit of treatment clearly outweighs the risk.
Pharmacokinetic data suggest that renal clearance in the elderly may be decreased by up to three fold.
Paediatric population
Experience with tizanidine in patients under the age of 18 years is limited. Tizanidine is not recommended for use in children.
Patients with renal impairment
In patients with renal insufficiency (creatinine clearance < 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. 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.
Patients with hepatic impairment
Tizanidine is contraindicated in patients with significantly impaired hepatic function. Tizanidine should not be used in patients with moderate hepatic impairment unless the potential benefit outweighs the potential risk to the patient. Any treatment should start with the lowest dose and afterwards, dosage increases should be done carefully and according to patient tolerability.
Method of administration
For oral administration.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
The use of Tizanidine in patients with significantly impaired hepatic function is contraindicated, because tizanidine is extensively metabolised by the liver (see section 5.2).
Concomitant use of tizanidine with strong inhibitors of CYP1A2 such as fluvoxamine or ciprofloxacin is contraindicated (see sections 4.4 and 4.5).
4.4 Special warnings and precautions for use
CYP inhibitors
Concomitant use of tizanidine with CYP1A2 inhibitors is not recommended (see sections 4.3 and 4.5).
Hypotension
Hypotension may occur during treatment with tizanidine (see section 4.8) and also as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive drugs (see section 4.5). 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 tizanidine, when it had been used chronically, and/or in high daily dosages, and/or concomitantly with antihypertensive drugs (see also section 4.5). In extreme cases, rebound hypertension might lead to cerebrovascular accident. Tizanidine should not be stopped abruptly, but rather gradually and blood pressure should be monitored regularly on withdrawal (see section 4.8).
Hepatic impairment
Since hepatic dysfunction has been reported in association with tizanidine. It is recommended that liver function tests should be monitored monthly for the first four months in all patients 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 and/or SGOT are persistently above three times the upper limit of normal range.
Renal impairment
Patients with renal impairment may require lower doses and therefore caution should be exercised when using tizanidine in these patients (see section 4.2).
Tizanidine should be kept out of the sight and reach of children.
Tizanidine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Tizanidine is almost exclusively metabolised by the cytochrome P450 isoenzyme CYP1A2.
Concomitant administration of drugs known to inhibit or induce the activity of CYP1A2 may affect the plasma levels of tizanidine.
Observed interactions resulting in a contraindication
Concomitant use of tizanidine with fluvoxamine or ciprofloxacin, both potent CYP450 1A2 inhibitors in man, is contraindicated. Concomitant use of tizanidine with fluvoxamine or ciprofloxacin resulted in a 33-fold and 10-fold increase in tizanidine AUC, respectively (see sections 4.3 and 4.4). Clinically significant and prolonged hypotension may result along with somnolence, dizziness and decreased psychomotor performance.
Observed interactions resulting in a concomitant use not recommended Co-administration of tizanidine with other inhibitors of CYP1A2 such as some antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin) and ticlopidine is not recommended (see section 4.4).
The increased plasma levels of tizanidine may result in overdose symptoms such as QT(c) prolongation (see also section 4.9). Concomitant use of tizanidine (in high doses) with other products that could cause QT(c) prolongation (e.g. amitryptyline and azithromycin) is not recommended.
Due to their potential additive hypotensive effects, concomitant use of tizanidine with other D2 adrenergic agonists (such as clonidine) is not recommended.
Oral contraceptives
Pharmacokinetic data following single and multiple doses of tizanidine suggested that clearance of tizanidine was reduced by approximately 50 % in women who were concurrently taking oral contraceptives. Although no specific pharmacokinetic study has been conducted to investigate a potential interaction between oral contraceptives and tizanidine, the possibility of a clinical response and/or adverse effects occurring at lower doses of tizanidine should be borne in mind when prescribing tizanidine to a patient taking the contraceptive pill. Clinically significant drug-drug interactions have not been reported in clinical trials.
Interactions to be considered
Rifampicin
Concomitant administration of tizanidine with rifampicin results in an approximate 50 % decrease in tizanidine concentrations (AUC and peak plasma concentration). Therefore, the therapeutic effects of tizanidine may be reduced during treatment with rifampicin, which may be of clinical significance in some patients. Long term coadministration should be avoided and if co-administration is considered a careful dose adjustment (increase) may be required.
Cigarette smoke
Exposure to the polycyclic aromatic hydrocarbons of cigarette smoke leads to induction of CYP1A2. In a study of young male smokers, administration of tizanidine (>10 cigarettes per day) results in about 30 % decrease in tizanidine systemic exposure. Long-term therapy with tizanidine in heavy smokers may require higher doses than the average doses
Antihypertensives
As tizanidine may induce hypotension (see section 4.4) it may potentiate the effect of antihypertensive drugs, including diuretics, and caution should therefore be exercised in patients receiving blood pressure lowering drugs.
Concomitant use of tizanidine with antihypertensives, including diuretics, may occasionally cause bradycardia. In some patients rebound hypertension and tachycardia have been observed upon abrupt discontinuation of tizanidine when concomitantly used with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident (see sections 4.4 and 4.8).
Alcohol
While on tizanidine therapy, alcohol consumption should be minimised or avoided as it may increase the potential for adverse events (e.g. sedation and hypotension). The central nervous system depressant effects of alcohol may be enhanced by tizanidine.
Caution should also be exercised when tizanidine is used concurrently with P-adrenoceptor blocking drugs (e.g. atenolol or propanolol) or digoxin as the combination may potentiate hypotension or bradycardia.
Caution should be exercised if concomitant use of tizanidine with sedative drugs including hypnotics (e.g. benzodiazepines), antihistamines (e.g. chlorphenamine) and baclofen is considered as this may enhance the sedative action of tizanidine.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of tizanidine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Tizanidine is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
Small amounts of tizanidine are excreted in ratmilk, (see section 5.3). A risk to the breast-fed child cannot be excluded.
Tizanidine should not be used during breast-feeding
Fertility
Animal studies have shown no effect on fertility at 10mg/kg/day and 3mg/kg/day in male and female rats, respectively (see section 5.3).
4.7 Effects on ability to drive and use machines
Patients experiencing blurred vision, 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 machinery.
4.8 Undesirable effects
Adverse reactions are ranked under the heading of frequency, the most frequent first, using 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 (<1/10,000); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
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Immune system disorders | |
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Not known |
Hypersensitivity reactions |
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Psychiatric disorders | |
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Common |
Insomnia, sleep disorder |
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Rare |
Hallucination1 |
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Not known |
Confusional state |
|
Nervous system disorders | |
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Very common |
Somnolence, dizziness |
|
Not known |
Convulsions, vertigo, dysarthria |
|
Eye disorders | |
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Not known |
Vision blurred |
|
Cardiac disorders | |
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Common |
Bradycardia |
|
Vascular disorders | |
|
Common |
Hypotension |
|
Not known |
Syncope |
|
Gastrointestinal disorders | |
|
Very common |
Gastrointestinal disorder, dry mouth |
|
Common |
Nausea |
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Not known |
Abdominal pain, vomiting |
|
Hepatobiliary disorders | |
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Very Rare |
Hepatitis, hepatic failure |
|
Musculoskeletal and connective tissue disorders | |
|
Very common |
Muscular weakness |
|
Skin and subcutaneous tissue disorders | |
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Not known |
Pruritus, rash |
|
General disorders and administration site conditions |
1 The hallucinations are self-limiting, without evidence of psychosis, and have invariably occurred in patients concurrently taking potentially hallucinogenic drugs, e.g. anti-depressants.
2 Increases in hepatic serum transaminases, which are reversible on stopping treatment, have occurred.
With low doses, 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 higher doses, the adverse reactions reported with low doses are more frequent and more pronounced, but seldom severe enough to require discontinuation of treatment.
Withdrawal syndrome
Rebound hypertension and tachycardia have been observed after sudden withdrawal may lead in severe cases 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 at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Clinical experience is limited. In one adult case, who ingested 400 mg tizanidine, recovery was uneventful. This patient received mannitol and frusemide.
Symptoms
Nausea, vomiting, hypotension, QT(c) prolongation, dizziness, somnolence, miosis, restlessness, respiratory distress, coma.
Treatment
General supportive measures are indicated and it is recommended to eliminate the ingested drug by repeated administration of high doses of activated charcoal or gastric lavage. The patient should be well hydrated. Forced diuresis is expected to accelerate the elimination of tizanidine. Further treatment should be symptomatic.
5. PHARMACOLOGICAL PROPERTIES
5.1
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Very common |
Fatigue |
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Not known |
Asthenia, withdrawal syndrome |
|
Investigations | |
|
Common |
Transaminase increase2 |
Pharmacodynamic properties
Pharmacotherapeutic group: Muscle relaxants, other centrally acting agents, ATC code: M03BX02.
Mechanism of action
Tizanidine is an a2-adrenergic receptor agonist within the central nervous system at supra-spinal and spinal levels.
Pharmacodynamic effects
This effect results in inhibition of spinal polysynaptic reflex activity. Tizanidine has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic spinal reflexes.
In humans, tizanidine reduces pathologically increased muscle tone, including resistance to passive movements and alleviates painful spasms and clonus.
5.2 Pharmacokinetic properties
Absorption and distribution
Tizanidine is rapidly absorbed, reaching peak plasma concentration in approximately 1 hour. Tizanidine is only about 30 % bound to plasma proteins and, in animal studies, was found to readily cross the blood-brain barrier. Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg (CV 21 %). Although tizanidine is well absorbed, first pass metabolism limits plasma availability to 34 % of that of an intravenous dose. The mean maximum plasma concentration (Cmax) of tizanidine is 12.3 ng/mL (coefficient of variation (CV) 56 %) and 15.6 ng/mL (CV 60 %) after single and repeated administration of 4 mg doses, respectively.
Concomitant food intake has no influence on the pharmacokinetic profile of tizanidine tablets (given as 4 mg tablets). Although Cmax is about one-third higher after administration of the tablet under fed conditions, this is not thought to be of any clinical relevance, and absorption (AUC) is not significantly affected.
Biotransformation and elimination
Tizanidine undergoes rapid and extensive (about 95 %) metabolism in the liver and the pattern of biotransformation in animals and humans is qualitatively similar. Tizanidine is mainly metabolised by cytochrome P450 1A2 in vitro. The metabolites are primarily excreted via the renal route (approximately 70 % of the administered dose) and appear to be inactive. Renal excretion (determined by percentage recovery in the urine of the total amount of administered radioactivity) is approximately 53 % after a single 5 mg dose and 66 % after dosing with 4 mg three times daily. The elimination half-life of tizanidine from plasma is 2-4 hours in patients.
Linearity
Tizanidine has linear pharmacokinetics over the dose range 1 to 20 mg.
Special populations Patients with renal impairment
In patients with severe renal impairment (creatinine clearance <25 mL/min) the maximal mean plasma levels were found to be twice as high as in normal volunteers.
The AUC was also increased (approximately 6-fold on average) resulting in the prolongation of the terminal half-life to approximately 14 hours (see section 4.2).
Patients with hepatic impairment
No specific studies were conducted in patients with hepatic impairment. As tizanidine is extensively metabolised in the liver by CYP1A2 enzyme, hepatic impairment may increase its systemic exposure. Tizanidine is contraindicated in patients with significant hepatic impairment (see section 4.3).
Elderly population
Pharmacokinetic data in the elderly population are limited.
Effect of gender and ethnicity
Gender has no clinically significant effect on the pharmacokinetics of tizanidine and the impact of ethnic sensitivity and race on the pharmacokinetics of tizanidine has not been studied.
5.3 Preclinical safety data
Acute toxicity
Tizanidine possesses a low order of acute toxicity. Signs of overdosage were seen after single doses >40 mg/kg in animals and are related to the pharmacological action of the drug.
Repeat dose toxicity
The toxic effects of tizanidine are mainly related to its pharmacological action. At doses of 24 and 40 mg/kg per day in subchronic and chronic rodent studies, the a2-agonist effects resulted in CNS 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 drug, were noted at 1 to 4 mg/kg per day in a 13 week dog study, and at 1.5 mg/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 1.0 mg/kg per day and above.
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 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 9 mg/kg per day in rats and up to 16 mg/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
Reproduction studies performed in rats at a dose of 3 mg/kg/day and in rabbits at 30 mg/kg/day did not show evidence of teratogenicity. Dose levels of 10 and 30 mg/kg/day increased gestation duration and dystocia in female rats. Prenatal and postnatal pup loss was increased and developmental retardation (as seen by lower foetal body weights and retarded skeletal ossification) occurred. At these doses, dams showed marked signs of muscle relaxation and sedation.
No impairment of fertility was observed in male rats at a dose of 10 mg/kg/day and in female rats at a dose of 3 mg/kg/day. Fertility was reduced in male rats receiving 30 mg/kg/day (fully reversible after a 2-week recovery period) and in female rats receiving 10 mg/kg/day. At these doses, maternal behavioural effects and clinical signs were observed including marked sedation, weight loss, and ataxia.
Passage of tizanidine and/or its metabolites into milk of rodents is known to occur.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Silica, colloidal anhydrous Stearic acid
Cellulose, microcrystalline Lactose, anhydrous.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25 °C.
6.5 Nature and contents of container
PVC/ PVdC /aluminium blister and HDPP containers with PE caps (with optional ullage filler) containing 15, 30, 50 or 120 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Ltd t/a Mylan
Station Close
Potters Bar
Herts
EN6 1TL
8. MARKETING AUTHORISATION NUMBER
PL 04569/0595
THE
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
Date of first authorisation: 18 September 2003 Date of latest renewal: 1 April 2009
10 DATE OF REVISION OF THE TEXT
28/01/2016