Skeletal muscle relaxant
PRESCRIPTION ONLY
Composition
Active substance: 5-chloro-4-(2-imidazolin-2-ylamino)-2.1.3-benzothiadiazole (=tizanidine).
Tablets containing 2 mg tizanidine as the hydrochloride.
Indications
Painful muscle spasm
- Associated with static and functional disorders of the spine (cervical and lumbar syndromes)
- Following surgery, e.g. for herniated intervertebral disc or osteoarthritis of the hip
Spasticity due to neurological disorders
- E.g. multiple sclerosis, chronic myelopathy, degenerative spinal cord diseases, cerebrovascular accidents, and cerebral palsy.
Posology and method of administration
Relief of painful muscle spasm 2 to 4 mg three times daily in tablet form. In severe cases an extra dose of 2 or 4 mg may be taken at night.
Spasticity due to neurological disorders
The dosage should be adjusted to the needs of the individual patient.
The initial daily dose should not exceed 6 mg given in 3 divided doses. It may be increased step wise at half weekly or weekly intervals by 2 to 4 mg. The optimum therapeutic response is generally achieved with a daily dose of between 12 and 24 mg, administered in 3 or 4 equally spaced doses. The dally dose of 36 mg should not be exceeded.
Use in children
Experience in children is limited and the use of Sirdalud in this patient population is not recommended.
Use in elderly
Experience with the use of Sirdalud in the elderly is limited. Pharmacokinetic data suggest the renal clearance In the elderly may in some cases be significantly decreased. Caution is therefore indicated when using Sirdalud in elderly patients.
Contraindications
In pregnancy.
Known hypersensitivity to tizanidine or any component of the formulations.
Significantly Impaired hepatic function (see section Pharmacokinetic properties).
Concomitant use of tizanidine with fluvoxamine or ciprofloxacin is contraindicated (see section Interaction with other medicinal products and other forms of interaction and section Special warnings and special precautions for use).
Special Warnings and Special Precautions for use
Special warnings
Concomitant use of tizanidine With CYP1A2 inhibitors is not recommended (see section Contraindications and section Interaction With other medicinal products and other forms of interaction).
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 Sirdalud should be discontinued if serum levels of SGPT or SGOT are persistently above three times the upper limit of the normal range.
Special precautions for use
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.
For Sirdalud tablets:
Sirdalud tablets contain lactose. This medicine is not recommended in patients with rare hereditary problem of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.
Interaction with other medicinal products and other forms of interaction
Concomitant use of tizanidine With fluvoxamine or ciprofloxacin, both CYP4501A2 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. Clinically significant and prolonged hypotension may result along with somnolence, dizziness and decreased psychomotor performance (see section Contraindications). Co-administration of tizanidine with other inhibitors of CYP1A2 such as some antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine is not recommended (see section Special warnings and special precautions for use). Concomitant use of Sirdalud with antihypertensives, including diuretics, may occasionally cause hypotension and bradycardia.
Alcohol and sedatives may enhance the sedative action of Sirdalud.
Pregnancy and lactation
Tizanidine has no teratogenic effects in rats and rabbits. As there have been no controlled studies in pregnant woman, however, it should not to be used during pregnancy unless the benefit clearly outweighs the risk.
Although only small amounts of tizanidine are excreted in animal milk, tizanidine should not be taken by woman who are breast-feeding.
Effects on ability to drive and use machines
Patients experiencing somnolence or dizziness should refrain from activities requiring a high degree of alertness, e.g. driving a vehicle or operating machines.
Undesirable effects
Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (= 1/10); common (= 1/100, ‹ 1/10); uncommon (= 1/1,000, ‹ 1/100); rare (= 1/10,000, ‹ 1/1,000) very rare (‹ 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 1
| Psychiatric disorders Rare: Hallucination, insomnia, sleep disorder Nervous system disorders Common: Somnolence, dizziness Cardiac disorders Common: Bradycardia Vascular disorders Common: Hypotension Gastrointestinal disorders Common: Dry mouth Rare: Nausea, gastrointestinal disorder Hepatobiliary disorders Very rare: Hepatitis Musculoskeletal and connective tissue disorders Rare: Muscularweakness General disorders and administration site conditions Common: Fatigue Investigations Common: Blood pressure decrease Rare: Transaminase Increase |
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: hypotension, bradycardia, muscular weakness, insomnia, sleep disorder, hallucination, hepatitis.
Overdose
In the few reports of Sirdalud overdosage received, recovery was uneventful, including by a patient who ingested 400 mg Sirdalud.
Signs and symptoms
Nausea, vomiting, hypotension, dizziness. Somnolence, miosis, restlessness, respiratory distress, coma.
Treatment
It is recommended to eliminate the ingested drug by repeated administration of high doses of activated charcoal. Forced diuresis is expected to accelerate the elimination of Sirdalud.
Further treatment should be symptomatic.
Pharmacological Properties
Pharmacotherapeutic group: Muscle relaxants. other centrally acting agents (ATC Code: M03B X02)
Pharmacodynamic Properties
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, In addition to its muscle-relaxant properties, tizanidine also exerts a moderate central analgesic effect.
Sirdalud is effective in both acute painful muscle spasms and chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movements, alleviates spasm and clonus and may improve voluntary strength.
Pharmacokinetic properties
Absorption and bioavailability
Tizanidine is rapidly and almost completely absorbed, reaching peak plasma concentration approximately 1 hour after dosing. Mean absolute bioavailability is about 34 % due to extensive first-pass metabolism.
Distribution
Mean steady-state volume of distribution (Vss) following l.v. administration is 26 L/kg. Plasma protein binding is 30 % Tizanidine has linear pharmacokinetics over the dose range 4 to 20 mg. The low intra individual variation in pharrnacokinetic parameter (Cmax an AUC) enables reliable prediction of plasma levels following oral administration. The pharmacokinetic parameters of tizanidine are not affected by gender.
Biotransformation
The drug has been shown to be rapidly and extensively metabolized by the liver. Tizanidine is mainly metabolized by cytochrome P450 1A2 In vitro The metabolites appear to be inactive.
Elimination
Tizanidine is eliminated from the systemic circulation with a mean terminal half-life of 2 to 4 hours. Excretion is primarily via the kidneys (approximately 70 % of dose) in the form of metabolites, with unchanged drug accounting for only about 2.7 % of urinary recovery.
Characteristics in special patient populations
In patient with renal insufficiency (creatinine clearance ‹ 25mL/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 (see special warnings and special precautions for use).
Effect of food
Concomitant food intake has no relevant influence on the pharmacokinetic profile of tizanidine (given as tablets or capsules). Although Cmax is about one-third higher, this is not thought to be of any clinical relevance, and absorption (AUC) is not significantly affected.
Preclinical Safety Data
Acute toxicity
The acute toxicity of tizanidine is of a low order. After single dose › 40 mg/kg in animals, signs of overdosage were seen related to the drug's pharmacological action.
Chronic and subchronic toxicity
In a 13 week oral toxicity study in rats given average daily doses of 1.7,8 and 40 mg/lg, the major findings were related to CNS stimulation (e.g. motor excitation, aggressiveness, tremor, and convulsions), and occurred mainly at the highest dose level.
ECG changes and CNS effects were observed at daily doses of 1 mg/kg and higher in dogs in a 13 week study with dose levels of 0.3, 1 and 3 mg/kg/day given as capsules and a 52 week study with 0.15, 0.45 and 1.5 mg/kg/day. These represent exaggerated pharmacological effects. Transient increase in SGPT seen at daily doses of 1 mg/kg and above were not related to hispathological findings but indicate that the liver IS a potential target organ.
Mutagenicity
No evidence of mutagenic potential was found in in vitro, in vivo or cytogenetic assays.
Carcinogenicity
No indication of carcinogenic potential was seen in rats or mice given doses up to 9 mg/kg/day and 16 mg/kg/day, respectively, in the feed.
Reproductive toxicity
No embryotoxic or teratogenic effects were observed in pregnant rats and rabbits at dose levels up to 100 mg/kg/day.
Increased prenatal mortality due to prolongation of gestation and dystocia occurred at dose levels of 10 and 30 mg/kg/day in female rats dosed at 3, 10 and 30 mg/kg/day from before mating through to lactation or from late pregnancy until weaning of the young.
Pharmaceutical Particulars
Incompatibilities
None known
Storage
Do not store above 25°C. Protect from light and humidity.
Sirdalud must be kept out of reach and sight of children.
Package
SIRDALUD Tablet, Box of 10 strips @ 10 tablets, Reg. No.: DKL 9330406410A1
HARUS DENGAN RESEP DOKTER
Manufactured by PT Boehringer Ingelheirn Indonesia
For PT Novartis Indonesia, Citeureup, Bogor, Indonesia, under license and control of Novartis Pharma AG, Basel, Switzerland
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