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Muscle relaxants, other centrally acting agents.
CLINICAL PHARMACOLOGY: Mechanism of action (MOA): 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 amino acids 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.
Pharmacodynamics (PD): Sirdalud is effective in both acute painful muscle spasms and chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movements, alleviates spasms and clonus, and may improve voluntary strength.
The antispastic activity (measured by the Ashworth score and pendulum test) and adverse effects (heart rate and blood pressure) of Sirdalud are related to plasma tizanidine concentrations.
CLINICAL STUDIES: No recent clinical data regarding the approved indications for Sirdalud are available.
Pharmacokinetics (PK): Absorption: Tizanidine is rapidly and almost completely absorbed, reaching peak plasma concentration approximately 1 hour after dosing. Mean absolute bioavailability from the tablet formulation is about 34% (CV 38%) due to extensive first-pass metabolism. The mean maximum plasma concentration (Cmax) of tizanidine is 12.3 ng/mL (CV 10%) and 15.6 ng/mL (CV 13%) after single and repeated administration of 4 mg doses, respectively.
Concomitant food intake has no relevant influence on the pharmacokinetic profile of tizanidine (given as 4 mg tablets). Although Cmax is about one-third higher after administration of the tablet under fed conditions, this is not considered to be of any clinical relevance, and absorption (AUC) is not significantly affected.
Distribution: Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg (CV 21%). Plasma protein binding is 30%.
Biotransformation/Metabolism: The drug has been shown to be rapidly and extensively (about 95%) 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 4.5% of urinary recovery.
Linearity: Tizanidine has linear pharmacokinetics over the dose range 1 to 20 mg.
Special populations: Renal impairment (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 (see PRECAUTIONS).
Hepatic impairment: No specific studies were conducted in this population. As tizanidine is extensively metabolized in the liver by the CYP1A2 enzyme, hepatic impairment may increase its systemic exposure. Sirdalud is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS).
Geriatrics (65 years of age and older): Pharmacokinetic data in this population are limited.
Gender: Gender has no clinically significant effect on the pharmacokinetics of tizanidine.
Ethnicity: Impact of ethnic sensitivity and race on the pharmacokinetics of tizanidine has not been studied.
Toxicology: NON-CLINICAL SAFETY DATA: Preclinical data reveal no special hazard for humans at the recommended therapeutic dose based on conventional studies of repeated dose toxicity, mutagenicity and carcinogenic potential.
Acute toxicity: The acute toxicity of tizanidine is of a low order. Signs of overdosage were seen related to the drug's pharmacological action.
Repeat dose toxicity: In a 13-week oral toxicity study in rats given average daily doses of 1.7, 8 and 40 mg/kg, 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 increases in SGPT seen at daily doses of 1 mg/kg and above were not related to histopathological findings but indicate that the liver is a potential target organ.
Carcinogenicity and Mutagenicity: No evidence of mutagenic potential was found in in vitro, in vivo, or cytogenetic assays.
No indication of carcinogenic potential was seen in rats or mice given doses of up to 9 mg/kg/day and 16 mg/kg/day, respectively, in the feed.
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 in female rats. Prenatal and postnatal pup loss was increased and development retardation occurred. At these doses, dams showed marked signs of muscle relaxation and sedation. (See FEMALES AND MALES OF REPRODUCTIVE POTENTIAL under USE IN PREGNANCY & LACTATION).
