Tizarex

Uses

Nimesulide is used for acute pain; extra-articular disorders; osteoarthritis; post-op pain; primary dysmenorrhoea

It is used in the symptomatic treatment of painful muscle spasm associated with musculoskeletal conditions and as an adjunct in the management of spasticity associated with multiple sclerosis or spinal cord disorders.

Tizarex is also used to associated treatment for these conditions: Menstrual Distress (Dysmenorrhea), Pain, Pain, Acute, NSAIDsAcute Low Back Pain, Drug Withdrawal Headache, Insomnia, Migraine, Pain, Seizures, Spasticity, Muscle, Withdrawal From Addictive Substance; Detoxification

How Tizarex works

The therapeutic effects of Nimesulide are the result of its complete mode of action which targets a number of key mediators of the inflammatory process such as: COX-2 mediated prostaglandins, free radicals, proteolytic enzymes and histamine.

Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular system .

Dosage

Tizarex dosage

100 mg twice daily.Should be taken with food. Take after meals.

The usual initial daily dose is 2 mg as a single dose. The daily dose may be increased thereafter according to response in steps of 2 mg at intervals of at least 3 to 4 days, usually up to 24 mg daily given in 3 to 4 divided doses. The maximum recommended dose is 36 mg daily.

Side Effects

Epigastric discomfort, heartburn or abdominal cramps, nausea, vomiting and diarrhoea; skin rash, pruritus, oedema, headache, dizziness, drowsiness; hypersensitivity reactions (e.g. bronchospasm, rhinitis, angioedema urticaria); GI haemorrhage/perforation; bullous/erosive stomatitis, purpura, thrombocytopenia, toxic epidermal necrolysis, haematuria, oliguria, and renal failure; increases in liver enzymes.

Tizanidine Hydrochloride may cause drowsiness, fatigue, dizziness, dry mouth, nausea, gastrointestinal disturbances, hypotension. Bradycardia, insomnia, hallucinations and altered liver enzymes, and rarely acute hepatitis have also been reported.

Toxicity

Oral TDLO (human): 1.429 mg/kg; Oral TDLO (woman): 2 mg/kg; Oral LD50 (rat): 200 mg/kg; Oral LD50 (mouse): 392 mg/kg

LD50 information

Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg

Use in pregnancy

Animal studies have determined that this drug causes fetal harm . Studies have not been performed in humans, and it is advisable to ensure that tizanidine use in pregnant women should be reserved for cases in which possible benefit clearly outweighs the possible risk to mother and unborn child .

Use in breastfeeding

In studies of rat models, this tizanidine was found excreted in the breastmilk with a milk-to-blood ratio of 1.8:1 . In young nursing rats, abnormal results were obtained in tests indicative of central nervous system function. Various developmental changes that may have been attributable to the drug were observed. It is unknown whether tizanidine is excreted in human milk. It is a lipid-soluble drug, however, and likely to be excreted into breast milk .

Carcinogenesis and mutagenesis

No signs of carcinogenicity were observed in two dietary studies performed in rodent models. Tizanidine was given to mice for 78 weeks at doses reaching a maximum 16 mg/kg (equivalent to twice the maximum recommended human dose). In addition, the drug was given to rats for 104 weeks at doses reaching 9 mg/kg (equivalent to 2.5 times the maximum recommended human dose). There was a lack of a statistically significant increase in the occurrence of tumors in either study group .

Tizanidine was not found to be mutagenic or clastogenic in several laboratory essays, including the bacterial Ames test, the mammalian gene mutation test, in addition to the chromosomal aberration test in Chinese hamster cells and several other assays .

Precaution

History of GI tract disease, infections, oedema, hypertension, elderly, lactation.

Patients with impaired kidney or liver function; when patients drive a vehicle or operate machinery.

Interaction

Additive hepatotoxic effects with known hepatotoxins: anti-convulsants (e.g. valproic acid), anti-fungals (e.g. ketoconazole), anti-tuberculous drugs (e.g. isoniazid), tacrine, pemoline, amiodarone, methotrexate, methyldopa, amoxicillin/clavulanic acid. May decrease the oral bioavailability of furosemide and the natriuretic and diuretic response to furosemide. Increased risks of GI and hepatic adverse effects with other NSAIDs, including aspirin. May increase anti-coagulant effect of warfarin. Potentiates the action of phenytoin. May be displaced from binding sites with fenofibrate, salicylic acid, and tolbutamide. Interactions between NSAIDs and lithium, probenecid and ciclosporin, have been documented.

Alcohol or other CNS depressants may enhance the CNS effects of Tizanidine. There may be an additive hypotensive effect when Tizanidine is used in patients receiving antihypertensive therapy.

Volume of Distribution

Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg .

Elimination Route

Rapidly absorbed following oral administration.

This drug undergoes significant first-pass metabolism. After the administration of an oral dose, tizanidine is mostly absorbed. The absolute oral bioavailability of tizanidine is measured to be about 40% .

Effect of food on absorption

Food has been shown to increase absorption for both the tablets and capsules. The increase in absorption with the tablet (about 30%) was noticeably higher than the capsule (~10%). When the capsule and tablet were administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet . It is therefore advisable to take this drug with food for increased absorption, especially in tablet form.

Half Life

1.8–4.7 hours

Approximately 2.5 hours .

Clearance

A note on renal impairment

Tizanidine clearance is found to be decreased by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. This drug should be used with caution in patients with renal impairment .

Elimination Route

Renal (50%), fecal (29%)

This drug is mainly eliminated by the kidney .

Pregnancy & Breastfeeding use

Category not classified

Tizanidine has no teratogenic effects in rats and rabbits. As there have been no controlled studies in pregnant women, it should not be used during pregnancy unless the benefit clearly outweighs the risk. Although only small amounts of Tizanidine are excreted in animal milk, lactating women should not take Tizanidine.

Contraindication

Hypersensitivity; GI bleeding, active peptic ulcer disease; severe renal and heart failure; hepatic impairment or known liver disease; coagulation disorders; pregnancy; children <12 yr.

Tizanidine Hydrochloride is contraindicated to the patients who have known hypersensitivity to this drug and in case of severe hepatic impairment.

Acute Overdose

Epigastric pain, nausea, vomiting, drowsiness, lethargy, GI haemorrhage, seizures, hypertension, apnoea, coma, anaphylactic reactions and renal failure. Treatment is supportive.

Children: Experience in children is limited and the use of Tizanidine in this patient group is not recommended.

Elderly: Renal clearance in the elderly may in some cases be significantly decreased. Caution is therefore indicated when using in elderly patients.

Storage Condition

Protect from heat and humidity; store at <25°C.

Store in a cool & dry place, protected from light & moisture. Do not freeze. Keep all medicines out of the reach of children.

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