Mef T

Uses

Mefenamic acid is used in mild to moderate pain including headache, dental pain, postoperative and postpartum pain, dysmenorrhoea, menorrhagia, in musculoskeletal and joint disorders such as osteoarthritis and rheumatoid arthritis; and in children with fever and juvenile idiopathic arthritis.

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.

Mef T is also used to associated treatment for these conditions: Mild pain, Primary Dysmenorrhoea, Gastrointestinal cramps, Moderate PainAcute Low Back Pain, Drug Withdrawal Headache, Insomnia, Migraine, Pain, Seizures, Spasticity, Muscle, Withdrawal From Addictive Substance; Detoxification

How Mef T works

Mefenamic acid binds the prostaglandin synthetase receptors COX-1 and COX-2, inhibiting the action of prostaglandin synthetase. As these receptors have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity, the symptoms of pain are temporarily reduced.

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

Mef T dosage

As with other NSAIDs, the lowest dose should be sought for each patient. Therefore, after observing the response to initial therapy with Mefenamic acid, the dose and frequency should be adjusted to suit an individual patient's needs.Administration is by the oral route, preferably with food.

• Adult: A 500 mg dose should be given to adults up to three times (1.5 g total) per day.
• Infants over 6 months: 25 mg/kg of body weight daily in divided doses for not longer than 7 days.

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

In patients taking Mefenamic acid or other NSAIDs, the most frequently reported adverse experiences include : abdominal pain, constipation, diarrhoea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers, vomiting, abnormal renal function, anaemia, dizziness, oedema, elevated liver enzymes, headache, increased bleeding time, pruritus, rash and tinnitus.

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, rat LD₅₀: 740 mg/kg. Symptoms of overdose may include severe stomach pain, coffee ground-like vomit, dark stool, ringing in the ears, change in amount of urine, unusually fast or slow heartbeat, muscle weakness, slow or shallow breathing, confusion, severe headache or loss of consciousness.

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

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. To minimise the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. In cases with pre-existing advanced kidney disease, treatment with Mefenamic acid is not recommended.

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

Interaction

Concomitant use with CYP2C9 isoenzyme inhibitors may alter safety and efficacy of mefenamic acid. May enhance methotrexate toxicity. Reduced BP response to ACE inhibitors or angiotensin II receptor antagonists. Increased risk of serious GI events with aspirin. May reduce the natriuretic effects of furosemide or thiazide diuretics. Reduced renal lithium clearance and elevated plasma lithium levels. May enhance anticoagulant effect of warfarin.

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

• 1.06 L/kg [Normal Healthy Adults (18-45 yr)]

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

Elimination Route

Mefenamic acid is rapidly absorbed after 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

2 hours

Approximately 2.5 hours .

Clearance

• Oral cl=21.23 L/hr [Healthy adults (18-45 yrs)]

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

The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid.3 The elimination half-life of mefenamic acid is approximately two hours. Mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys. Both renal and hepatic excretion are significant pathways of elimination.

This drug is mainly eliminated by the kidney .

Pregnancy & Breastfeeding use

Pregnancy: In late pregnancy, as with other NSAIDs, Mefenamic acid should be avoided because it may cause premature closure of the ductus arteriosus. In general there are no adequate and well controlled studies in pregnant women. Mefenamic acid should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Rated as Pregnancy Category C.

Lactation: Trace amounts of Mefenamic acid may be present in breast milk. Taking into account the importance of the drug to the mother , decision should be made whether to discontinue nursing or to discontinue the drug.

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

Mefenamic acid is contraindicated in patients with known hypersensitivity to Me Mefenamic acid acid. Mefenamic acid should not be given to patients who have experienced asthma, urticaria, or allergic type reactions after taking aspirin or other NSAIDs. Rarely fatal, anaphylactic like reactions to NSAIDs have been reported in such patients. Mefenamic acid is contraindicated in patients with active ulceration or chronic inflammation of upper gastrointestinal tract and should not be used in patients with preexisting renal disease.

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

Acute Overdose

Symptoms: Headache, nausea, vomiting, epigastric pain, GI bleeding. Rarely, diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus, fainting, and occasionally convulsions.

Management: Symptomatic and supportive treatment. In acute overdosage, empty the stomach immediately by inducing emesis or by gastric lavage followed by admin of activated charcoal.

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

Store between 20-25° 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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