Diclofenac Sodium

FORMULATION
Each enteric coated tablet contains:
Diclofenac Sodium BP …. 50 mg

PHARMACOLOGY
Diclofenac action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). Inhibition of COX also decreases prostaglandins in the epithelium of the stomach, making it more sensitive to corrosion by gastric acid. This is also the main side effect of diclofenac. Diclofenac has a low to moderate preference to block the COX2- isoenzyme (approximately 10-fold) and is said to have therefore a somewhat lower incidence of gastrointestinal complaints than noted with indomethacin and aspirin. Diclofenac may also be a unique member of the NSAlDs. There is some evidence that diclofenac inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). There is also speculation that diclofenac may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain the high potency of diclofenac it is the most potent NSAID on a broad basis.

PHARMACOKINETICS
Diclofenac is rapidly absorbed when given as an oral solution, sugar-coated tablets, rectal suppository, or by intramuscular injection. It is absorbed more slowly when given as enteric-coated tablets, especially when this dosage form is given with food. Although diclofenac given orally is almost completely absorbed, it is subject to first-pass metabolism so that about 50% of the drug reaches the systemic circulation in the unchanged form. Diclofenac is also absorbed percutaneously. At therapeutic concentrations it is more than 99% bound to plasma proteins. Diclofenac penetrates synovial fluid where concentrations may persist even when plasma concentrations fall; small amounts are distributed into breast milk. The terminal plasma half-life is about 1 to 2 hours. Diclofenac is metabolised to 4 ‘-hydroxydiclofenac, 5-hydroxydiclofenac, 3 ‘-hydroxydiclofenac and 4 ‘, 5-dihydroxydiclofenac. It is then excreted in the form of glucuronide and sulfate conjugates, mainly in the urine (about 60%) but also in the bile (about 35%); less than 1% is excreted as unchanged diclofenac.

INDICATION
Symptomatic treatment of mild to moderate pain in inflammatory and degenerative arthritis; relief of primary dysmenorrhea; relief of postoperative and post-traumatic pain; relief of chronic pain syndrome and cancer pain, especially those with bone metastasis.

DOSAGE AND ADMINISTRATION
Adult: 75 to 150 mg daily in divided doses.

CONTRAINDICATIONS
Known hypersensitivity to the active substance or to any of the excipients.

PRECAUTIONS
Diclofenac is contra-indicated in patients with active peptic ulceration; in addition, the non-selective NSAlDs should be used with caution, in patients with a history of such disorders. To reduce the risk of gastrointestinal effects, NSAlDs may be taken with or after food or milk. Histamine FL-antagonists, proton pump inhibitors such as omeprazole, or misoprostol may be used for a similar purpose in high-risk patients taking non-selective NSAlDs. However, food, milk, and such measures may reduce the rate and extent of drug absorption. NSAlDs associated with the lowest risk of gastrointestinal toxicity and should be tried first in the lowest recommended dose, and not more than one oral NSAID should be used at a time; selective inhibitors of cyclo-oxygenase-2 (COX-2) should be reserved for patients at highest risk of ulcer,perforation, or bleeding, and after assessment of cardiovascular risk. There is no evidence to justify the use of gastroprotective drugs with selective inhibitors of COX-2 to further reduce the risk of gastrointestinal effects. Diclofenac is also contra-indicated in severe heart failure; furthermore, selective COX-2 inhibitors should not be used in patients with moderate heart failure, ischaemic heart disease, peripheral arterial disease, or cerebrovascular disease. NSAlDs should be used with caution in patients with hypertension; the selective COX-2 inhibitors should also be used with caution in patients with left ventricular failure, oedema, or a history of cardiac failure, and in patients with risk factors for developing heart disease. Diclofenac should be used with caution in patients with infections, since symptoms such as fever and inflammation may be masked. They should also be used with caution in patients with asthma or allergic disorders. NSAlDs (including topical NSAlDs) are contra-indicated in patients with a history of hypersensitivity reactions to such drugs, including those in whom attacks of asthma, angioedema, urticaria, or rhinitis have been precipitated by aspirin or any other NSAID. Other general precautions to be observed include use in patients with haemorrhagic disorders or impaired renal or hepatic function. Patients undergoing therapy with some NSAlDs may need to be monitored for the development of blood, kidney, liver, or eye disorders. NSAlDs should be used with caution in the elderly and may need to be given in reduced doses. Some NSAlDs can interfere with thyroid function tests by lowering serum-thyroid hormone concentrations.

Pregnancy
Use of NSAlDs during pregnancy may delay the onset of labour and increase its duration.
Use of NSAlDs during the third trimester of pregnancy may result in the premature closure of fetal ductus arteriosus. A recent meta-analysis 1 suggested that the short-term use of NSAlDs was associated with a fifteen-fold increase in the risk of premature closure when compared to either placebo or other non-NSAlDs. There was insufficient data to predict the outcome of long-term NSAID treatment in late pregnancy; however, it seemed likely that the risk of premature. The risk of miscarriage may be increased with NSAID use; however, this observation remains to be confirmed. One study also found no association between NSAID use and congenital abnormalities, low birth weight, or pre-term birth.

Lactation
No data on the excretion into breast milk for diclofenac.

ADVERSE EFFECTS
The commonest adverse effects of NSAlDs are generally gastrointestinal disturbances, such as gastrointestinal discomfort, nausea, and diarrhoea; these are usually mild and reversible but in some patient’s peptic ulceration and severe gastrointestinal bleeding may occur. It is generally agreed that inhibition of cyclo-oxygenase-l (COX-I) plays an important role in the gastrointestinal effects of NSAlDs; the selective inhibition of COX-2 improves gastrointestinal tolerance. CNS-related adverse effects include headache, vertigo, dizziness, nervousness, tinnitus, depression, drowsiness, and insomnia. Hypersensitivity reactions may occur occasionally and include fever, angioedema,
bronchospasm, and rashes. Hepatotoxicity and aseptic meningitis, which occur rarely, may also be hypersensitivity reactions. Some patients may experience visual disturbances. Haematological adverse effects of NSAlDs include anaemias, thrombocytopenia, neutropenia, eosinophilia, and agranulocytosis. Unlike aspirin, inhibition of platelet aggregation is reversible with other NSAlDs.

DRUG INTERACTION
Interactions involving NSAlDs include enhancement of the effects of oral anticoagulants (especially by azapropazone and phenylbutazone) and increased plasma concentrations of lithium, methotrexate, and cardiac glycosides. The risk of nephrotoxicity may be increased if given with ACE inhibitors, ciclosporin, tacrolimus, or diuretics. Effects on renal function may lead to reduced excretion of some drugs. There may also be an increased risk of hyperkalaemia with ACE inhibitors and some diuretics, including potassium-sparing diuretics. The antihypertensive effects of some antihypertensives including ACE inhibitors, beta blockers, and diuretics may be reduced. Convulsions may occur due to an interaction with quinolones. NSAlDs may increase the effects of phenytoin and sulfonylurea antidiabetics.

CAUTION
Foods, Drugs, Devices and CosmeticsAct prohibits dispensing without prescription.

STORAGE CONDITION
Store at temperatures not exceeding 300C.

KEEP ALL MEDICINE OUT OF CHILDREN’S REACH.

AVAILABILITY
Alu / PVC Blister Pack of 10’s (box of 100’s).

“For suspected adverse drug reaction, report to the FDA: www.fda.gov.ph“