DESCRIPTION:

Diclofenac sodium enteric-coated tablets, is a benzene-acetic acid derivative and is available as enteric-coated tablets of 25 mg.

CLINICAL PHARMACOLOGY:

Pharmacodynamics: Diclofenac sodium enteric-coated tablets, is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of it, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption: Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. Food has no significant effect on the extent of Diclofenac absorption. T _max;  2.3 hr, Oral Clearance CL/F; 582 mL/min  Absolute Bioavailability; %55, Terminal Half-life; 2.3 hr

Distribution: Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Diclofenac diffuses into and out of the synovial fluid.

Metabolism: five Diclofenac metabolites have been identified in human plasma and urine.

Excretion: approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged Diclofenac plus metabolites.

Hepatic insufficiency: hepatic metabolism accounts for almost 100% of it elimination, so patients with hepatic disease may require reduced doses of it compared to patients with normal hepatic function.

WARNINGS:

Gastrointestinal (GI) effects - Risk of GI ulceration, bleeding, and perforation. Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding.

Anaphylactoid reactions: It should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs.

Advanced renal disease: In cases with advanced kidney disease, treatment with Diclofenac is not recommended.

Pregnancy: in late pregnancy, as with other NSAIDs, It should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS:

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAID thus periodic monitoring of transaminases is recommended.Caution is also recommended in patients with preexisting kidney disease. Long-term administration of Diclofenac has resulted in renal papillary necrosis and other renal medullary changes.

Diclofenac Sodium metabolites are eliminated primarily by the kidneys. Patients on long-term treatment with Diclofenac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. Patients with coagulation disorders or patients receiving anticoagulants should be carefully monitored. Diclofenac should be used with caution in patients with fluid retention, hypertension, or heart failure.

Diclofenac Sodium should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma.

Information for Patients: Patients should report to their physicians' signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, weight gain, edema, hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms).

Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction. In late pregnancy, Diclofenac Sodium should be avoided because it will cause premature closure of the ductus arteriosus.

Laboratory Tests: patients on long-term treatment, should have their CBC and a chemistry profile (including transaminases) checked periodically. Pregnancy: Pregnancy Category C

Labor and delivery: The effects of Diclofenac Sodium on labor and delivery in pregnant women are unknown.

Nursing Mothers: a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: safety and effectiveness in pediatric patients have not been established.

Geriatric Use: caution should be exercised in treating the elderly (65 years and older).

Drug Interactions:

Aspirin: concomitant administration of Diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.

Methotrexate: this may indicate that they could enhance the toxicity of methotrexate.

Cyclosporine: concomitant therapy with Diclofenac Sodium may increase cyclosporine's nephrotoxicity.

ACE-inhibitors: reports suggest that Diclofenac Sodium may diminish the antihypertensive effect of ACE-inhibitors.

Furosemide: during concomitant therapy with Diclofenac Sodium, the patient should be observed closely for signs of renal failure as well as to assure diuretic efficacy.

Lithium:  Diclofenac Sodium has produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.

Warfarin: users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

SIDE EFFECTS:

The most frequently reported adverse experiences occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting.

Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus.

Body as a whole: fever, infection, sepsis

Cardiovascular system: congestive heart failure, hypertension, tachycardia, syncope

Digestive system: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

Hemic and lymphatic system: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

Metabolic and nutritional: weight changes

Nervous system: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo

Respiratory system: asthma, dyspnea

Skin and appendages: alopecia, photosensitivity, sweating increased

Special senses: blurred vision

Urogenital system: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure.

OVERDOSAGE:

Symptoms following acute overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of Diclofenac Sodium, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following a Diclofenac Sodium overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

DOSAGE AND ADMINISTRATION:

The lowest dose should be sought for each patient. Therefore, after observing the response to initial therapy with Diclofenac sodium enteric-coated tablets, the dose and frequency should be adjusted to suit an individual patient's needs.

For the relief of osteoarthritis, the recommended dosage is 100-150 mg/day in divided doses.

For the relief of rheumatoid arthritis, the recommended dosage is 150-200 mg/day in divided doses.

For the relief of ankylosing spondylitis, the recommended dosage is 100-125 mg/day.

How Supplied: Each pack of Ruz-Diclofenac sodium 25 mg tablets contains 100 enteric coated tablets in 10 blisters.

storage: Do not store above 30°C. Protect from moisture.

Reference: PDR 2000, page 2004-7

                  USPDI for Professional Health Care, 2004, Page 374-91

                  Martindale 2005, Page 32-4