Diclofenac Sodium Delayed-release

Peptic ulceration and gastrointestinal bleeding have been reported in patients receiving diclofenac. Physicians and patients should therefore remain alert for ulceration and bleeding in patients treated chronically with diclofenac even in the absence of previous G.I. tract symptoms. It is recommended that patients be maintained on the lowest dose of diclofenac possible, consistent with achieving a satisfactory therapeutic response.

Elevations of one or more liver tests may occur during diclofenac therapy. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [*the Upper Limit of the Normal range]), or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the hepatic enzymes, ALT (SGPT) is the one recommended for the monitoring of liver injury.

In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5700 patients at some time during diclofenac sodium treatment. In a large, open, controlled trial, meaningful elevations of ALT and/or AST occurred in about 4% of 3700 patients treated for 2 to 6 months, including marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Transaminase elevations were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis (see ADVERSE REACTIONS).

In addition to enzyme elevations seen in clinical trials, postmarketing surveillance has found rare cases of severe hepatic reactions, including liver nacrosis, jaundice, and fulminant fatal hepatitis with and without jaundice. Some of these rare reported cases underwent liver transplantation.

Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. In the largest U.S. trial (open-label) that involved 3700 patients monitored first at 8 weeks and 1200 patients monitored again at 24 weeks, almost all meaningful elevations in transaminases were detected before patients became symptomatic. In 42 of the 51 patients in all trials who developed marked transaminase elevations, abnormal tests occurred during the first 2 months of therapy with diclofenac. Postmarketing experience has shown severe hepatic reactions can occur at any time during treatment with diclofenac. Cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first two months of therapy. Based on these experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac (see PRECAUTIONS-Laboratory Tests). As with other NSAIDs, if abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilla, rash, etc.), diclofenac should be discontinued immediately.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to diclofenac. Diclofenac should not be given to patients with the aspirin triad. The triad 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 nonsteroidal anti-inflammatory drugs. Fatal reactions have been reported in such patients (see CONTRAINDICATIONS, and PRECAUTIONS-Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

In cases with advanced kidney disease, treatment with diclofenac, as with other NSAIDs, should only be initiated with close monitoring of the patient’s kidney functions (see PRECAUTIONS-Renal Effects).

In late pregnancy, diclofenac should, as with other NSAIDs, be avoided because it will cause premature closure of the ductus arteriosus (see PRECAUTIONS-Pregnancy, Teratogenic Effects, Pregnancy Category B, and Labor and Delivery).