DICLOFENAC SODIUM

WARNINGS Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including diclofenac sodium delayed-release tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Caution should be used when initiating treatment with diclofenac sodium delayed-release tablets in patients with considerable dehydration. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease. Therefore, treatment with diclofenac sodium delayed-release tablets are not recommended in these patients with advanced renal disease. If diclofenac sodium delayed-release tablets therapy must be initiated, close monitoring of the patient’s renal function is advisable. Hepatic Effects Elevations of one or more liver tests may occur during therapy with Diclofenac delayed-release tablets. 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 [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of Diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during Diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 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. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with Diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the firth 2 months of therapy, but can occur at any time during treatment with Diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or 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. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with Diclofenac. However, severe hepatic reaction can occur at any time during treatment with Diclofenac. 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., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Diclofenac sodium delayed-release tablets 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, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk for an adverse liver related event in patients treated with Diclofenac sodium delayed-release tablets, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing Diclofenac sodium delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics). Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur both in patients with the aspirin traid and in patients without known sensitivity to NSAIDs or known prior exposure to Diclofenac Sodium Delayed-release Tablets. Diclofenac Sodium Delayed-release Tablets 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 (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma . ) Anaphylaxis-type reactions have been reported with NSAID products, including with Diclofenac products, such as Diclofenac Sodium Delayed-Release Tablet. Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including diclofenac sodium delayed-release tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, diclofenac sodium delayed-release tablets should be avoided because it may cause premature closure of the ductus arteriosus.