Diclofenac Sodium (Tablet, Delayed Release)

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Diclofenac sodium may be administered as 25 mg, 50 mg, or 75 mg delayed-release tablets. Regardless of the indication, the dosage of diclofenac should be individualized to the lowest effective dose to minimize adverse effects<br/>Osteoarthritis:: The recommended dosage is 100 to 150 mg/day in divided doses, 50 mg b.i.d. or t.i.d. or 75 mg b.i.d. Dosages above 150 mg/day have not been studied in patients with osteoarthritis.<br/>Rheumatoid Arthritis:: The recommended dosage is 150 to 200 mg/day in divided doses, 50 mg t.i.d. or q.i.d., or 75 mg b.i.d. Dosages above 225 mg/day are not recommended in patients with rheumatoid arthritis.<br/>Ankylosing Spondylitis:: The recommended dosage is 100 to 125 mg/day, administered as 25 mg q.i.d., with an extra 25 mg dose at bedtime if necessary. Dosages above 125 mg/day have not been studied in patients with ankylosing spondylitis.

Pharmacodynamics: Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac has shown anti-inflammatory, analgesic, and antipyretic activity. As with other NSAIDs, its mode of action is not known; its ability to inhibit prostaglandin synthesis, however, may be involved in its anti-inflammatory activity.<br/>Pharmacokinetics: Diclofenac sodium delayed-release tablets are in a pharmaceutic formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH-environment in the duodenum. Its pattern of drug release and absorption is illustrated below:<br/>Absorption: When diclofenac sodium delayed-release tablets are administered orally after fasting, diclofenac is completely absorbed from the gastrointestinal tract. Of this, only 50% of the absorbed dose of diclofenac from diclofenac sodium is systemically available, due to first-pass metabolism. Peak plasma levels are achieved in 2 hours in fasting normal volunteers, with a range from 1 to 4 hours. The area-under-the plasma-concentration curve (AUC) is dose-proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.0, 1.5, and 2��g/mL for 25 mg, 50 mg and 75 mg doses, respectively. It should be noted that the administration of several individual diclofenac sodium tablets may not yield equivalent results in peak concentration as the administration of one tablet of a higher strength. This is probably due to the staggered gastric emptying of tablets into the duodenum. After repeated oral administration of diclofenac sodium 50 mg b.i.d., diclofenac did not accumulate in plasma. When diclofenac sodium is taken with food, there is usually a delay in the onset of absorption of 1 to 4.5 hours, with delays as long as 10 hours in some patients, and a reduction in peak plasma levels of approximately 40%. The extent of absorption of diclofenac, however, is not significantly affected by food intake.<br/>Distribution: Plasma concentrations of diclofenac decline from peak levels in a biexponential fashion, with the terminal phase having a half-life of approximately 2 hours. Clearance and volume of distribution are about 350 mL/min and 550 mL/kg, respectively. More than 99% of diclofenac is reversibly bound to human plasma albumin. A 4-week study, comparing plasma level profiles of diclofenac (diclofenac sodium 50 mg b.i.d.) in younger (26 to 46 years) versus older (66 to 81 years) adults, did not show differences between age groups (10 patients per age group). As with other NSAIDs, diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.<br/>Metabolism and Elimination: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile. Conjugates of unchanged diclofenac account for 5 to 10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20 to 30% of the dose excreted in the urine and for 10 to 20% of the dose excreted in the bile. Conjugates of three other metabolites together account for 10 to 20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life 80 hours) accounts for only 1.4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity.<br/>Patients with Renal and/or Hepatic Impairment: To date, no differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal (50 mg intravenously) or hepatic impairment (100 mg oral solution). In patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min), AUC values and elimination rates were comparable to those in healthy subjects. In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubins, N=10), diclofenac concentrations and urinary elimination values were comparable to those in healthy subjects.<br/>Clinical Studies:<br/>Osteoarthritis:: Diclofenac sodium was evaluated for the management of the signs and symptoms of osteoarthritis of the hip or knee in a total of 633 patients treated for up to 3 months in placebo and active-controlled clinical trials against aspirin (N=449), and naproxen (N=92). Diclofenac sodium was given both in variable (100 to 150 mg/day) and fixed (150 mg/day) dosing schedules on either b.i.d. or t.i.d. dosing regimens. In these trials, diclofenac sodium was found to be comparable to 2400 to 3600 mg/day of aspirin or 500 mg/day of naproxen. Diclofenac was effective when administered as either b.i.d. or t.i.d. dosing regimens.<br/>Rheumatoid Arthritis:: Diclofenac sodium was evaluated for managing the signs and symptoms of rheumatoid arthritis in a total of 468 patients treated for up to 3 months in placebo- and active- controlled clinical trials against aspirin (N=290), and ibuprofen (N = 74). Diclofenac sodium was given in a fixed (150 or 200 mg/day) dosing schedule as either b.i.d. or t.i.d. dosing regimens. Diclofenac sodium was found to be comparable to 3600 to 4800 mg/day of aspirin, and 2400 mg/day of ibuprofen. Diclofenac sodium was used b.i.d. or t.i.d., administering 150 mg/day in most trials, but 50 mg q.i.d. (200 mg/day) was also studied.<br/>Ankylosing Spondylitis:: Diclofenac sodium was evaluated for the management of the signs and symptoms of ankylosing spondylitis in a total of 132 patients in one active controlled clinical trial against indomethacin (N=130). Both diclofenac sodium and indomethacin patients were started on 25 mg t.i.d. and were permitted to increase the dose 25 mg per day each week to a maximum dose of 125 mg/day. Diclofenac sodium 75 to 125 mg/day was found to be comparable to indomethacin 75 to 125 mg/day.<br/>G.I. Blood Loss/Endoscopy Data:: G.I. blood loss and endoscopy studies were performed with diclofenac sodium delayed-release [enteric-coated] tablets that, unlike immediate-release tablets, do not dissolve in the stomach where the endosopic lesions are primarily seen. A repeat-dose endoscopy study, in patients with rheumatoid arthritis or osteoarthritis treated with diclofenac sodium delayed-release tablets 75 mg b.i.d. (N=101), or naproxen (immediate-release tablets) 500 mg b.i.d. (N=103) for three months, resulted in a significantly smaller number of patients with an increase in endoscopy score from baseline and a significantly lower mean endoscopy score after treatment in the diclofenac sodium treated patients. Two repeat-dose endoscopic studies, in normal volunteers, showed that daily doses of diclofenac sodium delayed-release tablets 75 or 100 mg (N=6 and 14, respectively) for 1 weekcaused fewer gastric lesions, and those that did occur had lower scores than those observed following daily 500 mg doses of naproxen (immediate-release tablets). In healthy subjects, the daily administration of 150 mg of diclofenac sodium (N=8) for 3 weeks resulted in a mean fecal blood loss of less than that observed with 3 g of aspirin daily (N=8). In four repeat-dose studies, mean fecal blood loss with 150 mg of diclofenac was also less than that observed with 750 mg of naproxen (N=8 and 6) or 150 mgof indomethacin (N=8 and 6). The clinical significance of these findings is unknown since there is no evidence available to indicate that diclofenac sodium is less likely than other drugs of its class to cause serious gastrointestinal lesions when used in chronic therapy.<br/>Individualization of Dosage: Diclofenac, like other NSAIDs, shows interindividual differences in both pharmacokinetics and clinical response (pharmacodynamics). Consequently, the recommended strategy for initiating therapy is to use a starting dose likely to be effective for the majority of patients and to adjust dosage thereafterbased on observation of diclofenac's beneficial and adverse effects. In patients weighing less than 60 kg (132 lbs), or where the severity of the disease, concomitant medication, or other diseases warrant, the maximum recommended total daily dose of diclofenac should be reduced. Experience with other NSAIDs has shown that starting therapy with maximal doses in patients at increased risk due to renal or hepatic disease, low body weight (<60 kg), advanced age, a known ulcer diathesis, or known sensitivity to NSAID effects, is likely to increase frequency of adverse reactions and is not recommended .<br/>Osteoarthritis/Rheumatoid Arthritis/Ankylosing Spon-dylitis:: The usual starting dose of diclofenac sodium delayed-release tablets for patients with osteoarthritis, is 100 to 150 mg/day, using a b.i.d. or t.i.d. dosing regimen. In two variable-dose clinical trials in osteoarthritis, of 266 patients started on 100 mg/day, 176 chose to increase the dose to 150 mg/day. Dosages above 150 mg/day have not been studied in patients with osteoarthritis. The usual starting dose of diclofenac sodium for most patients with rheumatoid arthritis is 150 mg/day, using a b.i.d. or t.i.d. dosing regimen. Patients requiring more relief of pain and inflammation may increase the dose to 200 mg/day. In clinical trials, patients receiving 200 mg/day were less likely to drop form the trial due to lack of efficacy than patients receiving 150 mg/day. Dosages above 225 mg/day are not recommended in patients with rheumatoid arthritis because of increased risk of adverse events. The recommended dose of diclofenac sodium delayed-release tablets for patients with ankylosing spondylitis is 100 to 125 mg/day, using a q.i.d. dosing regimen . In a variable-dose clinical trial, of 132 patients started on 75 mg/day, 122 chose to increase the dose to 125 mg/day. Dosages above 125 mg/day have not been studied in patients with ankylosing spondylitis.

Diclofenac sodium delayed-release tablets are contraindicated in patients with hypersensitivity to the product. Diclofenac should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to diclofenac have been reported in such patients.

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Worldwide reports on overdosage with diclofenac cover 66 cases. In approximately one-half of these reports of overdosage, concomitant medications were also taken. The highest dose of diclofenac was 5 g in a 17-year-old male who suffered loss of consciousness, increased intracranial pressure, aspiration pneumonitis, and died 2 days after overdose. The next highest doses of diclofenac were 4 g and 3.75 g. The 24-year-old female who took 4g and the 28- and 42-year-old females, each of whom took 3.75 g, did not develop any clinically significant signs or symptoms. However, there was a report of a 17-year-old female who experienced vomiting and drowsiness after an overdose of 2.37 g of diclofenac. Animal LDvalues show a wide range of susceptibilities to acute overdosage, with primates being more resistant to acute toxicity than rodents (LDin mg/kg���rats, 55; dogs, 500; monkeys, 3200). In case of acute overdosage it is recommended that the stomach be emptied by vomiting or lavage. Forced diuresis may theoretically be beneficial because the drug is excreted in the urine. The effect of dialysis or hemoperfusion in the elimination of diclofenac remains unproven. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac.

Diclofenac Sodium (Tablet, Delayed Release)

Gastrointestinal Effects: 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.<br/>Risk of G.I. Ulcerations, Bleeding, and Perforation with NSAID Therapy: Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs even in the absence of previous G.I. tract symptoms. In patients observed in clinical trials of several months to 2 years duration, symptomatic upper G.I. ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients for 3 to 6 months, and in about 2 to 4% of patients treated for 1 year. Physicians should inform patients about the signs and/or symptoms of serious G.I. toxicity and what steps to take if they occur. Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious G.I. events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal G.I. events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of G.I. toxicity.<br/>Hepatic Effects: As with other NSAIDs, 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 . In addition to the enzyme elevations seen in clinical trials, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, have been reported. 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. Based on this experience, if diclofenac is used chronically, the first transaminase measurement should be made no later than 8 weeks after the start of diclofenac treatment. 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., eosinophilia, rash, etc.), diclofenac should be discontinued. 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.

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Diclofenac Sodium