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.

Pharmacokinetics

Diclofenac sodium delayed-release tablets are in a pharmaceutical 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 shown in Table 1.

Absorption

Under fasting condition, diclofenac is completely absorbed from the gastrointestinal tract. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available.

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 2.0 µg/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.

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 650 mL/kg, respectively. More than 99% of diclofenac is reversibly bound to human plasma albumin.

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.

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.

Special Populations

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).

Clinical Studies

Special Studies

(The clinical significance of the findings outlined below is unknown).

Osteoarthritis/Rheumatoid Arthritis/Ankylosing Spondylitis:

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 using diclofenac sodium delayed-release tablets, of 266 patients started on 100 mg/day, 176 chose to increase the dose to 150 mg/day. Dosages above 200 mg/day have not been studied in patients with osteoarthritis.

The usual starting dose of diclofenac sodium delayed-release tablets 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 from 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 (see DOSAGE AND ADMINISTRATION regarding the 125 mg/day 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.

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.

Hepatic Effects

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.

Anaphylactoid Reactions

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.

Advanced Renal Disease

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).

Pregnancy

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).

General

Diclofenac sodium delayed-release tablets should not be used concomitantly with other diclofenac-containing products since they also circulate in plasma as the diclofenac anion.

Information for Patients

Diclofenac, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, and more rarely, liver toxicity (see WARNINGS, Hepatic Effects), which may result in hospitalization and even fatal outcomes.

NSAIDs are often essential agents in the management of arthritis and have a major role in the management of pain, but they also may be commonly employed for conditions that are less serious.

Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.

Because serious G.I. tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulcerations and bleeding and should inform them of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects, Risk of G.I. Ulcerations, Bleeding and Perforation with NSAID Therapy). If diclofenac is used chronically, patients should also be instructed to report any signs and symptoms that might be due to hepatotoxicity of diclofenac; these symptoms may become evident between visits when periodic liver laboratory tests are performed (see WARNINGS, Hepatic Effects, and PRECAUTIONS-Laboratory Tests).

Laboratory Tests

Drug Interactions

Protein Binding

In vitro, diclofenac interferes minimally or not at all with the protein binding of salicylic acid (20% decrease in binding), tolbutamide, prednisolone (10% decrease in binding), or warfarin. Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence in vitro on the protein binding of diclofenac in human serum.

Drug/Laboratory Test Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day or (12 mg/m2/day, approximately the human dose) have revealed no significant increases in tumor incidence. There was a slight increase in benign mammary fibroadenomas in mid-dose-treated (0.5 mg/kg/day or 3 mg/m2/day) female rats (high-dose females had excessive mortality), but the increase was not significant for this common rat tumor. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m2/day) in males and 1 mg/kg/day (3 mg/m2/day) in females did not reveal any oncogenic potential. Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. Diclofenac sodium administered to male and female rats at 4 mg/kg/day (24 mg/m2/day) did not affect fertility.

Pregnancy, Teratogenic Effects, Pregnancy Category B

Reproduction studies have been performed in mice given diclofenac sodium ( up to 20 mg/kg/day or 60 mg/m2/day) and in rats and rabbits given diclofenac sodium (up to 10 mg/kg/day or 60 mg/m2/day for rats, and 80 mg/m2/day for rabbits), and have revealed no evidence of teratogenicity despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless the benefits to the mother justify the potential risk to the fetus. Because of the risk to the fetus resulting in premature closure of the ductus arteriosus, diclofenac should be avoided in late pregnancy.

Labor and Delivery

The effects of diclofenac on labor and delivery in pregnant women are unknown. Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), use of diclofenac during late pregnancy should be avoided and, as with other nonsteroidal anti-inflammatory drugs, it is possible that diclofenac may inhibit uterine contractions and delay parturition.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from diclofenac, 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 of diclofenac in pediatric patients have not been established.

Geriatric Use

Of the more than 6000 patients treated with diclofenac in U.S. trials, 31% were older than 65 years of age. No overall difference was observed between efficacy, adverse event, or pharmacokinetic profiles of older and younger patients. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients.

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 200 mg/day have not been studied in patients with osteoarthritis.

Rheumatoid Arthritis:

The recommended dosage is 150 to 200 mg/day in divided doses, 50 mg t.i.d. or g.i.d. or 75 mg b.i.d. Dosages above 225 mg/day are not recommended in patients with rheumatoid arthritis.

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.