Prescription Drug Information: Diclofenac Sodium (Page 3 of 4)

Anticoagulants:

While studies have not shown diclofenac to interact with anti-coagulants of the warfarin type, caution should be exercised, nonetheless, since interactions have been seen with other NSAIDs. Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function as well, concurrent therapy with all NSAIDs, including diclofenac, and warfarin requires close monitoring of patients to be certain that no change in their anticoagulant dosage is required.

Digoxon, Methotrexate, Cyclosporine:

Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Ingestion of diclofenac may increase serum concentrations of digoxin and methotrexate and increase cyclosporine’s nephrotoxicity. Patients who begin taking diclofenac or who increase their diclofenac dose or any other NSAID while taking digoxin, methotrexate, or cyclosporine may develop toxicity characteristics of these drugs. They should be observed closely, particularly if renal function is impaired. In case of digoxin, serum levels should be monitored.

Lithium:

Diclofenac decreases lithium renal clearance and increases lithium plasma levels. In patients taking diclofenac and lithium concomitantly, lithium toxicity may develop.

Oral Hypoglycemics:

Diclofenac does not alter glucose metabolism in normal subjects nor does it alter the effects of oral hypoglycemic agents. There are rare reports, however, from marketing experiences of changes in effects of insulin or oral hypoglycemic agents in the presence of diclofenac that necessitated changes in the doses of such agents. Both hypo- and hyperglycemic effects have been reported. A direct causal relationship has not been established, but physicians should consider the possibility that diclofenac may alter a diabetic patient’s response to insulin or oral hypoglycemic agents.

Diuretics:

Diclofenac and other NSAIDs can inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels.

Other Drugs:

In small groups of patients (7 to 10/interaction study), the concomitant administration of azathioprine, gold, chloroquine, D-penicillamine, prednisolone, doxycycline, or digitoxin did not significantly affect the peak levels and AUC values of diclofenac.

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

Effect on Blood Coagulation:

Diclofenac increases platelet aggregation time but does not affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, or factors V and VII to XII. Statistically significant changes in prothrombin and partial thromboplastin times have been reported in normal volunteers. The mean changes were observed to be less than 1 second in both instances, however, and are unlikely to be clinically important. Diclofenac is a prostaglandin synthetase inhibitor, however, and all drugs that inhibit prostaglandin synthesis interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (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 two-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 did not affect fertility.

Teratogenic Effects

There are no adequate and well-controlled studies in pregnant women. Diclofenac should be used during pregnancy only if the benefits to the mother justify the potential risk to the fetus.

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.

Labor and Delivery

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

Nursing Mothers

Diclofenac has been found in the milk of nursing mothers. As with other drugs that are excreted in milk, diclofenac is not recommended for use in nursing women.

Pediatric Use

Safety and effectiveness of diclofenac in pediatric patients have not been established.

Geriatic 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.

ADVERSE REACTIONS

Adverse reaction information is derived from blinded, controlled and open-label clinical trials as well as worldwide marketing experience. In the description below, rates of more common events represent clinical study results; rarer events are derived principally from marketing experience and publications, and accurate rate estimates are generally not possible.

The incidence of common adverse reactions (greater than 1%) is based upon controlled clinical trials in 1543 patients treated up to 13 weeks with diclofenac sodium delayed-release tablets. By far the most common adverse effects were gastrointestinal symptoms, most of them minor, occurring in about 20%, and leading to discontinuation in about 3%, of patients. Peptic ulcer or G.I. bleeding occurred in clinical trials in 0.6% (95%-confidence interval: 0.2% to 1%) of approximately 1800 patients during their first 3 months of diclofenac treatment and 1.6% (95%-confidence interval: 0.8% to 2.4%) of approximately 800 patients followed for 1 year.

Gastrointestinal symptoms were followed in frequency by central nervous system side effects such as headache (7%) and dizziness (3%).

Meaningful (exceeding 3 times the Upper Limit of Normal) elevations of ALT (SGPT) or AST (SGOT) occurred at an overall rate of approximately 2% during the first 2 months of diclofenac sodium treatment. Unlike aspirin-related elevations, which occur more frequently in patients with rheumatoid arthritis, these elevations were more frequently observed in patients with osteoarthritis (2.6%) than in patients with rheumatoid arthritis (0.7%). Marked elevations (exceeding 8 times the ULN) were seen in 1% of patients treated for 2 to 6 months (see WARNINGS: Hepatic Effects).

The following adverse reactions were reported in patients treated with diclofenac:

Incidence Greater Than 1%–Causal Relationship Probable

(All derived from clinical trials)

Body as a Whole:

Abdominal pain or cramps*, headache*, fluid retention, abdominal distention.

Digestive:

Diarrhea*, indigestion*, nausea*, constipation*, flatulence, liver test abnormalities*, PUB, i.e., peptic ulcer, with or without bleeding and/or perforation, or bleeding without ulcer (see above and also WARNINGS).

Nervous System:

Dizziness.

Skin and Appendages:

Rash, pruritus.

Special Senses:

Tinnitus.

*Incidence, 3% to 9% (incidence of unmarked reactions is 1 to 3%)

Incidence Less Than 1% — Causal Relationship Probable

The following reactions have been reported in patients taking diclofenac under circumstances that do not permit a clear attribution of the reaction to diclofenac. These reactions are being included as alerting information for physicians. Adverse reactions reported only in worldwide marketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized.

Body as a Whole:

Malaise, swelling of lips and tongue, photosensitivity, anaphylaxis , anaphylactoid reactions.

Cardiovascular:

Hypertension, congestive heart failure.

Digestive:

Vomiting, jaundice, melena, aphthous stomatitis, dry mouth and mucous membranes, bloody diarrhea, hepatitis, hepatic necrosis , appetite change, pancreatitis with or without concomitant hepatitis, colitis.

Hemic and Lymphatic:

Hemoglobin decrease, leukopenia, thrombocytopenia, hemolytic anemia , aplastic anemia , agranulocytosis , purpura, allergic purpura.

Metabolic and Nutritional Disorders:

Azotemia.

Nervous System:

Insomnia, drowsiness, depression, diplopia, anxiety, irritability, aseptic meningitis.

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