Diflunisal

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of diflunisal tablets and other treatment options before deciding to use diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Diflunisal tablets are indicated for acute or long-term use for symptomatic treatment of the following: 1. Mild to moderate pain 2. Osteoarthritis 3. Rheumatoid arthritis

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of diflunisal tablets and other treatment options before deciding to use diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to initial therapy with diflunisal tablets, the dose and frequency should be adjusted to suit an individual patient's needs. Concentration-dependent pharmacokinetics prevail when diflunisal is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with repetitive doses. For mild to moderate pain, an initial dose of 1000 mg followed by 500 mg every 12 hours is recommended for most patients. Following the initial dose, some patients may require 500 mg every 8 hours. A lower dosage may be appropriate depending on such factors as pain severity, patient response, weight, or advanced age; for example, 500 mg initially, followed by 250 mg every 8 to 12 hours. For osteoarthritis and rheumatoid arthritis, the suggested dosage range is 500 mg to 1000 mg daily in two divided doses. The dosage of diflunisal may be increased or decreased according to patient response. Maintenance doses higher than 1500 mg a day are not recommended. Tablets should be swallowed whole, not crushed or chewed.

CONTRAINDICATIONS Diflunisal tablets are contraindicated in patients with known hypersensitivity to diflunisal or the excipients (see DESCRIPTION ). Diflunisal tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS , Anaphylactic/Anaphylactoid Reactions and PRECAUTIONS , Preexisting Asthma ). Diflunisal tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

ADVERSE REACTIONS The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients. Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255 patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks. In general, the adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-term treatment for mild to moderate pain. Incidence Greater Than 1% Gastrointestinal The most frequent types of adverse reactions occurring with diflunisal are gastrointestinal: these include nausea*, vomiting, dyspepsia*, gastrointestinal pain*, diarrhea*, constipation, and flatulence. Psychiatric Somnolence, insomnia. Central Nervous System Dizziness. Special Senses Tinnitus. Dermatologic Rash*. Miscellaneous Headache*, fatigue/tiredness. * Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk. Incidence Less Than 1 in 100 The following adverse reactions, occurring less frequently than 1 in 100, were reported in clinical trials or since the drug was marketed. The probability exists of a causal relationship between diflunisal and these adverse reactions. Dermatologic Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug reaction (FDE), urticaria, pruritus, sweating, dry mucous membranes, stomatitis, and photosensitivity. Gastrointestinal Peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis. Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis. Hematologic Thrombocytopenia; agranulocytosis; hemolytic anemia. Genitourinary Dysuria; renal impairment, including renal failure; interstitial nephritis; hematuria; proteinuria. Psychiatric Nervousness, depression, hallucinations, confusion, disorientation. Central Nervous System Vertigo; light-headedness; paresthesias. Special Senses Transient visual disturbances including blurred vision. Hypersensitivity Reactions Acute anaphylactic reaction with bronchospasm; angioedema; flushing. Hypersensitivity vasculitis. Hypersensitivity syndrome (see PRECAUTIONS ). Miscellaneous Asthenia, edema. Causal Relationship Unknown Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians. Respiratory Dyspnea. Cardiovascular Palpitation, syncope. Musculoskeletal Muscle cramps. Genitourinary Nephrotic syndrome. Special Senses Hearing loss. Miscellaneous Chest pain. A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β -hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including diflunisal, sometimes with fatal outcome (see also PRECAUTIONS, General ). Potential Adverse Effects In addition, a variety of adverse effects not observed with diflunisal in clinical trials or in marketing experience, but reported with other non-steroidal analgesic/anti-inflammatory agents should be considered potential adverse effects of diflunisal.

Drug Interactions ACE-inhibitors and Angiotensin II Anagonists Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the coadministration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Acetaminophen In normal volunteers, concomitant administration of diflunisal and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of diflunisal. Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of diflunisal tablets and acetaminophen should be used cautiously, with careful monitoring of patients. Concomitant administration of diflunisal and acetaminophen in dogs, but not in rats, at approximately 2 times the recommended maximum human therapeutic dose of each (40 to 52 mg/kg/day of diflunisal/acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these findings has not been established. Antacids Concomitant administration of antacids may reduce plasma levels of diflunisal. This effect is small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous schedule. Aspirin When diflunisal is administered with aspirin, its protein binding is reduced, although the clearance of free diflunisal is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diflunisal tablets and aspirin is not generally recommended because of the potential of increased adverse effects. In normal volunteers, a small decrease in diflunisal levels was observed when multiple doses of diflunisal and aspirin were administered concomitantly. Cyclosporine Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored. Diuretics Clinical studies, as well as postmarketing observations, have shown that diflunisal can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. In normal volunteers, concomitant administration of diflunisal and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. Diflunisal decreased the hyperuricemic effect of hydrochlorothiazide. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS , Renal Effects ), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. NSAIDs The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal clear …

DESCRIPTION Diflunisal is 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its structural formula is: C 13 H 8 F 2 O 3 M.W. 250.20 Diflunisal is a stable, white to off-white, crystalline compound with a melting point of 211° to 213°C. It is practically insoluble in hexane and water. It is soluble in most organic solvents including acetone and ethyl acetate and it is slightly soluble in chloroform, carbon tetrachloride and methylene chloride. Each diflunisal tablet intended for oral administration contains 500 mg of diflunisal. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, microcrystalline cellulose, pregelatinised starch and sodium stearyl fumarate. Additionally, each diflunisal tablets contain opadry blue 03B505010 which contains FD&C blue #2, FD&C yellow #6, hypromellose, polyethylene glycol and titanium dioxide. Structure

OVERDOSAGE Cases of overdosage have occurred and deaths have been reported. Most patients recovered without evidence of permanent sequelae. The most common signs and symptoms observed with overdosage were drowsiness, vomiting, nausea, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. Diminished urine output and cardiorespiratory arrest have also been reported. The lowest dosage of diflunisal at which a death has been reported was 15 grams without the presence of other drugs. In a mixed drug overdose, ingestion of 7.5 grams of diflunisal resulted in death. In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Because of the high degree of protein binding, hemodialysis may not be effective. The oral LD 50 of the drug is 500 mg/kg and 826 mg/kg in female mice and female rats, respectively.

HOW SUPPLIED Diflunisal Tablets USP, 500 mg are light blue to blue color, capsule shaped, biconvex, coated tablets, debossed with "530" on one side and plain on the other side and are supplied as follows: NDC 68382-530-06 in bottle of 30 tablets NDC 68382-530-14 in bottle of 60 tablets NDC 68382-530-16 in bottle of 90 tablets NDC 68382-530-01 in bottle of 100 tablets NDC 68382-530-05 in bottle of 500 tablets NDC 68382-530-10 in bottle of 1000 tablets NDC 68382-530-30 in unit-dose blister cartons of 100 (10 X 10) unit-dose tablets Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container (USP). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Manufactured by: Zydus Lifesciences Limited., Baddi-173205, India Distributed by: Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 Rev.: 07/24