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: Mild to moderate pain Osteoarthritis Rheumatoid arthritis

CLINICAL PHARMACOLOGY Action Diflunisal is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance, and addiction have not been reported. Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the O -acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure. The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of prostaglandins in peripheral tissues. Pharmacokinetics and Metabolism Diflunisal is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours. The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is excreted in the feces. Diflunisal appears in human milk in concentrations of 2 to 7% of those in plasma. More than 99% of diflunisal in plasma is bound to proteins. As is the case with salicylic acid, 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. Following single doses, peak plasma concentrations of 41 ± 11 mcg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 mcg/mL were observed following 500 mg and 124 ± 11 mcg/mL following single 1000 mg doses. However, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 mcg/mL was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 mcg/mL. In contrast to salicylic acid which has a plasma half-life of 2 1/2 hours, the plasma half-life of diflunisal is 3 to 4 times longer (8 to 12 hours), because of a difluorophenyl substituent at carbon 1. Because of its long half-life and nonlinear pharmacokinetics, several days are required for diflunisal plasma levels to reach steady state following multiple doses. For this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and 2 to 3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used. Studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of diflunisal, und

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.

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, toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, 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. To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diflunisal, increases the risk of serious gastrointestinal (GI) events (see WARNINGS ). Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS ). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of diflunisal tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diflunisal tablets is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including diflunisal tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including diflunisal tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid

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 ). In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ) .

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.