WARNINGS
Peptic ulceration and gastrointestinal bleeding have been reported in patients receiving DOLOBID. Fatalities have occurred rarely. Gastrointestinal bleeding is associated with higher morbidity and mortality in patients acutely ill with other conditions, the elderly and patients with hemorrhagic disorders. In patients with active gastrointestinal bleeding or an active peptic ulcer, the physician must weigh the benefits of therapy with DOLOBID against possible hazards, institute an appropriate ulcer regimen, and carefully monitor the patient's progress. When DOLOBID is given to patients with a history of either upper or lower gastrointestinal tract disease, it should be given only after consulting the ADVERSE REACTIONS section and under close supervision. Risk of GI 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 GI tract symptoms. In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI 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 GI 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 GI 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 GI toxicity.
PRECAUTIONS
General
Non-steroidal anti-inflammatory drugs, including DOLOBID, may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing infection.
Although DOLOBID has less effect on platelet function and bleeding time than aspirin, at higher doses it is an inhibitor of platelet function; therefore, patients who may be adversely affected should be carefully observed when DOLOBID is administered (see CLINICAL PHARMACOLOGY).
Because of reports of adverse eye findings with agents of this class, it is recommended that patients who develop eye complaints during treatment with DOLOBID have ophthalmologic studies.
Peripheral edema has been observed in some patients taking DOLOBID. Therefore, as with other drugs in this class, DOLOBID should be used with caution in patients with compromised cardiac function, hypertension, or other conditions predisposing to fluid retention.
Acetylsalicylic acid has been associated with Reye syndrome. Because diflunisal is a derivative of salicylic acid, the possibility of its association with Reye syndrome cannot be excluded. Hypersensitivity Syndrome
A potentially life-threatening, apparent hypersensitivity syndrome has been reported. This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings (see ADVERSE REACTIONS, Dermatologic). It may also include involvement of major organs (changes in liver function, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment, including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation). If evidence of hypersensitivity occurs, therapy with DOLOBID should be discontinued. Renal Effects
As with other non-steroidal anti-inflammatory drugs, long term administration of diflunisal to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria and proteinuria and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal and renal conditions leading to a reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with conditions such as renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion from any cause, congestive heart failure, septicemia, pyelonephritis, or concomitant use of any nephrotoxic drug. DOLOBID or other NSAIDs should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
Since DOLOBID is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be anticipated to avoid excessive drug accumulation. Information for Patients
DOLOBID, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.
NSAIDs (Non-steroidal Anti-inflammatory Drugs) are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions which 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.
Laboratory Tests Liver Function Tests: As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reactions while on therapy with DOLOBID. Severe hepatic reactions, including jaundice, have been reported with DOLOBID as well as with other non-steroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), DOLOBID should be discontinued, since liver reactions can be fatal.
Gastrointestinal: Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see WARNINGS, Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).
Drug Interactions Oral Anticoagulants: In some normal volunteers, the concomitant administration of DOLOBID and warfarin, acenocoumarol, or phenprocoumon resulted in prolongation of prothrombin time. This may occur because diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when DOLOBID is administered with oral anticoagulants, the prothrombin time should be closely monitored during and for several days after concomitant drug administration. Adjustment of dosage of oral anticoagulants may be required. Tolbutamide: In diabetic patients receiving DOLOBID and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose. Hydrochlorothiazide: In normal volunteers, concomitant administration of DOLOBID and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. DOLOBID decreased the hyperuricemic effect of hydrochlorothiazide.
Furosemide: In normal volunteers, the concomitant administration of DOLOBID and furosemide had no effect on the diuretic activity of furosemide. DOLOBID decreased the hyperuricemic effect of furosemide.
Antacids: Concomitant administration of antacids may reduce plasma levels of DOLOBID. This effect is small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous schedule.
Acetaminophen: In normal volunteers, concomitant administration of DOLOBID and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of DOLOBID. Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of DOLOBID and acetaminophen should be used cautiously, with careful monitoring of patients.
Concomitant administration of DOLOBID and acetaminophen in dogs, but not in rats, at approximately 2 times the recommended maximum human therapeutic dose of each (40-52 mg/kg/day of DOLOBID/acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these findings has not been established. Methotrexate: Caution should be used if DOLOBID is administered concomitantly with methotrexate. Non-steroidal anti-inflammatory drugs have been reported to decrease the tubular secretion of methotrexate and to potentiate its toxicity.
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. Drug Interactions: Non-steroidal Anti-inflammatory Drugs
The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients the combined use of indomethacin and DOLOBID has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and DOLOBID should not be used concomitantly.
The concomitant use of DOLOBID and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy. The following information was obtained from studies in normal volunteers. Aspirin: In normal volunteers, a small decrease in diflunisal levels was observed when multiple doses of DOLOBID and aspirin were administered concomitantly. Sulindac: The concomitant administration of DOLOBID and sulindac in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third. Naproxen: The concomitant administration of DOLOBID and naproxen in normal volunteers had no effect on the plasma levels of naproxen, but significantly decreased the urinary excretion of naproxen and its glucuronide metabolite. Naproxen had no effect on plasma levels of DOLOBID. Drug/Laboratory Test Interactions Serum Salicylate Assays: Caution should be used in interpreting the results of serum salicylate assays when diflunisal is present. Salicylate levels have been found to be falsely elevated with some assay methods. Carcinogenesis, Mutagenesis, Impairment of Fertility
Diflunisal did not affect the type or incidence of neoplasia in a 105-week study in the rat given doses up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or in long-term carcinogenic studies in mice given diflunisal at doses up to 80 mg/kg/day (equivalent to approximately 2.7 times the maximum recommended human dose). It was concluded that there was no carcinogenic potential for DOLOBID.
Diflunisal passes the placental barrier to a minor degree in the rat. Diflunisal had no mutagenic activity after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79 Chinese hamster lung cell assay.
No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day. Pregnancy Pregnancy Category C. A dose of 60 mg/kg/day of diflunisal (equivalent to two times the maximum human dose) was maternotoxic, embryotoxic, and teratogenic in rabbits. In three of six studies in rabbits, evidence of teratogenicity was observed at doses ranging from 40 to 50 mg/kg/day. Teratology studies in mice, at doses up to 45 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to diflunisal. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species, including the rat and rabbit, at doses ranging from 50 to 400 mg/ kg/day (approximately one to eight times the human dose). There are no adequate and well controlled studies with diflunisal in pregnant women. DOLOBID should be used during the first two trimesters of pregnancy only if the potential benefit justifies the potential risk to the fetus. The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid
incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis. Use during the third trimester of pregnancy is not recommended.
In rats at a dose of one and one-half times the maximum human dose, there was an increase in the average length of gestation. Similar increases in the length of gestation have been observed with aspirin, indomethacin, and phenylbutazone, and may be related to inhibition of prostaglandin synthetase. Drugs of this class may cause dystocia and delayed parturition in pregnant animals. Nursing Mothers
Diflunisal is excreted in human milk in concentrations of 2-7% of those in plasma. Because of the potential for serious adverse reactions in nursing infants from DOLOBID, 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 DOLOBID in pediatric patients have not been established. Use of DOLOBID in pediatric patients below the age of 12 years is not recommended.
The adverse effects observed following diflunisal administration to neonatal animals appear to be species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic dose, both aspirin (200 to 400 mg/kg/ day) and diflunisal (80 mg/kg/day) resulted in death, leukocytosis, weight loss, and bilateral cataracts in neonatal (4 to 5-day-old) beagle puppies after 2 to 10 doses. Administration of an 80 mg/kg/day dose of diflunisal to 25-day-old puppies resulted in lower mortality, and did not produce cataracts. In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased mortality and some cataracts, whereas the effects of diflunisal administration at doses up to 140 mg/kg/day were limited to a decrease in average body weight gain.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS, Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see PRECAUTIONS, Renal Effects).
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