Dolobid (Diflunisal)

DOLOBID®

Frosst

Diflunisal

Analgesic – Anti-inflammatory

Action And Clinical Pharmacology: Diflunisal is a nonsteroidal drug with analgesic, anti-inflammatory and antipyretic properties.

The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known; however, it appears to be a peripherally acting analgesic drug. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandin 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 in part to a decrease of prostaglandins in peripheral tissues.

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 2 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 g/mL (mean±S.D.) were observed following 250 mg doses, 87±17 g/mL were observed following 500 mg and 124 ±11 g/mL following single 1 000 mg doses. However, following administration of 250 mg twice a day, a mean peak level of 56±14 g/mL was observed on day 8, while the mean peak level after 500 mg twice a day for 11 days was 190±33 g/mL. The plasma half-life of diflunisal is 8 to 12 hours. 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.

Indications And Clinical Uses: The relief of mild to moderate pain accompanied by inflammation in conditions such as musculoskeletal trauma, post-dental extraction or post-episiotomy; symptomatic relief of osteoarthritis and rheumatoid arthritis.

Contra-Indications: Patients who are hypersensitive to any component of this product.

Patients in whom acute asthmatic attacks, urticaria, or rhinitis are precipitated by ASA or other nonsteroidal anti-inflammatory drugs. Fatal anaphylactoid reactions have occurred in such individuals.

Active peptic ulcer or any other active inflammatory disease of the gastrointestinal tract.

Manufacturers’ Warnings In Clinical States: Gastrointestinal: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with NSAIDs including diflunisal.

Diflunisal should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physician must weigh the benefits of treatment against the possible hazards.

Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (see Precautions).

Pregnancy: The safety of the drug in pregnancy has not been established, and its use during pregnancy is therefore not recommended.

A dose of 60 mg/kg/day (equivalent to 2 times the maximum human dose) was maternotoxic, embryotoxic, and teratogenic in rabbits. In 3 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 50 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to diflunisal. ASA 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 1 to 8 times the human dose).

In rats at a dose of 1.5 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 ASA, 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.

Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use during the third trimester of pregnancy is not recommended.

Lactation: Diflunisal is excreted in human milk in concentrations of 2 to 7% of those in plasma. Because of the potential for serious adverse reactions in nursing infants a decision should be made whether to initiate nursing or to administer the drug, taking into account the importance of the drug to the mother.

Children: Safety and effectiveness in infants and children have not been established, and use of the drug in children below the age of 12 years is not recommended.

Precautions: ASA has been associated with Reye’s syndrome. Because diflunisal is a derivative of salicylic acid, the possibility of its association with Reye’s syndrome cannot be excluded.

Gastrointestinal: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs diflunisal should be discontinued, an appropriate treatment instituted and patient closely monitored.

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of diflunisal therapy when and if these adverse reactions appear.

When diflunisal was given to normal volunteers at 500 mg twice daily, fecal blood loss was not significantly different from placebo. Diflunisal 1 000 mg twice daily caused a statistically significant increase in fecal blood loss.

Renal: As with other NSAIDs, 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, 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, the elderly, extracellular volume depletion from any cause, congestive heart failure, sepsis, or concomitant use of diuretics or any nephrotoxic drug. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.

Since diflunisal is eliminated primarily by the kidneys, this drug should be used with great caution in patients with impaired renal function and the elderly; a lower daily dosage should be anticipated to avoid excessive drug accumulation, and patients should be carefully monitored. During long-term therapy kidney function should be monitored periodically.

Hepatic: As with other NSAIDs, 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 ALT test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of AST or ALT 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 reaction while on therapy with diflunisal. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with nonsteroidal 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.). diflunisal should be discontinued since liver reactions can be fatal.

During long-term therapy, liver function tests should be monitored periodically. If this drug is to be used in the presence of impaired liver function, it must be done under strict observation.

Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with diflunisal. Therefore, as with many other nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be born in mind. Diflunisal should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.

Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Hematology: As an inhibitor of prostaglandin synthetase, diflunisal has a dose-related effect on platelet function and bleeding time. In normal volunteers, 250 mg twice daily for 8 days had no effect on platelet function, and 500 mg twice daily had a slight effect. At 1 000 mg twice daily, diflunisal inhibited platelet function. In contrast to acetylsalicylic acid these effects of diflunisal were reversible. Bleeding time was not altered by a dose of 250 mg twice daily, but was slightly increased at 500 mg twice daily. At 1 000 mg twice daily, a greater increase occurred, but was not statistically significantly different from the change in the placebo group. Therefore, patients who may be adversely affected should be carefully observed when diflunisal is administered.

Blood dyscrasias associated with the use of NSAIDs are rare, but could have severe consequences.

Infection: In common with other anti-inflammatory drugs, diflunisal may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of diflunisal and other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patients receiving this drug for an extended period of time.

Hypersensitivity Reactions: A potentially life-threatening, apparent hypersensitivity syndrome has been reported. This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings (see Adverse Effects). 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, arthritis, malaise, anorexia, disorientation).

Uricosuric Effect: In normal volunteers, an increase in the renal clearance of uric acid and a decrease in serum uric acid was observed when diflunisal was administered at 500 or 750 mg daily in divided doses. Patients on long-term therapy taking diflunisal at 500 to 1 000 mg daily in divided doses showed a prompt and consistent reduction in mean serum uric acid levels, which were lowered as much as 1.4 mg%. It is not known whether diflunisal interferes with the activity of other uricosuric agents.

Antipyretic Activity: Diflunisal is not recommended for use as an antipyretic agent. In single 250, 500 or 750 mg doses, diflunisal produced measurable but not clinically useful decreases in temperature in patients with fever; however, the possibility that it may mask fever in some patients, particularly with chronic or high doses, should be considered.

Drug Interactions: Nonsteroidal anti-inflammatory drugs: Severe adverse reactions involving the gastrointestinal tract have occurred when dilfunisal is administered concomitantly with other NSAIDs. The following information was obtained from studies in normal volunteers.

ASA: In normal volunteers a small decrease in diflunisal levels was observed when multiple doses of diflunisal and ASA were administered concomitantly.

Indomethacin: The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin. Further, the combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and diflunisal should not be used concomitantly.

Sulindac: The concomitant administration of diflunisal 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 diflunisal 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 diflunisal.

Oral Anticoagulants: In some normal volunteers, the concomitant administration of diflunisal and warfarin or acenocoumarol resulted in prolongation of prothrombin time. This may occur because diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when diflunisal is administered with oral anticoagulants, the prothombin 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 diflunisal and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.

Furosemide: In normal volunteers, the concomitant administration of diflunisal and furosemide had no effect on the diuretic activity of furosemide. Diflunisal decreased the hyperuricemic effect of furosemide.

Hydrochlorothiazide: In normal volunteers, concomitant administration of diflunisal and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. Diflunisal decreased the hyperuricemic effect of hydrochlorothiazide.

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.

Coadministration of aluminium hydroxide suspension significantly decreases absorption of diflunisal by approximately 40%.

Methotrexate: Caution should be used if diflunisal is administered concomitantly with methotrexate. NSAIDs have been reported to decrease the tubular secretion of methotrexate and potentiate the toxicity.

Lithium: Concurrent use of NSAIDs with lithium has been reported to increase steady-state plasma lithium concentration. It is recommended to monitor lithium plasma concentration during and following concurrent use.

Acetaminophen: Concomitant administration of diflunisal and acetaminophen to normal volunteers resulted in significantly increased (50%) 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 and acetaminophen should be used cautiously, with careful monitoring of patients.

Adverse Reactions: The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly.

The adverse reactions (see Table I), listed by body system, have been observed in controlled clinical trials or since the drug was marketed.

Other reactions have been reported in clinical trials or since the drug was marketed abroad, 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.

Miscellaneous: chest pain, muscle cramps.

Renal: nephrotic syndrome.

Symptoms And Treatment Of Overdose: Symptoms: 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 g without the presence of other drugs. Death has been reported from a mixed drug overdose which included 7.5 g of diflunisal. A dose that is usually fatal has not yet been identified.

Treatment: 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.

Dosage And Administration: Diflunisal has slow onset and long duration of action. Diflunisal produces significant analgesia in one hour and maximum analgesia in 2 to 4 hours. Analgesic effect lasts 8 to 12 hours. These characteristics should be considered when prescribing this drug.

Mild to moderate pain: 1 000 mg initially, followed by 500 mg every 12 hours is recommended for most patients.

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 12 hours.

For osteoarthritis and rheumatoid arthritis, the dosage range is 500 mg to 1 000 mg daily in 2 divided doses according to patient response.

Maintenance doses higher than 1 000 mg a day are not recommended.

Diflunisal may be administered with water, milk or meals. Tablets should be swallowed whole, not crushed or chewed.

Availability And Storage: Each orange-colored, capsule-shaped, film-coated tablet, coded DOLOBID on one side, contains: diflunisal 500 mg. Nonmedicinal ingredients: cellulose, FD&C Yellow #6 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, starch, talc and titanium dioxide. Gluten-, lactose- and tartrazine-free. Bottles of 60. (Shown in Product Recognition Section)

DOLOBID® Frosst Diflunisal Analgesic – Anti-inflammatory

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