Dolobid (Diflunisal)
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Dolobid (Diflunisal)

DOLOBID®
(diflunisal) Tablets

Cardiovascular Risk

  • NSAIDS may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS.)
  • DOLOBID (diflunisal) is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

  • NSAIDS cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.)

DRUG DESCRIPTION

Diflunisal is 2', 4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its empirical formula is C13H8F2O3 and its structural formula is:

DOLOBID® (DIFLUNISAL) Structural Formula Illustration

Diflunisal has a molecular weight of 250.20. It is a stable, white, crystalline compound with a melting point of 211-213°C. It is practically insoluble in water at neutral or acidic pH. Because it is an organic acid, it dissolves readily in dilute alkali to give a moderately stable solution at room temperature. It is soluble in most organic solvents including ethanol, methanol, and acetone.

DOLOBID* (Diflunisal) is available in 250 and 500 mg tablets for oral administration. Tablets DOLOBID (diflunisal) contain the following inactive ingredients: cellulose, FD&C Yellow 6, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, starch, talc, and titanium dioxide.

* Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1988, 2005 MERCK & CO., Inc. All rights reserved

What are the possible side effects of diflunisal (Dolobid)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking diflunisal and call your doctor at once if you have any of these serious side effects:

  • chest pain, slurred speech, problems with vision or balance, and feeling weak or short of breath;
  • bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
  • fever, chills, body aches, flu symptoms;
  • pale or yellowed skin, dark colored urine,...

Read All Potential Side Effects and See Pictures of Dolobid »

What are the precautions when taking diflunisal (Dolobid)?

Before taking diflunisal, tell your doctor or pharmacist if you are allergic to it; or to aspirin or other salicylates (e.g., choline salicylate), or other NSAIDs (e.g., ibuprofen, naproxen, celecoxib); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease, aspirin-sensitive asthma (a history of worsening breathing with runny/stuffy nose after taking aspirin or other NSAIDs), recent heart bypass surgery (CABG).

Before using this medication, tell your doctor or pharmacist your...

Read All Potential Precautions of Dolobid »

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Carefully consider the potential benefits and risks of DOLOBID (diflunisal) and other treatment options before deciding to use DOLOBID (diflunisal) . Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

DOLOBID (diflunisal) is 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 DOLOBID (diflunisal) and other treatment options before deciding to use DOLOBID (diflunisal) . 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 DOLOBID (diflunisal) , the dose and frequency should be adjusted to suit an individual patient's needs.

Concentration-dependent pharmacokinetics prevail when DOLOBID (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 8-12 hours.

For osteoarthritis and rheumatoid arthritis, the suggested dosage range is 500 mg to 1000 mg daily in two divided doses. The dosage of DOLOBID (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.

HOW SUPPLIED

Tablets DOLOBID (diflunisal) are capsule-shaped, film-coated tablets supplied as follows:

No. 3390 250 mg peach colored, coded DOLOBID (diflunisal) on one side and MSD 675 on the other.

NDC 0006-0675-61 unit of use bottles of 60
(6505-01-164-0501, 250 mg 60's).

No. 3392 500 mg orange colored, coded DOLOBID (diflunisal) on one side and MSD 697 on the other.

NDC 0006-0697-61 unit of use bottles of 60
(6505-01-144-9724, 500 mg 60's).

Distributed by: MERCK & Co. Inc, Whitehouse Station, NJ 08889, USA, Issued January 2007. FDA revision date: 3/16/2007

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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 DOLOBID (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 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 DOLOBID (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 WARNINGS, Hypersensitivity Syndrome).

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 α-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 DOLOBID (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 DOLOBID (diflunisal) .

**Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk.

Read the Dolobid (diflunisal) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

ACE-Inhibitors and Angiotensin II Antagonists

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 co-administration 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 DOLOBID (diflunisal) and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of DOLOBID (diflunisal) . Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of DOLOBID (diflunisal) and acetaminophen should be used cautiously, with careful monitoring of patients. Concomitant administration of DOLOBID (diflunisal) 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 (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 DOLOBID (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 DOLOBID (diflunisal) is administered with aspirin, its protein binding is reduced, although the clearance of free DOLOBID (diflunisal) is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diflunisal 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 DOLOBID (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 post marketing observations, have shown that DOLOBID (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 DOLOBID (diflunisal) and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. DOLOBID (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 clearance and significantly increased the plasma levels of indomethacin. In some patients the combined use of indomethacin and DOLOBID (diflunisal) has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and DOLOBID (diflunisal) should not be used concomitantly.

The concomitant use of DOLOBID (diflunisal) 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.

Sulindac: The concomitant administration of DOLOBID (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 DOLOBID (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 DOLOBID (diflunisal) .

Oral Anticoagulants

In some normal volunteers, the concomitant administration of DOLOBID (diflunisal) 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 (diflunisal) 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. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Tolbutamide

In diabetic patients receiving DOLOBID (diflunisal) and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.

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.

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see GI WARNINGS).

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 (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including DOLOBID (diflunisal) , can lead to onset of new hypertension or worsening of pre-existing 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 DOLOBID (diflunisal) , 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.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. DOLOBID (diflunisal) should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including DOLOBID (diflunisal) , can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of DOLOBID (diflunisal) in patients with advanced renal disease. Therefore, treatment with DOLOBID (diflunisal) is not recommended in these patients with advanced renal disease. If DOLOBID (diflunisal) therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactic/Anaphylactoid Reactions

As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to DOLOBID (diflunisal) . DOLOBID (diflunisal) should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including DOLOBID (diflunisal) , can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

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 (diflunisal) should be discontinued.

Pregnancy

In late pregnancy, as with other NSAIDs, DOLOBID (diflunisal) should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

DOLOBID (diflunisal) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of DOLOBID (diflunisal) in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including DOLOBID (diflunisal) . These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

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 a more severe hepatic reaction while on therapy with DOLOBID (diflunisal) . If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), DOLOBID (diflunisal) should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including DOLOBID (diflunisal) . This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including DOLOBID (diflunisal) , should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving DOLOBID (diflunisal) who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, DOLOBID (diflunisal) should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Ocular Effects

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 (diflunisal) have ophthalmologic studies.

Reye's Syndrome

Acetylsalicylic acid 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.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

  1. DOLOBID (diflunisal) , like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR EFFECTS).
  2. DOLOBID (diflunisal) , like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
  3. DOLOBID (diflunisal) , like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
  4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
  5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
  6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
  7. In late pregnancy, as with other NSAIDs, DOLOBID (diflunisal) should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, DOLOBID (diflunisal) should be discontinued.

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

Teratogenic Effects. 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). Animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies with diflunisal in pregnant women. DOLOBID (diflunisal) should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

The known effects of drugs of this class on the human fetus during the third trimester 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.

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.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of DOLOBID (diflunisal) on labor and delivery in pregnant women are unknown.

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 (diflunisal) , 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 (diflunisal) in pediatric patients below the age of 12 have not been established. Use of DOLOBID (diflunisal) in pediatric patients below the age of 12 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, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).

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 WARNINGS, Renal Effects).

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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 DOLOBID (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 DOLOBID (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 LD50 of the drug is 500 mg/kg and 826 mg/kg in female mice and female rats respectively.

CONTRAINDICATIONS

DOLOBID (diflunisal) is contraindicated in patients with known hypersensitivity to diflunisal or the excipients (see DESCRIPTION).

DOLOBID (diflunisal) 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/anaphylactoid reactions to NSAIDS have been reported in such patients (see WARNINGS - Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS - Preexisting asthma).

DOLOBID (diflunisal) is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Action

DOLOBID (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 0-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

DOLOBID (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 2-7% 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 DOLOBID (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 μg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 μg/mL were observed following 500 mg and 124 ± 11 μg/mL following single 1000 mg doses. However, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 μg/mL was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 μg/mL. In contrast to salicylic acid which has a plasma half-life of 2½ 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, under normal or acidotic conditions are transported into the cerebrospinal fluid (CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of diflunisal was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF ratio of 5:1.

Mild to Moderate Pain

DOLOBID (diflunisal) is a peripherally-acting analgesic agent with a long duration of action. DOLOBID (diflunisal) produces significant analgesia within 1 hour and maximum analgesia within 2 to 3 hours.

Consistent with its long half-life, clinical effects of DOLOBID (diflunisal) mirror its pharmacokinetic behavior, which is the basis for recommending a loading dose when instituting therapy. Patients treated with DOLOBID (diflunisal) , on the first dose, tend to have a slower onset of pain relief when compared with drugs achieving comparable peak effects. However, DOLOBID (diflunisal) produces longer-lasting responses than the comparative agents.

Comparative single dose clinical studies have established the analgesic efficacy of DOLOBID (diflunisal) at various dose levels relative to other analgesics. Analgesic effect measurements were derived from hourly evaluations by patients during eight and twelve-hour postdosing observation periods. The following information may serve as a guide for prescribing DOLOBID (diflunisal) .

DOLOBID (diflunisal) 500 mg was comparable in analgesic efficacy to aspirin 650 mg, acetaminophen 600 mg or 650 mg, and acetaminophen 650 mg with propoxyphene napsylate 100 mg. Patients treated with DOLOBID (diflunisal) had longer lasting responses than the patients treated with the comparative analgesics.

DOLOBID (diflunisal) 1000 mg was comparable in analgesic efficacy to acetaminophen 600 mg with codeine 60 mg. Patients treated with DOLOBID (diflunisal) had longer lasting responses than the patients who received acetaminophen with codeine.

A loading dose of 1000 mg provides faster onset of pain relief, shorter time to peak analgesic effect, and greater peak analgesic effect than an initial 500 mg dose.

In contrast to the comparative analgesics, a significantly greater proportion of patients treated with DOLOBID (diflunisal) did not remedicate and continued to have a good analgesic effect eight to twelve hours after dosing. Seventy-five percent (75%) of patients treated with DOLOBID (diflunisal) continued to have a good analgesic response at four hours. When patients having a good analgesic response at four hours were followed, 78% of these patients continued to have a good analgesic response at eight hours and 64% at twelve hours.

Chronic Anti-inflammatory Therapy in Osteoarthritis and Rheumatoid Arthritis

In the controlled, double-blind clinical trials in which DOLOBID (diflunisal) (500 mg to 1000 mg a day) was compared with anti-inflammatory doses of aspirin (2-4 grams a day), patients treated with DOLOBID (diflunisal) had a significantly lower incidence of tinnitus and of adverse effects involving the gastrointestinal system than patients treated with aspirin. (See also Effect on Fecal Blood Loss).

Osteoarthritis

The effectiveness of DOLOBID (diflunisal) for the treatment of osteoarthritis was studied in patients with osteoarthritis of the hip and/or knee. The activity of DOLOBID (diflunisal) was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, DOLOBID (diflunisal) , 500 or 750 mg daily, was shown to be comparable in effectiveness to aspirin, 2000 or 3000 mg daily. In open-label extensions of this study to 24 or 48 weeks, DOLOBID (diflunisal) continued to show similar effectiveness and generally was well tolerated.

Rheumatoid Arthritis

In controlled clinical trials, the effectiveness of DOLOBID (diflunisal) was established for both acute exacerbations and long-term management of rheumatoid arthritis. The activity of DOLOBID (diflunisal) was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, DOLOBID (diflunisal) 500 or 750 mg daily was comparable in effectiveness to aspirin 2600 or 3900 mg daily. In open-label extensions of this study to 52 weeks, DOLOBID (diflunisal) continued to be effective and was generally well tolerated.

DOLOBID (diflunisal) 500, 750, or 1000 mg daily was compared with aspirin 2000, 3000, or 4000 mg daily in a multicenter study of 8 weeks' duration in which dosages were adjusted according to patient response. In this study, DOLOBID (diflunisal) was comparable in efficacy to aspirin.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient needs, DOLOBID (diflunisal) 500 or 750 mg daily and ibuprofen 1600 or 2400 mg daily were comparable in effectiveness and tolerability.

In a double-blind multicenter study of 12 weeks' duration, DOLOBID (diflunisal) 750 mg daily was comparable in efficacy to naproxen 750 mg daily. The incidence of gastrointestinal adverse effects and tinnitus was comparable for both drugs. This study was extended to 48 weeks on an open-label basis. DOLOBID (diflunisal) continued to be effective and generally well tolerated.

In patients with rheumatoid arthritis, DOLOBID (diflunisal) and gold salts may be used in combination at their usual dosage levels. In clinical studies, DOLOBID (diflunisal) added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease.

Antipyretic Activity

DOLOBID (diflunisal) is not recommended for use as an antipyretic agent. In single 250 mg, 500 mg, or 750 mg doses, DOLOBID (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.

Uricosuric Effect

In normal volunteers, an increase in the renal clearance of uric acid and a decrease in serum uric acid was observed when DOLOBID (diflunisal) was administered at 500 mg or 750 mg daily in divided doses. Patients on long-term therapy taking DOLOBID (diflunisal) at 500 mg to 1000 mg daily in divided doses showed a prompt and consistent reduction across studies in mean serum uric acid levels, which were lowered as much as 1.4 mg%. It is not known whether DOLOBID (diflunisal) interferes with the activity of other uricosuric agents.

Effect on Platelet Function

As an inhibitor of prostaglandin synthetase, DOLOBID (diflunisal) has a dose-related effect on platelet function and bleeding time. In normal volunteers, 250 mg b.i.d. for 8 days had no effect on platelet function, and 500 mg b.i.d., the usual recommended dose, had a slight effect. At 1000 mg b.i.d., which exceeds the maximum recommended dosage, however, DOLOBID (diflunisal) inhibited platelet function. In contrast to aspirin, these effects of DOLOBID (diflunisal) were reversible, because of the absence of the chemically labile and biologically reactive 0-acetyl group at the carbon 4 position. Bleeding time was not altered by a dose of 250 mg b.i.d., and was only slightly increased at 500 mg b.i.d. At 1000 mg b.i.d., a greater increase occurred, but was not statistically significantly different from the change in the placebo group.

Effect on Fecal Blood Loss

When DOLOBID (diflunisal) was given to normal volunteers at the usual recommended dose of 500 mg twice daily, fecal blood loss was not significantly different from placebo. Aspirin at 1000 mg four times daily produced the expected increase in fecal blood loss. DOLOBID (diflunisal) at 1000 mg twice daily (NOTE: exceeds the recommended dosage) caused a statistically significant increase in fecal blood loss, but this increase was only one-half as large as that associated with aspirin 1300 mg twice daily.

Effect on Blood Glucose

DOLOBID (diflunisal) did not affect fasting blood sugar in diabetic patients who were receiving tolbutamide or placebo.

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.This chance increases:

  • with longer use of NSAID medicines
  • in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment.

Ulcers and bleeding:

  • can happen without warning symptoms
  • may cause death

The chance of a person getting an ulcer or bleeding increases with:

  • taking medicines called “corticosteroids” and “anticoagulants”
  • longer use
  • smoking
  • drinking alcohol
  • older age
  • having poor health

NSAID medicines should only be used:

  • exactly as prescribed
  • at the lowest dose possible for your treatment
  • for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

  • different types of arthritis
  • menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine:

  • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
  • for pain right before or after heart bypass surgery

Tell your healthcare provider:

  • about all of your medical conditions.
  • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
  • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
  • if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include:
  • heart attack
  • stroke
  • high blood pressure
  • heart failure from body swelling (fluid retention)
  • kidney problems including kidney failure
  • bleeding and ulcers in the stomach and intestine
  • low red blood cells (anemia)
  • life-threatening skin reactions
  • life-threatening allergic reactions
  • liver problems including liver failure
  • asthma attacks in people who have asthma
Other side effects include:
  • stomach pain
  • constipation
  • diarrhea
  • gas
  • heartburn
  • nausea
  • vomiting
  • dizziness

Get emergency help right away if you have any of the following symptoms:

  • shortness of breath or trouble breathing
  • chest pain
  • weakness in one part or side of your body
  • slurred speech
  • swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

  • nausea
  • more tired or weaker than usual
  • itching
  • your skin or eyes look yellow
  • stomach pain
  • flu-like symptoms
  • vomit blood
  • there is blood in your bowel movement or it is black and sticky like tar
  • unusual weight gain
  • skin rash or blisters with fever
  • swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

  • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
  • Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic Name Tradename
Celecoxib Celebrex
Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal Dolobid
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Flurbiprofen Ansaid
Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone)
Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Ketoprofen Oruvail
Ketorolac Toradol
Mefenamic Acid Ponstel
Meloxicam Mobic
Nabumetone Relafen
Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin Daypro
Piroxicam Feldene
Sulindac Clinoril
Tolmetin Tolectin, Tolectin DS, Tolectin 600

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.This chance increases:

  • with longer use of NSAID medicines
  • in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment.

Ulcers and bleeding:

  • can happen without warning symptoms
  • may cause death

The chance of a person getting an ulcer or bleeding increases with:

  • taking medicines called “corticosteroids” and “anticoagulants”
  • longer use
  • smoking
  • drinking alcohol
  • older age
  • having poor health

NSAID medicines should only be used:

  • exactly as prescribed
  • at the lowest dose possible for your treatment
  • for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

  • different types of arthritis
  • menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine:

  • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
  • for pain right before or after heart bypass surgery

Tell your healthcare provider:

  • about all of your medical conditions.
  • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
  • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
  • if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include:
  • heart attack
  • stroke
  • high blood pressure
  • heart failure from body swelling (fluid retention)
  • kidney problems including kidney failure
  • bleeding and ulcers in the stomach and intestine
  • low red blood cells (anemia)
  • life-threatening skin reactions
  • life-threatening allergic reactions
  • liver problems including liver failure
  • asthma attacks in people who have asthma
Other side effects include:
  • stomach pain
  • constipation
  • diarrhea
  • gas
  • heartburn
  • nausea
  • vomiting
  • dizziness

Get emergency help right away if you have any of the following symptoms:

  • shortness of breath or trouble breathing
  • chest pain
  • weakness in one part or side of your body
  • slurred speech
  • swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

  • nausea
  • more tired or weaker than usual
  • itching
  • your skin or eyes look yellow
  • stomach pain
  • flu-like symptoms
  • vomit blood
  • there is blood in your bowel movement or it is black and sticky like tar
  • unusual weight gain
  • skin rash or blisters with fever
  • swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

  • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
  • Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic Name Tradename
Celecoxib Celebrex
Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal Dolobid
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Flurbiprofen Ansaid
Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone)
Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Ketoprofen Oruvail
Ketorolac Toradol
Mefenamic Acid Ponstel
Meloxicam Mobic
Nabumetone Relafen
Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin Daypro
Piroxicam Feldene
Sulindac Clinoril
Tolmetin Tolectin, Tolectin DS, Tolectin 600

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Dolobid Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

DIFLUNISAL - ORAL

(dye-FLEW-niss-all)

COMMON BRAND NAME(S): Dolobid

WARNING: This drug may infrequently cause serious (rarely fatal) bleeding from the stomach or intestines. This side effect can occur without warning at any time during treatment with diflunisal. The elderly are at increased risk for serious stomach/intestinal bleeding.

Drugs related to diflunisal have rarely caused blood clots to form, resulting in serious (possibly fatal) heart attacks and strokes. This medication might also rarely cause similar problems. The risk of these serious side effects may increase if you have heart disease and with longer use of this medication. Talk to your doctor or pharmacist about the benefits and risks of treatment, as well as other possible medication choices.

Stop taking diflunisal and seek immediate medical attention if you notice any of the following rare but very serious side effects: black stools, persistent stomach/abdominal pain, vomit that looks like coffee grounds, chest pain, shortness of breath, weakness on one side of the body, sudden vision changes, slurred speech.

This medication should not be used right before or after heart bypass surgery.

USES: Diflunisal is used to relieve mild to moderate pain from various conditions. It also reduces pain, swelling, and joint stiffness caused by arthritis. Reducing these symptoms helps you do more of your normal daily activities. This medication is known as a nonsteroidal anti-inflammatory drug (NSAID).

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using diflunisal and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth with a full glass of water (8 ounces or 240 milliliters) unless your doctor directs you otherwise. Do not lie down for at least 10 minutes after taking this drug. Take this medication with food/milk or right after meals to prevent stomach upset.

Swallow this medication whole. Do not crush or chew the tablets. Doing so may increase side effects.

Dosage is based on your medical condition and response to therapy. Do not take more than 1,500 milligrams per day. To minimize side effect risks (e.g., stomach bleeding), use this medication at the lowest effective dose for the shortest possible length of time. Do not increase your dose or take it more often than prescribed. For ongoing conditions such as arthritis, continue taking it as directed by your doctor. Discuss the risks and benefits with your doctor or pharmacist.

In certain conditions (e.g., arthritis), it may take up to 2 weeks of regular use before the full benefits of this drug take effect.

If you are taking this drug on an "as needed" basis (not on a regular schedule), remember that pain medications work best if they are used as the first signs of pain occur. If you wait until the pain has significantly worsened, the medicine may not work as well.

Inform your doctor if your condition worsens.

Disclaimer

Dolobid Consumer (continued)

SIDE EFFECTS: See also Warning section.

Upset stomach, heartburn, headache, tiredness, drowsiness, or dizziness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: stomach pain, swelling of the hands/feet, sudden/unexplained weight gain, vision changes, hearing changes (e.g., ringing in the ears), mental/mood changes (e.g., confusion, hallucinations), fast/pounding heartbeat, persistent/severe headache, fainting, difficult/painful swallowing.

Tell your doctor immediately if any of these rare but very serious side effects occur: change in the amount of urine, easy bruising/bleeding, signs of infection (e.g., fever, persistent sore throat), unexplained stiff neck.

This drug may rarely cause serious (possibly fatal) liver disease. If you notice any of the following rare but very serious side effects, stop taking diflunisal and tell your doctor immediately: yellowing eyes/skin, dark urine, unusual/extreme tiredness, severe stomach/abdominal pain, persistent nausea/vomiting.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Dolobid (diflunisal) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking diflunisal, tell your doctor or pharmacist if you are allergic to it; or to aspirin or other salicylates (e.g., choline salicylate), or other NSAIDs (e.g., ibuprofen, naproxen, celecoxib); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease, aspirin-sensitive asthma (a history of worsening breathing with runny/stuffy nose after taking aspirin or other NSAIDs), recent heart bypass surgery (CABG).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, poorly controlled diabetes, stomach/intestine/esophagus problems (e.g., bleeding, ulcers), heart disease (e.g., congestive heart failure, history of heart attack), stroke, high blood pressure, swelling (edema, fluid retention), a severe loss of body water (dehydration), blood disorders (e.g., anemia), bleeding or clotting problems, asthma, growths in the nose (nasal polyps).

Before having surgery, tell your doctor or dentist that you are using this medication.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely.

This medicine may cause stomach bleeding. Daily use of alcohol and tobacco may increase your risk for stomach bleeding, especially when combined with this medicine. Limit alcohol and stop smoking. Consult your doctor or pharmacist for more information.

The elderly may be more sensitive to the side effects of this drug, especially stomach/intestinal bleeding and kidney effects.

This medication is not recommended for use in children under 12 years of age. In addition, since diflunisal is related to aspirin, children and teenagers should not take diflunisal if they have chickenpox, influenza, or any undiagnosed illness without first consulting a doctor about Reye's syndrome, a rare but serious illness.

This medication should be used only when clearly needed during the first 6 months of pregnancy. It is not recommended for use during the last 3 months of pregnancy due to possible harm to the unborn baby and interference with normal labor/delivery. Discuss the risks and benefits with your doctor.

This drug passes into breast milk. Therefore, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Dolobid Consumer (continued)

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: high doses of aspirin and related drugs (salicylates), cidofovir, live influenza vaccine, other NSAIDs (e.g., indomethacin, ketorolac).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting diflunisal.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: acetaminophen, antacids (regular use), anti-platelet drugs (e.g., cilostazol, clopidogrel), oral bisphosphonates (e.g., alendronate), "blood thinners" (e.g., enoxaparin, heparin, warfarin), corticosteroids (e.g., prednisone), cyclosporine, digoxin, high blood pressure drugs (including ACE inhibitors such as captopril, angiotensin receptor blockers such as losartan, and beta-blockers such as metoprolol), lithium, methotrexate, pemetrexed, probenecid, SSRI antidepressants (e.g., fluoxetine, sertraline), "water pills" (diuretics such as furosemide, hydrochlorothiazide, triamterene).

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (acetaminophen, NSAIDs such as aspirin, ibuprofen or naproxen) which if taken together with diflunisal may increase your risk for side effects. Low-dose aspirin, as prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually at dosages of 81-325 milligrams per day), should be continued. Consult your doctor or pharmacist for more details.

This medication can affect the results of certain lab tests. Make sure laboratory personnel and your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include severe stomach pain, vomit that looks like coffee grounds, extreme drowsiness, fast breathing, confusion, loss of consciousness.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count, liver and kidney function tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Non-drug treatment for arthritis that is approved by your doctor (e.g., weight loss if needed, strengthening and conditioning exercises) may help improve your flexibility, range of motion, and joint function. Consult your doctor for specific instructions.

MISSED DOSE: If you are prescribed this drug on a regular schedule (not just "as needed") and you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Dolobid Patient Information Including Side Effects

Brand Names: Dolobid

Generic Name: diflunisal (Pronunciation: dye FLOO ni sal)

What is diflunisal (Dolobid)?

Diflunisal is in a group of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). It works by reducing hormones that cause inflammation and pain in the body.

Diflunisal is used to treat mild to moderate pain, osteoarthritis, or rheumatoid arthritis.

Diflunisal may also be used for other purposes not listed in this medication guide.

Diflunisal 250 mg-END

oblong, orange, imprinted with WPPh, 195

Diflunisal 500 mg-END

oblong, orange, imprinted with 196, WPPh

Diflunisal 500 mg-TEV

oblong, blue, imprinted with 755/93

Dolobid 500 mg

oblong, orange, imprinted with DOLOBID, MSD697

What are the possible side effects of diflunisal (Dolobid)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking diflunisal and call your doctor at once if you have any of these serious side effects:

  • chest pain, slurred speech, problems with vision or balance, and feeling weak or short of breath;
  • bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
  • fever, chills, body aches, flu symptoms;
  • pale or yellowed skin, dark colored urine, confusion;
  • swelling or rapid weight gain;
  • urinating less than usual or not at all;
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • skin rash, bruising, severe tingling, numbness, pain, muscle weakness;
  • fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; or
  • the first sign of any skin rash, no matter how mild.

Less serious side effects may include:

  • mild nausea, stomach pain, vomiting, upset stomach;
  • diarrhea, constipation, gas;
  • dizziness, drowsiness, headache, tired feeling;
  • sleep problems (insomnia); or
  • ringing in your ears.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Dolobid (diflunisal) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about diflunisal (Dolobid)?

This medicine may cause life-threatening heart or circulation problems such as heart attack or stroke, especially if you use it long term. Do not use diflunisal just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Get emergency medical help if you have chest pain, weakness, shortness of breath, slurred speech, or problems with vision or balance.

This medicine may also cause serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and can occur without warning while you are taking diflunisal, especially in older adults.

Call your doctor at once if you have symptoms of stomach bleeding such as black, bloody, or tarry stools, or coughing up blood or vomit that looks like coffee grounds.

If you drink more than three alcoholic beverages per day, do not take this medication without your doctor's advice.

Side Effects Centers

Dolobid Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking diflunisal (Dolobid)?

This medicine may cause life-threatening heart or circulation problems such as heart attack or stroke, especially if you use it long term.

This medicine may also cause serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and can occur without warning while you are taking diflunisal, especially in older adults.

Do not use this medication if you are allergic to diflunisal, or if you have a history of allergic reaction to aspirin or other NSAIDs. Do not use diflunisal just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

If you have any of these other conditions, you may need a diflunisal dose adjustment or special tests:

  • a history of heart attack, stroke, or blood clot;
  • heart disease, congestive heart failure, high blood pressure;
  • a history of stomach ulcers or bleeding;
  • liver or kidney disease;
  • asthma;
  • polyps in your nose;
  • a bleeding or blood clotting disorder; or
  • if you smoke.

FDA pregnancy category C. It is not known whether diflunisal is harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Taking diflunisal during the last 3 months of pregnancy may result in birth defects. Do not take diflunisal during pregnancy unless your doctor has told you to.

Diflunisal can pass into breast milk and could cause harm to a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give this medicine to a child younger than 12 years old without the advice of a doctor.

How should I take diflunisal (Dolobid)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Diflunisal is usually taken every 8 to 12 hours. Follow your doctor's instructions.

If you use this medication long-term, your blood may need to be tested often. Your blood pressure may also need to be checked. Visit your doctor regularly.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using diflunisal.

Store at room temperature away from moisture and heat.

Side Effects Centers

Dolobid Patient Information including If I Miss a Dose

What happens if I miss a dose (Dolobid)?

Since diflunisal is sometimes taken as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Dolobid)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, diarrhea, sweating, gasping, fast heart rate, extreme drowsiness, and fainting.

What should I avoid while taking diflunisal (Dolobid)?

Avoid drinking alcohol. It may increase your risk of stomach bleeding.

Avoid taking aspirin or other NSAIDs without your doctor's advice. This includes ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn), indomethacin, piroxicam (Feldene), nabumetone (Relafen), etodolac (Lodine), sulindac (Clinoril), and others.

Ask a doctor or pharmacist before using any over-the-counter cold, allergy, or pain medicine. Many combination medicines contain aspirin or other medicines similar to diflunisal (such as ibuprofen, ketoprofen, or naproxen). Taking certain products together can cause you to get too much of this type of medication. Check the label to see if a medicine contains aspirin, ibuprofen, ketoprofen, or naproxen.

Avoid exposure to sunlight or tanning beds. Diflunisal can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 15 or higher) when you are outdoors.

Avoid using antacids without your doctor's advice. Use only the type of antacid your doctor recommends. Some antacids can make it harder for your body to absorb diflunisal.

What other drugs will affect diflunisal (Dolobid)?

Tell your doctor if you are taking an antidepressant such as citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, Symbyax), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), or venlafaxine (Effexor). Taking any of these drugs with diflunisal may cause you to bruise or bleed easily.

Before taking diflunisal, tell your doctor if you are using any of the following drugs:

  • acetaminophen (Tylenol);
  • a blood thinner such as warfarin (Coumadin);
  • cyclosporine (Gengraf, Neoral, Sandimmune);
  • a diuretic (water pill);
  • lithium (Eskalith, Lithobid);
  • methotrexate (Rheumatrex, Trexall); or
  • heart or blood pressure medication such as benazepril (Lotensin), enalapril (Vasotec), lisinopril (Prinivil, Zestril), quinapril (Accupril), ramipril (Altace), and others.

This list is not complete and other drugs may interact with diflunisal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about diflunisal.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 5.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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