Diflunisal

Name: Diflunisal

Why is this medication prescribed?

Diflunisal is used to relieve pain, tenderness, swelling and stiffness caused by osteoarthritis (arthritis caused by a breakdown of the lining of the joints) and rheumatoid arthritis (arthritis caused by swelling of the lining of the joints). Diflunisal is also used to relieve mild to moderate pain from other causes. Diflunisal is in a class of medications called NSAIDs. It works by stopping the body's production of a substance that causes pain, fever, and inflammation.

What special precautions should I follow?

Before taking diflunisal,

  • tell your doctor and pharmacist if you are allergic to diflunisal, aspirin or other NSAIDs such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn), or any other medications. Ask your doctor or pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: acetaminophen (Tylenol); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), captopril, enalapril (Vasotec, in Vaseretic), fosinopril , lisinopril (in Zestoretic), moexipril (Univasc), perindopril (Aceon, in Prestalia), quinapril (Accupril, in Quinaretic), ramipril (Altace), and trandolapril (Mavik, in Tarka); angiotensin II receptor antagonists such as candesartan (Atacand, in Atacand HCT), eprosartan (Teveten), irbesartan (Avapro, in Avalide), losartan (Cozaar, in Hyzaar), olmesartan (Benicar, in Azor, in Benicar HCT, in Tribenzor), telmisartan (Micardis, in Micardis HCT, in Twynsta), and valsartan (in Exforge HCT); antacids; cyclosporine (Gengraf, Neoral, Sandimmune); diuretics ('water pills'); indomethacin (Indocin, Tivorbex); lithium (Lithobid); methotrexate (Otrexup, Rasuvo, Trexall); and sulindac. Your doctor may need to change the dose of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had any of the conditions mentioned in the IMPORTANT WARNING section or asthma, especially if you also have frequent stuffed or runny nose or nasal polyps (swelling of the lining of the nose); heart failure; swelling of the hands, feet, ankles, or lower legs; or liver or kidney disease.
  • tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy, you plan to become pregnant, or you are breastfeeding. If you become pregnant while taking diflunisal, call your doctor.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking diflunisal.
  • call your doctor if you think you may have a virus, such as chicken pox or the flu. Do not take diflunisal if you have a virus, and do not give diflunisal to a child who has a virus.

Is diflunisal safe to take if I'm pregnant or breastfeeding?

Diflunisal is excreted in human milk and has a potential for adverse events to infants.

What Is Diflunisal?

Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID). 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 purposes not listed in this medication guide.

Diflunisal can increase your risk of fatal heart attack or stroke, especially if you use it long term or take high doses, or if you have heart disease. Do not use this medicine just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Diflunisal may also cause stomach or intestinal bleeding, which can be fatal. These conditions can occur without warning while you are using diflunisal, especially in older adults.

Diflunisal can increase your risk of fatal heart attack or stroke, especially if you use it long term or take high doses, or if you have heart disease. Even people without heart disease or risk factors could have a stroke or heart attack while taking this medicine.

Do not use this medicine just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Diflunisal may also cause stomach or intestinal bleeding, which can be fatal. These conditions can occur without warning while you are using diflunisal, especially in older adults.

You should not use diflunisal if you are allergic to it, or if you have ever had an asthma attack or severe allergic reaction after taking aspirin or an NSAID.

To make sure diflunisal is safe for you, tell your doctor if you have:

  • heart disease, high blood pressure, high cholesterol, diabetes, or if you smoke;
  • a history of heart attack, stroke, or blood clot;
  • a history of stomach ulcers or bleeding;
  • asthma;
  • liver or kidney disease; or
  • fluid retention.

Taking diflunisal during the last 3 months of pregnancy may harm the unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using diflunisal.

Diflunisal can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Diflunisal is not approved for use by anyone younger than 12 years old. Ask a doctor before giving this medicine to a child or teenager with a fever, flu symptoms, or chicken pox.

Diflunisal Dosage

Follow all directions on your prescription label. Do not take this medicine in larger amounts or for longer than recommended. Use the lowest dose that is effective in treating your condition.

Do not crush, break, or chew a diflunisal tablet. Swallow it whole.

If you use this medicine long-term, you may need frequent medical tests.

This medicine 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. Keep the bottle tightly closed when not in use.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

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

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

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

Description

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

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

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

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.

Diflunisal Brand Names

Diflunisal may be found in some form under the following brand names:

  • Dolobid

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.

What is diflunisal?

Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID). 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 purposes not listed in this medication guide.

What happens if I overdose?

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

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

Diflunisal Dosage and Administration

General

  • Consider potential benefits and risks of diflunisal therapy as well as alternative therapies before initiating therapy with the drug.1

Administration

Oral Administration

Administer orally.1 75 If GI disturbances occur, administer with meals or milk.1 75

Do not break, crush, or chew diflunisal tablets.1 75 Swallow intact.1 75

Dosage

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.1 Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.1

Exhibits concentration-dependent pharmacokinetics.1 75 Plasma diflunisal concentrations increase more than proportionally with increasing and/or multiple doses; use caution when adjusting doses.1 75

Adults

Pain Oral

Mild to moderate pain: Initially, 1 g, followed by 500 mg every 12 hours.1 75 Some patients may require 500 mg every 8 hours.1 75

Patients with lower dosage requirements (less severe pain, heightened response, low body weight): Initially, 500 mg, followed by 250 mg every 8–12 hours.1

Inflammatory Diseases Osteoarthritis or Rheumatoid Arthritis Oral

500 mg–1 g daily in 2 divided doses.1 75

Prescribing Limits

Adults

Oral

Maximum 1.5 g daily.1 75 b

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.1

Initially, 500 mg, followed by 250 mg every 8–12 hours.1

Stability

Storage

Oral

Tablets, film-coated

<40°C; preferably 15–30°C.34

Commonly used brand name(s)

In the U.S.

  • Dolobid

Available Dosage Forms:

  • Tablet

Therapeutic Class: Analgesic

Pharmacologic Class: NSAID

Chemical Class: Salicylate, Non-Aspirin

How is this medicine (Diflunisal) best taken?

Use diflunisal as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with food to prevent an upset stomach.
  • Swallow tablet whole. Do not chew, break, or crush.

What do I do if I miss a dose?

  • If you take this medicine on a regular basis, take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
  • Many times diflunisal is taken on an as needed basis. Do not take more often than told by the doctor.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Contraindications

Diflunisal tablets are contraindicated in patients with known hypersensitivity to Diflunisal or the excipients (see DESCRIPTION).

Diflunisal tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactic/Anaphylactoid Reactions and PRECAUTIONS, Preexisting Asthma).

Diflunisal tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Pronunciation

(dye FLOO ni sal)

Use Labeled Indications

Osteoarthritis/Rheumatoid arthritis (RA): Treatment of osteoarthritis and RA

Pain, mild to moderate: Treatment of mild to moderate pain

Dosing Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Test Interactions

Falsely elevated increase in serum salicylate levels; may lead to false-positive aldosterone/renin ratio (ARR) (Funder 2016)

Monitoring Parameters

CBC, chemistry profile, occult blood loss, and periodic liver function tests; renal function (urine output, serum BUN and creatinine); signs or symptoms of GI bleeding; blood pressure.

For Healthcare Professionals

Applies to diflunisal: compounding powder, oral tablet

General

The most frequently reported side effects were gastrointestinal in nature and included nausea, vomiting, dyspepsia, gastrointestinal pain, diarrhea, constipation, and flatulence.[Ref]

Gastrointestinal

Common (1% to 10%): Gastrointestinal (GI) pain, dyspepsia, diarrhea, nausea, vomiting, constipation, flatulence
Frequency not reported: Peptic ulcer, GI perforation, GI bleeding, gastritis, hematemesis, melena, ulcerative stomatitis, colitis exacerbated, Crohn's disease exacerbated, eructation, GI perforation[Ref]

Cardiovascular

Frequency not reported: Palpitation, hypertension, cardiac failure, flushing, myocardial infarction[Ref]

Dermatologic

Common (1% to 10%): Rash
Frequency not reported: Pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, angioedema, sweating, dry mucous membranes, stomatitis, photosensitivity[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness, somnolence
Frequency not reported: Lightheadedness, paresthesia, syncope, stroke

Hematologic

Frequency not reported: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia

Hepatic

Frequency not reported: Jaundice, cholestasis, liver function abnormal, hepatitis

Renal

Frequency not reported: Renal impairment, renal failure, interstitial nephritis, nephritic syndrome

Hypersensitivity

Frequency not reported: Hypersensitivity vasculitis, hypersensitivity syndrome[Ref]

Other

Common (1% to 10%): Tinnitus, fatigue
Frequency not reported: Vertigo, asthenia, edema, chest pain, fulminant necrotizing fasciitis, hearing loss[Ref]

Metabolic

Frequency not reported: Anorexia[Ref]

Psychiatric

Common (1% to 10%): Insomnia
Frequency not reported: Nervousness, depression, hallucination, confusion, disorientation[Ref]

Musculoskeletal

Frequency not reported: Muscle cramp[Ref]

Ocular

Frequency not reported: Blurred vision, transient visual disturbance[Ref]

Respiratory

Frequency not reported: Bronchospasm, dyspnea

Genitourinary

Frequency not reported: Dysuria, hematuria, proteinuria[Ref]

Immunologic

Frequency not reported: Acute anaphylaxis[Ref]

Some side effects of diflunisal may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Usual Pediatric Dose for Osteoarthritis

12 years or older: 500 to 1000 mg orally per day in 2 divided doses

Comments:
-Dosage may be increased or decreased based on patient response.
-Not to exceed 1500 mg/day.

Uses: For the treatment of osteoarthritis and rheumatoid arthritis

Diflunisal Breastfeeding Warnings

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Yes Comments: The effects in the nursing infant are unknown.

Milk levels range from 2% to 7% of simultaneous maternal serum levels after 7 days of administration of 125 or 250 mg twice a day. This would represent milk levels ranging from 0.3 to 0.9 mg/L with a dose of 125 mg/day and 0.8 to 2.7 mg/L with a dose of 250 mg/day. A shorter-acting agent with more published information available may be preferred, especially while nursing a newborn or preterm infant.

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