Diflunisal

Unless your doctor tells you otherwise, continue your normal diet.

Diflunisal may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• vomiting
• diarrhea
• constipation
• gas
• headache
• dizziness
• ringing in the ears
• problems with vision

Some side effects can be serious. If you experience any of the following symptoms or those mentioned in the IMPORTANT WARNING section, call your doctor immediately. Do not take any more diflunisal until you speak to your doctor.

• upset stomach
• shortness of breath or difficulty breathing
• swelling of the abdomen, feet, ankles, or lower legs
• excessive tiredness
• unusual bleeding or bruising
• itching
• lack of energy
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• flu-like symptoms
• rash
• blisters
• fever or chills
• pale skin
• fast heartbeat
• easy bruising or bleeding
• muscle or joint pain
• unexplained weight gain
• back pain
• cloudy, discolored, or bloody urine
• difficult or painful urination
• frequent urination, especially at night
• swelling of the face, throat, tongue, lips, eyes, or hands
• hoarseness
• difficulty swallowing

Diflunisal may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Dolobid (This brand is no longer available in the U.S.)

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

Avoid taking aspirin or other NSAIDs while you are taking diflunisal.

Ask a doctor or pharmacist before using any cold, allergy, or pain medication. Many medicines available over the counter contain aspirin or other medicines similar to diflunisal. 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.

Ask your doctor before using an antacid, and use only the type your doctor recommends. Some antacids can make it harder for your body to absorb diflunisal.

Ask your doctor before using diflunisal if you take an antidepressant such as citalopram, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, or vilazodone. Taking any of these medicines with an NSAID may cause you to bruise or bleed easily.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• acetaminophen (Tylenol);
• cyclosporine;
• lithium;
• methotrexate;
• a blood thinner (warfarin, Coumadin, Jantoven);
• heart or blood pressure medication, including a diuretic or "water pill"; or
• steroid medicine (such as prednisone).

This list is not complete. Other drugs may interact with diflunisal, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

>10%

Increased liver function test (up to 15%)

1-10%

Body fluid retention

Rash

Abdominal pain

Constipation

Diarrhea

Flatulence

Indigestion

Nausea

Dizziness

Headache

Insomnia

Tinnitus

<1%

Edema (<1%)

Hypertension

Myocardial infarction

Vasculitis (<1%)

Erythema multiforme (<1%)

Scaling eczema, Stevens-Johnson syndrome (<1%)

Toxic epidermal necrolysis (<1%)

Gastrointestinal hemorrhage (<1%)

Gastrointestinal perforation (<1%)

Inflammatory disorder of digestive tract

Agranulocytosis (<1%)

Anemia (<1%)

Thrombocytopenia (<1%)

Hepatitis (<1%)

Jaundice (<1%)

Anaphylactoid reaction (<1%)

Immune hypersensitivity reaction (<1%)

Cerebrovascular accident

Impaired renal function disorder (<1%)

Interstitial nephritis (<1%)

Renal failure (<1%)

Bronchospasm

Pregnancy Category: C (avoid in late pregnancy; may cause premature closure of ductus arteriosus)

The Quebec Pregnancy Registry identified 4705 women who had spontaneous abortions by 20 weeks' gestation; each case was matched to 10 control subjects (n=47,050) who had not had spontaneous abortions; exposure to nonaspirin NSAIDs during pregnancy was documented in approximately 7.5% of cases of spontaneous abortions and in approximately 2.6% of controls. (CMAJ, September 6, 2011; DOI:10.1503/cmaj.110454)

Lactation: enters breast milk/not recommended

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Inhibits cyclooxygenase-1 (COX-1) & -2 (COX-2), thereby inhibiting prostaglandin synthesis

Pharmcokinetics

Bioavailability: 80-100%

Peak Plasma Time: within 2-3 hr

Protein Bound: at least 98-99%

Vd: 0.11 L/kg

Metabolism: Liver (to glucuronide conjugates, not to salicylic acid)

Metabolites: salicylurate, salicyl phenolic glucuronide, salicyl acyl glucuronide, 2,5-dihydroxybenzoic acid (gentisic acid), 2,3-dihydroxybenzoic acid, 2,3,5-trihydroxybenzoic acid, gentisuric acid (active)

Enzymes inhibited: Prostaglandin synthesis (insignificant)

Half-life: 8-12 hr

Excretion: Urine ~90%; feces <5%

Renal Clearance: 80-100% in 24-72 hr

Dialyzable: Yes

Diflunisal is a prescription medication used to treat mild to moderate pain. It is also used to treat the symptoms of arthritis (osteoarthritis and rheumatoid arthritis). Diflunisal belongs to a group of drugs called NSAIDs. These work by blocking chemicals in the body that cause pain and inflammation. 

This medication comes in an oral (by mouth) tablet form and can be taken up to every 8 hours, with food or milk. 

Tablets should be swallowed whole, not crushed or chewed.

Common side effects of diflunisal include nausea, dyspepsia (indigestion), stomach pain, and diarrhea.

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.

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%

The most frequent types of adverse reactions occurring with DOLOBID (diflunisal) are gastrointestinal: these include nausea** , vomiting, dyspepsia**, gastrointestinal pain**, diarrhea**, constipation, and flatulence.

  Somnolence, insomnia.

  Dizziness.  

  Tinnitus.

  Rash**.

  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.

Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity.

Peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis.

Thrombocytopenia; agranulocytosis; hemolytic anemia.

Dysuria; renal impairment, including renal failure; interstitial nephritis; hematuria; proteinuria.

Nervousness, depression, hallucinations, confusion, disorientation.

Vertigo; light-headedness; paresthesias.

Transient visual disturbances including blurred vision.

Acute anaphylactic reaction with bronchospasm; angioedema; flushing.

Hypersensitivity syndrome (see WARNINGS, Hypersensitivity Syndrome).

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.

  Dyspnea.

  Palpitation, syncope.

  Muscle cramps.

  Nephrotic syndrome.

 Hearing loss.

  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 entire FDA prescribing information for Dolobid (Diflunisal)

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.

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.

Prototypical NSAIA; a difluorophenyl derivative of salicylic acid.1 2 3

Diflunisalis a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild to moderate pain, and helps to relieve symptoms of arthritis (osteoarthritis and rheumatoid arthritis), such as inflammation, swelling, stiffness, and joint pain. diflunisal does not cure arthritis and will help you only as long as you continue to take it .

diflunisal is available only with your doctor's prescription .

For safe and effective use of diflunisal, do not take more of it, do not take it more often, and do not take it for a longer time than ordered by your doctor. Taking too much of diflunisal may increase the chance of unwanted effects, especially in elderly patients .

When used for severe or continuing arthritis, diflunisal must be taken regularly as ordered by your doctor in order for it to help you. diflunisal usually begins to work within one week, but in severe cases up to two weeks or even longer may pass before you begin to feel better. Also, several weeks may pass before you feel the full effects of diflunisal.

Swallow the tablet whole with a full glass of water. Do not crush or chew it .

To lessen stomach upset, you may take diflunisal with food.

Dosing

The dose of diflunisal will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of diflunisal. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For mild to moderate pain:
    • Adults and teenagers—1000 milligrams (mg) for the first dose, then 500 mg every eight to twelve hours as needed. Some people may need only 500 mg for the first dose, then 250 mg every eight to twelve hours as needed. Usually, no more than a total of 1500 mg a day should be taken.
    • Children below 12 years of age—Use and dose must be determined by your doctor .
  • For osteoarthritis and rheumatoid arthritis:
    • Adults and teenagers—At first, 250 or 500 mg twice a day. Your doctor may increase or decrease your dose as needed. However, the dose usually is not more than 1500 mg once a day.
    • Children below 12 years of age—Use and dose must be determined by your doctor .

Missed Dose

If you miss a dose of diflunisal, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Belly pain.
• Upset stomach or throwing up.
• Loose stools (diarrhea).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Known hypersensitivity to diflunisal or any component of the formulation; in the setting of coronary artery bypass graft (CABG) surgery; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.

May administer with food or milk to decrease GI upset.

Frequency not always defined.

1% to 10%:

Central nervous system: Headache (3% to 9%), dizziness (1% to 3%), drowsiness (1% to 3%), fatigue (1% to 3%), insomnia (1% to 3%)

Dermatologic: Skin rash (3% to 9%)

Gastrointestinal: Diarrhea (3% to 9%), dyspepsia (3% to 9%), gastrointestinal pain (3% to 9%), nausea (3% to 9%), constipation (1% to 3%), flatulence (1% to 3%), vomiting (1% to 3%), gastrointestinal ulcer

Otic: Tinnitus (1% to 3%)

<1% (Limited to important or life-threatening): Agranulocytosis, anaphylactic reaction (acute), angioedema, anorexia, auditory impairment, blurred vision, bronchospasm, chest pain, cholestasis, confusion, cystitis, depression, diaphoresis, disorientation, DRESS syndrome, dry mucous membranes, dyspnea, dysuria, edema, eructation, erythema multiforme, esophagitis, exfoliative dermatitis, flushing, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, hallucination, hearing loss, hematuria, hemolytic anemia, hepatitis, hepatotoxicity (idiosyncratic; Chalasani 2014), hypersensitivity angiitis, hypersensitivity reaction, interstitial nephritis, jaundice, muscle cramps, necrotizing fasciitis, nephrotic syndrome, nervousness, palpitations, paresthesia, peptic ulcer, peripheral neuropathy, proteinuria, pruritus, renal failure, renal insufficiency, seizure, skin photosensitivity, Stevens-Johnson syndrome, stomatitis, syncope, tachycardia, thrombocytopenia, toxic epidermal necrolysis, tremor, urticaria, vasculitis, vertigo, weakness, wheezing

Data not available

Administration advice:
-Swallow tablets whole; do not crush or chew.

General:
-Concentration-dependent pharmacokinetics prevail with this drug; a doubling of dosage produces a greater than doubling of drug accumulation and effects become more apparent with repetitive doses.
-Following initial response to therapy, dose and frequency should be adjusted to suit individual patient needs.
-Prior to initiating treatment, the potential benefits and risks of this drug should be weighed against other treatment options.
-The lowest effective dose for the shortest duration consistent with individual patient treatment goals should be used.
-There is an increased risk of heart attack, heart failure, and stroke when taking nonsteroidal anti-inflammatory drugs (NSAIDs); these events may occur at any time during treatment and risk increases with long term use, a history of cardiovascular (CV) disease or risk factors for CV disease, and higher doses.

Monitoring:
-Cardiovascular: Monitor blood pressure closely during initiation and throughout the course of therapy.
-Gastrointestinal: Monitor for signs/symptoms of gastrointestinal bleeding.
-Renal function: Monitor renal status, especially in patients with conditions where renal prostaglandins have a supportive role in the maintenance of renal perfusion.
-Monitor blood counts, renal, and hepatic function periodically for patients receiving long-term therapy.

Patient advice:
-Patients should seek medical advice for signs and symptoms of gastrointestinal events, adverse skin reactions, allergic reactions, hepatotoxicity, or unexplained weight gain or edema.
-Patients should seek medical attention immediately if signs/symptoms of cardiovascular events occur including, shortness of breath, slurred speech, chest pain, or weakness on one side of the body.
-Patients should talk to their health care provider if they are pregnant, planning to become pregnant, or breastfeeding; this drug is not recommended for use while breastfeeding or during pregnancy.

Summary of Use during Lactation

The small amounts of diflunisal in milk do not appear to pose a serious risk to breastfeeding infants. However, a shorter-acting agents having more published information may be preferred, especially while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. Review articles report that milk levels are 2 to 7% of simultaneous maternal serum levels after 7 days of administration of 125 or 250 mg twice daily; however, no study details are provide.[1][2] This would represent milk levels ranging from 0.3 to 0.9 mg/L with a dose of 125 mg daily and 0.8 to 2.7 mg/L with a dose of 250 mg daily.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Acetaminophen, Flurbiprofen, Ibuprofen, Indomethacin, Naproxen, Piroxicam

References

1. Steelman SL, Breault GO, Tocco D et al. Pharmacokinetics of MK-647, a novel salicylate. Clin Pharmacol Ther. 1975;17:245. Abstract.

2. Tempero KF, Cirillo VJ, Steelman SL. Diflunisal: chemistry, toxicology, experimental and human pharmacology. In: Huskisson EC, Caldwell ADS, eds. Diflunisal: new perspectives in analgesia. Royal Soc Med Int'l Con Sym Ser. 1979;6:3-4.

Substance Name

Diflunisal

CAS Registry Number

22494-42-4

Drug Class

Analgesic Agents

Nonsteroidal Antiinflammatory Agents