Diflunisal

Diflunisal is a Analgesic and Antipyretic belonging to Non-Steroidal anti-inflammatory Drug

Diflunisal is used in the treatment of rheumatoid arthritis and mild to moderate pain.

Diflunisal is well absorbed from the GI tract. Time to peak plasma concentration: Approx 2-3 hr. and get Distributed into breast milk. Volume of distribution: 7.53 L. Plasma protein binding: >99% and is Extensively metabolised in the liver to glucuronide conjugates and get excreted Via urine (approx 90% as glucuronide conjugates) and faeces (<5%). Plasma half-life: Approx 8-12 hr.

Diflunisal shows common side effects like Nausea, vomiting, dyspepsia, GI pain, bleeding or perforation; diarrhoea, constipation, flatulence, somnolence, insomnia, dizziness, tinnitus, rash, headache, fatigue, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome.

The onset of action of Diflunisal is approx 1 hour.

The Duration of action of Diflunisal is approx 8-12 hour.

Diflunisal is available in tablet.

Diflunisal is available in India, Germany, Canada, France, USA.

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.

Diflunisal is available in the form of tablets.

Diflunisal is used in the treatment of rheumatoid arthritis and mild to moderate pain.

Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties.

Diflunisal is approved for use in the following clinical indications

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

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

Osteoarthritis, rheumatoid arthritis: Oral: 500 mg to 1 g daily in 2 divided doses; maximum dose: 1.5 g/day.

Pain, mild to moderate: Oral: Initial: 1 g, followed by 500 mg every 12 hours; maintenance doses of 500 mg every 8 hours may be necessary in some patients; maximum dose: 1.5 g/day.

Dosage adjustments: A lower dosage may be appropriate depending on pain severity, patient response, or weight; Initial: 500 mg, followed by 250 mg every 8 to 12 hours; maximum dose: 1.5 g/day.

Diflunisal is available in the dosage strength of 250mg, 500 mg.

Diflunisal is available in the form of tablets.

Dose Adjustment in Kidney Patient:

• GFR ≤50 mL/minute: Administer 50% of normal dose.
• Hemodialysis: No supplement required.
• CAPD: No supplement required.
• KDIGO 2012 guidelines provide the following recommendations for NSAIDs:
• GFR 30 to <60 mL/minute/1.73 m²: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury.
• GFR <30 mL/minute/1.73 m²: Avoid use.

Dosage Adjustment for Pediatric Patients:-

• Osteoarthritis, rheumatoid arthritis: Adolescents ≥12 years: Oral: Refer to adult dosing.
• Pain, mild to moderate: Adolescents ≥12 years: Oral: Refer to adult dosing.

Take after eating and with a full glass of water to decrease gastric upset.

Diflunisal is contraindicated in patients with:

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 nonsteroidal anti-inflammatory drugs (NSAIDs).

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

• Cardiovascular events: Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention; use with caution in patients with edema. Avoid use in heart failure (FDA 2015). Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

• GI events: [US Boxed Warning]: NSAIDs cause an increased risk of serious GI inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk of serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis (Strate 2016). Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt 2008).

• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).

• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare, sometimes fatal severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if clinical signs or symptoms of hepatic disease develop or if systemic manifestations occur.

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.

• Hypersensitivity syndrome: A potentially life-threatening, hypersensitivity syndrome has been reported; monitor for constitutional symptoms and cutaneous findings; other organ dysfunction may be involved.

• Ophthalmic events: Blurred vision has been reported; refer for ophthalmologic evaluation if symptoms occur.

• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics and ACE inhibitors, and elderly patients are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.

• Reye's syndrome: Diflunisal is a derivative of acetylsalicylic acid and therefore may be associated with Reye’s syndrome.

• NSAIDs may cause potentially fatal, serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).

Diflunisal may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Food may decrease the rate but not the extent of absorption. Diflunisal peak serum levels may be delayed if taken with food. Management: Administer with food or milk to minimize GI upset.

• Common Adverse effects: Nausea, vomiting, dyspepsia, GI pain, bleeding or perforation; diarrhea, constipation, flatulence, somnolence, insomnia, dizziness, tinnitus, rash, headache, fatigue, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome.

• Less Common Adverse effects toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity, peptic ulcer, anorexia, eructation, gastritis, liver function abnormalities, jaundice, fever, cholestasis, hepatitis, thrombocytopenia

• Rare Adverse Effects: hemolytic anemia, nervousness, depression, hallucinations, confusion, disorientation, vertigo; light-headedness; paranesthesia's, dyspnea, palpitation, syncope, muscle cramps, nephrotic syndrome, hearing loss, chest pain.

Increased risk of GI bleeding w/ warfarin. Decreased absorption w/ antacids. Decreased plasma concentration w/ aspirin. Increases plasma concentration of paracetamol. Increased risk of convulsion when used w/ quinolones.

Potentially Fatal: May cause fatal GI hemorrhage w/ indomethacin.

The common side effects of Diflunisal include the following :

Nausea, vomiting, dyspepsia, GI pain, bleeding or perforation; diarrhea, constipation, flatulence, somnolence, insomnia, dizziness, tinnitus, rash, headache, fatigue, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome.

Symptoms: Drowsiness, nausea, vomiting, diarrhea, decreased urinary output, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, coma and cardiorespiratory arrest.

• Pharmacodynamics

Diflunisal is a nonsteroidal 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.

• Pharmacokinetics

Absorption: Well absorbed from the GI tract. Time to peak plasma concentration: Approx 2-3 hr.

Distribution: Distributed into breast milk. Volume of distribution: 7.53 L. Plasma protein binding: >99%.

Metabolism: Extensively metabolized in the liver to glucuronide conjugates.

Excretion: Via urine (approx 90% as glucuronide conjugates) and faeces (<5%). Plasma half-life: Approx 8-12 hr.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Diflunisal -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Diflunisal
5. https://europepmc.org/article/med/6988203