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DIFLUNISAL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Diflunisal is a salicylic acid derivative with analgesic, antiinflammatory, and antipyretic properties. Diflunisal is not metabolized to salicylic acid.

Specific Substances

    1) MK 647
    2) Diflunisalum
    3) 5-(2,4-Difluorophenyl)salicylic acid
    4) 2,4, difluoro-4-hydroxy-3-biphenylcarboxylic acid
    5) CAS 22494-42-4
    1.2.1) MOLECULAR FORMULA
    1) C13H8F2O3

Available Forms Sources

    A) FORMS
    1) Diflunisal is available as 500 mg film coated tablets (Prod Info diflunisal oral film coated tablets, 2012).
    B) USES
    1) Diflunisal is indicated for the acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis (Prod Info diflunisal oral film coated tablets, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Diflunisal is indicated for the acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis.
    B) PHARMACOLOGY: Diflunisal is a reversible inhibitor of cyclooxygenase, thus, inhibits prostaglandin synthesis. It is a salicylic acid derivative with analgesic, antiinflammatory, and antipyretic properties. Diflunisal is not metabolized to salicylic acid.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON 3% TO 9%: Nausea, dyspepsia, abdominal pain, diarrhea, rash, and headache. 1% TO 3%: Vomiting, constipation, somnolence, dizziness, tinnitus, and fatigue. RARE: Erythema multiforme, exfoliative dermatitis, urticaria, pruritus, sweating, dry mucous membranes, photosensitivity, toxic epidermal necrolysis, Stevens-Johnson syndrome, gastrointestinal hemorrhage and ulcer, thrombocytopenia, elevated liver enzymes, cholestatic jaundice, hepatosplenomegaly, and hypersensitivity reaction, including anaphylactoid reaction.
    E) WITH POISONING/EXPOSURE
    1) A small number of overdose cases have been reported with diflunisal. The most common symptoms were drowsiness, disorientation, vomiting, diarrhea, hyperventilation, hypotension, tachycardia, hyperthermia, sweating, tinnitus, ataxia, stupor, and coma. Sudden deterioration has occurred 8 to 10 hours following massive overdoses. Acute renal failure, hepatotoxicity, and cardiorespiratory arrest have also been reported.
    0.2.20) REPRODUCTIVE
    A) Diflunisal is classified as FDA pregnancy category C. NSAIDs have been shown to adversely effect prostaglandin inhibition on the human fetal cardiovascular system (closure of ductus arteriosus). Other serious adverse effects to the fetus have occurred during the third trimester of pregnancy. In one study, there was an 80% increased risk of miscarriage with the use of NSAIDs. In animal studies, there was evidence of teratogenicity, maternotoxicity, and fetotoxicity when rabbits were exposed to diflunisal. Teratogenic effects, characteristically axial skeletal defects, have been noted in rabbits treated with diflunisal, although cynomolgus monkeys showed no teratogenic effects.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of diflunisal in humans.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor for evidence of gastrointestinal bleeding.
    F) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    G) Diflunisal cross-reacts with salicylates, resulting in falsely positive salicylates levels in commonly used analytic techniques (TDx fluorescence polarization immunoassay and the Trinder colorimetric assay).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops. If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, hemodynamic instability, significant CNS depression, respiratory distress, severe allergic reactions, or severe GI bleeding.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Diflunisal is not effectively removed by hemodialysis. In one study, forced alkaline diuresis was ineffective in enhancing diflunisal renal elimination.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable. Early symptoms of overdose may be delayed or not evident. Sudden deterioration in clinical condition has been demonstrated 8 to 10 hours postingestion in substantial overdoses. Reliable follow-up is imperative. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected diflunisal overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Tmax: 2 to 3 hours. Absorption: Well-absorbed from the GI tract. Protein binding: About 99%. Vd: 7.53 L. Metabolism: Liver, extensive. Diflunisal does NOT metabolize to salicylate. Excretion: Kidney: 80% to 90%. Elimination half-life: 8 to 12 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other NSAIDs or other drugs that cause CNS depression (eg, toxic alcohols, benzodiazepines, opiates/opioids, antipsychotic medications), or other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers) or hepatotoxicity (eg, acetaminophen, ethanol).

Range Of Toxicity

    A) TOXICITY: Serious effects have been described in adults after doses of 7.5 grams or more. However, in one case series, mild symptoms (drowsiness, GI irritation) were reported in 21 adults ingesting up to 8.25 grams. More serious symptoms (tinnitus, hyperventilation, tachycardia, cardiorespiratory arrest) occurred with ingestion of 15 grams or more in 5 adults. The lowest lethal dose (without other drugs) was 15 grams.
    B) THERAPEUTIC DOSE: ADULT: Initial dose of 1000 mg orally followed by a maintenance dose of 500 mg every 8 to 12 hours. MAX: Doses above 1500 mg/day NOT recommended OR 500 to 1000 mg orally daily in 2 divided doses. MAX: Doses above 1500 mg/day NOT recommended. PEDIATRIC: 12 YEARS OF AGE AND OLDER: Initial dose of 1000 mg orally followed by a maintenance dose of 500 mg every 8 to 12 hours. MAX: Doses above 1500 mg/day NOT recommended. UNDER 12 YEARS OF AGE: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Diflunisal is indicated for the acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis.
    B) PHARMACOLOGY: Diflunisal is a reversible inhibitor of cyclooxygenase, thus, inhibits prostaglandin synthesis. It is a salicylic acid derivative with analgesic, antiinflammatory, and antipyretic properties. Diflunisal is not metabolized to salicylic acid.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON 3% TO 9%: Nausea, dyspepsia, abdominal pain, diarrhea, rash, and headache. 1% TO 3%: Vomiting, constipation, somnolence, dizziness, tinnitus, and fatigue. RARE: Erythema multiforme, exfoliative dermatitis, urticaria, pruritus, sweating, dry mucous membranes, photosensitivity, toxic epidermal necrolysis, Stevens-Johnson syndrome, gastrointestinal hemorrhage and ulcer, thrombocytopenia, elevated liver enzymes, cholestatic jaundice, hepatosplenomegaly, and hypersensitivity reaction, including anaphylactoid reaction.
    E) WITH POISONING/EXPOSURE
    1) A small number of overdose cases have been reported with diflunisal. The most common symptoms were drowsiness, disorientation, vomiting, diarrhea, hyperventilation, hypotension, tachycardia, hyperthermia, sweating, tinnitus, ataxia, stupor, and coma. Sudden deterioration has occurred 8 to 10 hours following massive overdoses. Acute renal failure, hepatotoxicity, and cardiorespiratory arrest have also been reported.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) HYPERVENTILATION may occur in substantial ingestions (Court & Volans, 1984; Augenstein et al, 1987).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) ANIMAL STUDIES: RABBITS given 400 mg/kg of diflunisal showed a sudden increase in rectal temperature 6 to 18 hours post-ingestion (Smith et al, 1984).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTENSION has been reported following overdose ingestions (Court & Volans, 1984; Augenstein et al, 1987).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) TACHYCARDIA may occur in substantial ingestions (Court & Volans, 1984; Augenstein et al, 1987).

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) TINNITUS has been reported (Prod Info diflunisal oral film coated tablets, 2012).
    B) WITH POISONING/EXPOSURE
    1) TINNITUS has been reported in one adult who ingested 15 grams (Court & Volans, 1984).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Sinus tachycardia has been reported in one adult who ingested 15 grams (Court & Volans, 1984), and in one adult who took 7.5 to 10 grams (Augenstein et al, 1987).
    B) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Cardiorespiratory arrest was reported in a patient believed to have ingested 33 grams of diflunisal. Hyperventilation, restlessness, and sweating occurred 5 hours after the overdose (Court & Volans, 1984).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Hypotension was reported in one adult who ingested 2.5 to 7.5 grams (Court & Volans, 1984), and in a 23-year-old woman who ingested 7.5 to 10 grams. In this case, hypotension was persistent and required treatment with levarterenol for 8 hours (Augenstein et al, 1987).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Hyperventilation has been reported in 2 adults who ingested 25 and 33 grams, respectively (Court & Volans, 1984), and in one adult who ingested 7.5 to 10 grams (Augenstein et al, 1987).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, somnolence was reported at an incidence between 1% and 3% (Prod Info diflunisal oral film coated tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) Drowsiness has been reported in children, who ingested more than 3.5 grams, and in adults, who ingested up to 8.25 grams (Court & Volans, 1984).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, dizziness was reported at an incidence between 1% and 3% (Prod Info diflunisal oral film coated tablets, 2012).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, headache was reported at an incidence between 3% and 9% (Prod Info diflunisal oral film coated tablets, 2012).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, fatigue was reported at an incidence between 1% and 3% (Prod Info diflunisal oral film coated tablets, 2012).
    E) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Ataxia 1 hour post-ingestion, followed by drowsiness 3 hours postingestion and coma 10 hours post-ingestion were reported in a 47-year-old woman who ingested 29 grams of diflunisal. Consciousness returned by 24 hours post-ingestion (Upadhyay & Gupta, 1978).
    b) CASE REPORT: Coma was reported 4 hours after ingestion of 7.5 to 10 grams in an adult, which resolved within 12 hours post-ingestion (Augenstein et al, 1987).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal hemorrhage has rarely been reported (Prod Info diflunisal oral film coated tablets, 2012; Admani & Khaleque, 1979).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Diffuse gastritis and guaiac-positive stools, leading to anemia, were noted in an 82-year-old woman who ingested 10 grams over 40 hours (Flessner & Atuk, 1989).
    B) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Gastrointestinal irritation and drowsiness were the only symptoms reported after overdose of diflunisal in 21 patients ingesting 250 mg to 8.25 grams (Court & Volans, 1984).
    C) GASTROINTESTINAL ULCER
    1) WITH THERAPEUTIC USE
    a) Patients who are treated with non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal adverse effects including ulcerations, bleeding, or perforation. These adverse effects may occur at any time during treatment with or without warning symptoms. Information from clinical trials indicate that approximately 1% of patients treated for 3 to 6 months and 2% to 4% of patients treated for one year with NSAIDs will develop ulcers, bleeding, or perforation. Any patient treated with a NSAID is at risk for serious gastrointestinal adverse effects; however, patients with a prior history of peptic ulcer disease with or without complications have an increased risk. Patients, who are elderly or debilitated, tolerate serious gastrointestinal adverse effects less well. Most case reports of fatalities have occurred in this group of patients (FDA, 2005).
    D) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, nausea was reported at an incidence between 3% and 9% (Prod Info diflunisal oral film coated tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Diarrhea and vomiting occurred in a child who ingested more than 3.5 grams (Court & Volans, 1984).
    E) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, diarrhea was reported at an incidence between 3% and 9% (Prod Info diflunisal oral film coated tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Diarrhea and vomiting occurred in a child who ingested more than 3.5 grams (Court & Volans, 1984).
    F) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, dyspepsia was reported at an incidence between 3% and 9% (Prod Info diflunisal oral film coated tablets, 2012).
    G) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, gastrointestinal pain was reported at an incidence between 3% and 9% (Prod Info diflunisal oral film coated tablets, 2012).
    H) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of 1314 patients receiving diflunisal for two weeks or longer, constipation was reported at an incidence between 1% and 3% (Prod Info diflunisal oral film coated tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In two cases of severe hypersensitivity reactions, following 4 weeks of diflunisal therapy, liver function tests were markedly elevated with alkaline phosphatase at 349 and 545 U/L, AST at 813 and 1389 U/L, GGT at 143 and 391 U/L, ALT at 810 and 500 U/L (Cook et al, 1988)
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Mild liver dysfunction (SGOT 519 U/L, SGPT 134 U/L, LDH 1696 U/L) was noted in an 82-year-old woman who ingested 10 grams over 40 hours (Flessner & Atuk, 1989).
    B) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cholestatic jaundice was reported in a 64-year-old man receiving therapeutic doses for 5 days (Warren, 1978).
    C) HEPATOSPLENOMEGALY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hepatosplenomegaly developed in one patient, who experienced a severe hypersensitivity reaction following 4 weeks of diflunisal therapy (Cook et al, 1988).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) OLIGURIA
    1) WITH POISONING/EXPOSURE
    a) Diminished urine output has been reported (Prod Info diflunisal oral film coated tablets, 2012).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Acute renal failure was documented in an 82-year-old woman who ingested 10 grams over 40 hours (Flessner & Atuk, 1989).

Acid-Base

    3.11.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ACIDOSIS
    a) ANIMAL STUDIES: Respiratory alkalosis and metabolic acidosis developed in rabbits given 10 to 400 mg/kg by feeding tube. A dose dependent effect was seen with doses of 200 mg/kg or greater (equivalent to 14 grams in a 70 kg adult) (Smith et al, 1984).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported following two weeks of chronic therapy (Bobrove, 1988).
    b) Diflunisal has a dose-related effect on platelet function and bleeding time. In normal volunteers 250 mg BID had no effect, 500 mg BID had a slight effect and 1000 mg BID inhibited platelet function (Prod Info Dolobid(R) tablets, diflunisal, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Erythema multiforme, exfoliative dermatitis, urticaria, pruritus, sweating, dry mucous membranes, and photosensitivity have rarely been reported in patients (Prod Info diflunisal oral film coated tablets, 2012).
    B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis has rarely been reported (Prod Info diflunisal oral film coated tablets, 2012).
    b) CASE REPORT: Lichenoid photoreactive epidermal necrosis has been reported in one patient on diflunisal, 500 mg twice daily (Street & Winkelmann, 1989).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome has rarely been reported (Prod Info diflunisal oral film coated tablets, 2012).
    b) CASE REPORT: A 48-year-old Asian man experienced painful buccal blisters within 3 hours of the administration of diflunisal as premedication for dental procedures on three separate occasions. The blisters progressed to extensive oral ulcerations over the next 3 days. Following the third exposure, the patient also developed lip and facial swelling accompanied by burning eyes, dysphagia, and a painful bullous, erythematous penile lesion. The only other drug given consistently as premedication was a mepivacaine 2% solution with neo-cobefin 1:20,000 (a vasoconstrictor). The patient was treated with systemic corticosteroids, steroid creams, steroid ophthalmic preparations and diphenhydramine, with persistent signs and symptoms over the next 2 months and diminution and resolution within 3 months(Yusin et al, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 47-year-old, with no previous history of allergic reactions or asthma, developed itching of her hands and feet, lightheadedness, and subsequently collapsed at her desk approximately one hour after ingesting a single 500 mg dose. She was successfully resuscitated and discharged from the hospital approximately 24 hours after the initial anaphylactoid reaction (Poe et al, 1989).
    b) CASE SERIES: Arias et al (1995) reported anaphylactoid reactions in two patients following single dose ingestions of diflunisal 500 mg. Both patients experienced itching of the hands and feet and generalized urticaria 30 minutes after the diflunisal ingestion. One patient also developed chest tightness and tongue angioedema (Arias et al, 1995).
    B) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Severe generalized hypersensitivity, with fever, hepatitis, erythroderma, and eosinophilia, developed within 4 weeks of starting diflunisal therapy in three patients (Cook et al, 1988).

Reproductive

    3.20.1) SUMMARY
    A) Diflunisal is classified as FDA pregnancy category C. NSAIDs have been shown to adversely effect prostaglandin inhibition on the human fetal cardiovascular system (closure of ductus arteriosus). Other serious adverse effects to the fetus have occurred during the third trimester of pregnancy. In one study, there was an 80% increased risk of miscarriage with the use of NSAIDs. In animal studies, there was evidence of teratogenicity, maternotoxicity, and fetotoxicity when rabbits were exposed to diflunisal. Teratogenic effects, characteristically axial skeletal defects, have been noted in rabbits treated with diflunisal, although cynomolgus monkeys showed no teratogenic effects.
    3.20.2) TERATOGENICITY
    A) PREMATURE CLOSURE OF DUCTUS ARTERIOSUS
    1) NSAIDs have been shown to adversely effect prostaglandin inhibition on the human fetal cardiovascular system (closure of ductus arteriosus) (Prod Info diflunisal oral tablets, 2006; Levin, 1980; Needs & Brooks, 1985).
    B) OTHER ADVERSE EFFECTS
    1) Adverse effects to the fetus during the third trimester of pregnancy include constriction of the ductus arteriosus prenatally, tricuspid incompetence, pulmonary hypertension, myocardial degenerative changes, platelet dysfunction with bleeding, intracranial bleeding, renal dysfunction, failure, or injury, oligohydramnios, gastrointestinal bleeding or perforation, and an increased risk of necrotizing enterocolitis (Prod Info diflunisal oral tablets, 2006).
    C) ANIMAL STUDIES
    1) Teratogenicity has been observed following exposure to aspirin and other salicylates at doses ranging from 50 to 400 mg/kg/day (about 1 to 8 times the human dose) in various animal species, including rats and rabbits (Prod Info diflunisal oral tablets, 2006).
    2) MONKEYS: Diflunisal at doses of 20 and 60 mg/kg was not teratogenic in cynomolgus monkeys (Rowland et al, 1987).
    3) RABBITS: There was evidence of teratogenicity when rabbits were given diflunisal at a dose of 60 mg/kg/day (2 times the human recommended dose). In 3 out of 6 rabbit studies, teratogenicity was reported at doses ranging from 40 to 50 mg/kg/day (Prod Info diflunisal oral tablets, 2006). Teratogenic effects, characteristically axial skeletal defects, have been noted in rabbits treated with diflunisal 40 to 180 mg/kg. This effect appears to be species-specific and is secondary to hemolytic anemia-induced hypoxia (Clark et al, 1984).
    4) RATS, MICE: In teratogenicity studies, there was no evidence of fetal harm when rat and mice were given diflunisal at doses up to 100 and 45 mg/kg/day, respectively (Prod Info diflunisal oral tablets, 2006).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified diflunisal as FDA pregnancy category C (Prod Info diflunisal oral tablets, 2006).
    B) MISCARRIAGE
    1) Use of NSAIDs during the first 20 weeks of pregnancy was associated with an 80% increased risk of miscarriage over non-use (hazard ratio (HR), 1.8; 95% confidence interval (CI), 1 to 3.2) in a study of 1055 women. Risk of miscarriage was highest when the drug was taken around the time of conception (HR, 5.6; 95% CI, 2.3 to 13.7) or used for more than a week (HR, 8.1; 95% CI, 2.8 to 23.4). Absolute risk of NSAID-associated miscarriage was 10% for any use, 35% for use around the time of conception, and 52% for use longer than one week (Li et al, 2003).
    C) ANIMAL STUDIES
    1) RABBITS: There was evidence of maternotoxicity and fetotoxicity when rabbits were given diflunisal at a dose of 60 mg/kg/day (2 times the human recommended dose) (Prod Info diflunisal oral tablets, 2006).
    2) RATS: The mean length of gestation was increased in rats following exposure to diflunisal at a dose that was one and one-half times the maximum human dose. This may be related to inhibition of prostaglandin synthetase as similar effects have been observed with aspirin, indomethacin, and phenylbutazone. There was also an increased incidence of dystocia, delayed parturition, and reduced pup survival in rats exposed to NSAIDs (Prod Info diflunisal oral tablets, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) The concentration of diflunisal in breast milk is 2% to 7% of that in maternal plasma (Prod Info diflunisal oral tablets, 2006; Steelman et al, 1975). Determinants of drug secretion into breast milk include the drug's molecular weight, lipid solubility, elimination half-life, serum protein binding, pKa, degree to which metabolites are formed and the amount of maternal drug consumption. Because breast milk has a pH of 6.9 to 7.6, weak acids are ionized so drugs such NSAIDs are not readily distributed into breast milk (Anon, 1989).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: There was no evidence of impaired fertility when rats were given diflunisal at doses up to 50 mg/kg/day (Prod Info diflunisal oral tablets, 2006).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of diflunisal in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of diflunisal in humans (Prod Info diflunisal oral tablets, 2006).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) RATS, MICE: There was no effect on the incidence or type of neoplasia when rats were given diflunisal doses up to 40 mg/kg/day (approximately 1.3 times the maximum recommended human dose (MRHD)) in a 105-week study or when mice were given doses up to 80 mg/kg/day (approximately 2.7 times the MRHD) in a long-term carcinogenicity study (Prod Info diflunisal oral tablets, 2006).

Genotoxicity

    A) There was no evidence of mutagenicity in the following tests: dominant lethal assay, Ames microbial mutagen test, and the V-79 Chinese hamster lung cell assay (Prod Info diflunisal oral tablets, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor for evidence of gastrointestinal bleeding.
    F) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    G) Diflunisal cross-reacts with salicylates, resulting in falsely positive salicylates levels in commonly used analytic techniques (TDx fluorescence polarization immunoassay and the Trinder colorimetric assay).
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Monitor arterial blood gases, blood pH, and rectal temperature in symptomatic patients or after large ingestions.
    2) ANIMAL STUDIES: Acidosis was maximal 12 to 18 hours post-ingestion in animal studies (Smith et al, 1984).
    B) HEMATOLOGIC
    1) Monitor CBC with differential and platelet count in symptomatic patients.
    C) BLOOD/SERUM CHEMISTRY
    1) Monitor liver enzymes and renal function tests in patients with symptoms or substantial ingestions.
    D) LABORATORY INTERFERENCE
    1) Diflunisal cross-reacts with salicylate, resulting in falsely positive salicylate levels in commonly used analytic techniques (TDx fluorescence polarization immunoassay and the Trinder colorimetric assay) (Szucs et al, 2000; Duffens et al, 1987; Augenstein et al, 1987; Leff et al, 1998).
    4.1.3) URINE
    A) OTHER
    1) Monitor urine output in patients with symptoms or large ingestions.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG, and institute continuous cardiac monitoring.
    2) FECAL
    a) Monitor for evidence of gastrointestinal bleeding. Stool guaiac test is recommended to detect GI bleeding.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable. Early symptoms of overdose may be delayed or not evident.
    B) Sudden deterioration in clinical condition has been demonstrated 8 to 10 hours postingestion in substantial overdoses (Upadhyay & Gupta, 1978; Court & Volans, 1984).
    C) Reliable follow-up is imperative. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor for evidence of gastrointestinal bleeding.
    F) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    G) Diflunisal cross-reacts with salicylates, resulting in falsely positive salicylates levels in commonly used analytic techniques (TDx fluorescence polarization immunoassay and the Trinder colorimetric assay).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops. If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Obtain an ECG, and institute continuous cardiac monitoring.
    5) Monitor for evidence of gastrointestinal bleeding.
    6) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    7) Diflunisal cross-reacts with salicylates, resulting in falsely positive salicylates levels in commonly used analytic techniques (TDx fluorescence polarization immunoassay and the Trinder colorimetric assay).
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) TACHYCARDIA
    1) TACHYCARDIA SUMMARY
    a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    c) ESMOLOL/ADULT LOADING DOSE
    1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).
    d) ESMOLOL/ADULT MAINTENANCE DOSE
    1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
    2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
    3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    e) CAUTION
    1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Verbeeck et al (1979) report that diflunisal is not effectively removed by hemodialysis (Verbeeck, 1979).
    B) URINE ALKALINIZATION
    1) Forced alkaline diuresis was ineffective in enhancing diflunisal renal elimination in a study of 6 volunteers ingesting 750 mg in a single dose (Balali-Mood & Prescott, 1980).

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) ADULT
    a) A 47-year-old woman made an uneventful recovery from an intentional diflunisal overdose. She took 116 250-mg tablets (29 grams) over a 40 minute period for a backache. She was also taking pseudoephedrine for a cold. Within 1 hour, she was giddy and within 3 hours she was admitted to the hospital with blurred vision, drowsiness, and blood pressure of 130/90. She was deeply comatose for 10 hours. She regained consciousness spontaneously at 24 hours and recovered uneventfully (Upadhyay & Gupta, 1978).
    b) A 33-year-old man who ingested 14 grams of diflunisal along with ethanol developed only mild symptoms of lethargy, dizziness, tinnitus, diaphoresis, sinus tachycardia (120 to 140), and slight tachypnea (18 to 28 breaths per minute) and recovered uneventfully (Duffens et al, 1987).
    c) A 23-year-old woman developed coma 4 hours after ingestion of 7.5 to 10 grams. Hypotension, tachycardia, and tachypnea were also present. Coma and hypotension resolved within 12 to 13 hours postingestion (Augenstein et al, 1987).
    d) An 82-year-old woman ingested 500 mg every 2 hours for 40 hours (total dose 10 grams) due to a prescription labeling error. Initial symptoms included dizziness, tinnitus, drowsiness, nausea, anorexia, confusion, and diarrhea. On admission, anemia, guaiac-positive stools, elevated liver function tests, and renal impairment were noted. Her hospital course was complicated over the next 27 days, mostly due to the hemodialysis procedures. On day 27, her renal function had normalized, and anemia was corrected by transfusion. Gastritis was seen on the upper GI series. She recovered completely (Flessner & Atuk, 1989).
    2) PEDIATRIC
    a) One child (age not specified) ingested at least 3.5 grams diflunisal and developed vomiting, diarrhea, and drowsiness. He recovered with supportive care within 12 hours (Court & Volans, 1984).

Range Of Toxicity

Summary

    A) TOXICITY: Serious effects have been described in adults after doses of 7.5 grams or more. However, in one case series, mild symptoms (drowsiness, GI irritation) were reported in 21 adults ingesting up to 8.25 grams. More serious symptoms (tinnitus, hyperventilation, tachycardia, cardiorespiratory arrest) occurred with ingestion of 15 grams or more in 5 adults. The lowest lethal dose (without other drugs) was 15 grams.
    B) THERAPEUTIC DOSE: ADULT: Initial dose of 1000 mg orally followed by a maintenance dose of 500 mg every 8 to 12 hours. MAX: Doses above 1500 mg/day NOT recommended OR 500 to 1000 mg orally daily in 2 divided doses. MAX: Doses above 1500 mg/day NOT recommended. PEDIATRIC: 12 YEARS OF AGE AND OLDER: Initial dose of 1000 mg orally followed by a maintenance dose of 500 mg every 8 to 12 hours. MAX: Doses above 1500 mg/day NOT recommended. UNDER 12 YEARS OF AGE: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) MILD TO MODERATE PAIN
    a) Initial dose of 1000 mg orally followed by a maintenance dose of 500 mg every 8 to 12 hours. MAX: Doses above 1500 mg/day NOT recommended (Prod Info diflunisal oral film coated tablets, 2012)
    b) ADMINISTRATION: Swallow tablets whole; DO NOT crush or chew (Prod Info diflunisal oral film coated tablets, 2012)
    2) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS
    a) 500 to 1000 mg orally daily in 2 divided doses. MAX: Doses above 1500 mg/day NOT recommended (Prod Info diflunisal oral film coated tablets, 2012)
    b) ADMINISTRATION: Swallow tablets whole; DO NOT crush or chew (Prod Info diflunisal oral film coated tablets, 2012)
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) MILD TO MODERATE PAIN
    a) CHILDREN 12 YEARS OF AGE AND OLDER: Initial dose of 1000 mg orally followed by a maintenance dose of 500 mg every 8 to 12 hours. MAX: Doses above 1500 mg/day NOT recommended (Prod Info diflunisal oral film coated tablets, 2012)
    b) CHILDREN UNDER 12 YEARS OF AGE: Safety and efficacy have not been established. Use in this age group is NOT recommended (Prod Info diflunisal oral film coated tablets, 2012).
    c) ADMINISTRATION: Swallow tablets whole; DO NOT crush or chew (Prod Info diflunisal oral film coated tablets, 2012)
    2) OSTEOARTHRITIS/RHEUMATOID ARTHRITIS
    a) CHILDREN 12 YEARS OF AGE AND OLDER: 500 to 1000 mg orally daily in 2 divided doses. MAX: Doses above 1500 mg/day NOT recommended (Prod Info diflunisal oral film coated tablets, 2012)
    b) CHILDREN UNDER 12 YEARS OF AGE: Safety and efficacy have not been established. Use in this age group is NOT recommended (Prod Info diflunisal oral film coated tablets, 2012).
    c) ADMINISTRATION: Swallow tablets whole; DO NOT crush or chew (Prod Info diflunisal oral film coated tablets, 2012)

Minimum Lethal Exposure

    A) CASE REPORTS
    1) DIFLUNISAL ALONE: A death has been reported following ingestion of 15 grams of diflunisal with no concurrent agents (Prod Info Dolobid(R) tablets, diflunisal, 1998).
    2) MIXED INGESTION: In a mixed overdose, death occurred following 7.5 grams and 9 grams, respectively (S Sweetman , 2000; Prod Info Dolobid(R) tablets, diflunisal, 1998; Levine et al, 1987).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) OVERDOSE
    a) Severe symptoms with survival were reported in an adult with plasma diflunisal level of 500 milligrams/liter 16 hours postingestion and 263 milligrams/liter 36 hours postingestion (Court & Volans, 1984).
    b) POSTMORTEM: Blood levels in a 38-year-old man who reportedly ingested 9 grams of diflunisal were 260 mg/L (Levine et al, 1987).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 124 mg/kg ((RTECS, 2000))
    2) LD50- (ORAL)MOUSE:
    a) 439 mg/kg ((RTECS, 2000))
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 212 mg/kg ((RTECS, 2000))
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 159 mg/kg ((RTECS, 2000))
    5) LD50- (ORAL)RAT:
    a) 392 mg/kg ((RTECS, 2000))
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 185 mg/kg ((RTECS, 2000))

Maximum Tolerated Exposure

    A) ADULT
    1) SUMMARY: In general, mild to moderate symptoms have occurred with 7.5 grams or less and serious symptoms with more than 10 grams. Fourteen grams have been ingested without serious effects.
    2) Mild symptoms (drowsiness, GI irritation) were reported in 21 adults ingesting up to 8.25 grams. More serious symptoms (tinnitus, hyperventilation, tachycardia, cardiorespiratory arrest) occurred with ingestion of 15 grams or more in 5 adults (Court & Volans, 1984).
    3) Coma, hypotension requiring vasopressors, and tachycardia were reported in an adult after ingestion of 7.5 to 10 grams (Augenstein et al, 1987).
    4) Gastritis, anemia, drowsiness, and liver and renal dysfunction were described after ingestion of 10 grams over 40 hours in an 82-year-old woman (Flessner & Atuk, 1989).
    5) Uneventful recovery occurred in a 33-year-old man who ingested 14 grams of diflunisal concurrently with ethanol (BAL 450 milligrams/deciliter) (Duffens et al, 1987).
    6) Recovery from coma induced by diflunisal, with supportive care, has been reported after ingestion of 29 grams (Upadhyay & Gupta, 1978).
    B) PEDIATRIC
    1) MILD SYMPTOMS occurred with 3.5 grams.
    a) One child (age not specified) ingested at least 3.5 grams diflunisal and developed vomiting, diarrhea, and drowsiness. He recovered with supportive care within 12 hours (Court & Volans, 1984).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Diflunisal is a nonsteroidal anti-inflammatory drug with antipyretic property. It is a peripherally-acting non-narcotic analgesic that inhibits prostaglandin synthetase resulting in decreased prostaglandin, which is a known mediator of pain and inflammation (Prod Info diflunisal oral film coated tablets, 2012).

Physicochemical

Physical Characteristics

    A) Diflunisal is a white crystalline compound that is practically insoluble in water at a neutral or acidic pH and is soluble in dilute alkali solutions, ethanol, methanol, and acetone. Diflunisal has a melting point of 211 to 213 degrees C (Prod Info diflunisal oral tablets, 2006).

Molecular Weight

    A) 250.2 (Prod Info diflunisal oral tablets, 2006)

Animal Toxicology

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) Remove the patient and other animals from the source of contamination.
    5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    6) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic.
    3) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    4) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) ACTIVATED CHARCOAL - Administer activated charcoal, 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) MAINTAIN VITAL FUNCTIONS as necessary.
    2) ANEMIA - Prior to running large amounts of fluids, check hematocrit. Blood transfusions may be necessary and clinical condition may be worsened by giving large amounts of fluids.
    a) TRANSFUSION - Transfuse with whole blood or plasma, 25 milliliters/kilogram.
    b) FLUID THERAPY - If necessary, begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.
    3) GASTRIC PROTECTANTS - Administer antacids, protectants such as sucralfate, and cimetidine as needed for gastric irritation and damage.
    4) ALKALINE DIURESIS will speed elimination of many NSAIDs such as phenylbutazone and ibuprofen. Adding sodium bicarbonate to the IV fluids to maintain urine pH at 7 to 8 is advisable.
    5) MONITOR for CBC changes and renal and hepatic damage. Provide good supportive care; treatment may need to be continued for several days.

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) Remove the patient and other animals from the source of contamination.
    5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    6) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic.
    3) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    4) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) ACTIVATED CHARCOAL - Administer activated charcoal, 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

References

General Bibliography

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    38) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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