DIFLUNISAL (diflunisal)

There are 4 contraindications. Absolute contraindication.

Contraindication List
History of roux-en-Y gastric bypass
Lactation
Post-operative from CABG surgery
Pregnancy

There are 10 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute myocardial infarction
Cerebrovascular accident
Chronic heart failure
Gastrointestinal hemorrhage
Gastrointestinal ulcer
Increased risk of bleeding
Increased risk of bleeding due to coagulation disorder
Kidney disease with reduction in glomerular filtration rate (GFr)
Peptic ulcer
Tobacco smoker

There are 2 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Disease of liver
Hypertension

There are 64 severe adverse reactions.

More Frequent	Less Frequent
Skin rash	Pruritus of skin Tinnitus

Rare/Very Rare

Abnormal hepatic function tests Acute cognitive impairment Acute myocardial infarction Agranulocytosis Allergic dermatitis Altered mental status Anaphylaxis Anemia Angioedema Aphthous stomatitis Bloody stools Bloody vomit Blurred vision Body fluid retention Bronchospastic pulmonary disease Cerebrovascular accident Chest pain Chest tightness Cramps Cystitis Depression Diplopia Disseminated intravascular coagulation Drug-induced hepatitis Dyspnea Dysuria Edema Eosinophilia Erythema multiforme Esophageal ulcer Exfoliative dermatitis Gastric ulcer Gastritis Gastrointestinal hemorrhage Gastrointestinal perforation Gastrointestinal ulcer Hallucinations Hemolytic anemia Hepatitis Hyperkalemia Hypertension Interstitial nephritis Jaundice Kidney disease with reduction in glomerular filtration rate (GFr) Leukopenia Mood changes Myalgia Nephrotic syndrome Nephrotoxicity Peptic ulcer Peripheral neuropathy Proteinuria Renal failure Stevens-johnson syndrome Syncope Thrombocytopenic disorder Toxic epidermal necrolysis Urticaria Vasculitis Visual changes Wheezing

There are 21 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal pain with cramps Diarrhea Gastric acid hypersecretory conditions Headache disorder Nausea	Constipation Dizziness Drowsy Fatigue Flatulence Insomnia Malaise Mouth irritation Vomiting Xerostomia

Rare/Very Rare
Anorexia Hyperhidrosis Irritability Nervousness Palpitations Skin photosensitivity

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used. Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.

Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation. Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis. Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.

Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.

Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis. Deaths associated with neonatal renal failure have been reported. Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.

These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain. Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.

In animal studies, inhibitors of prostaglandin synthesis, such as diflunisal, were associated with increased pre- and post-implantation losses. Prostaglandins also have an important role in fetal kidney development. In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.

Diflunisal has been shown to be maternotoxic, embryotoxic, and teratogenic in rabbits when given in dosages of 60 mg/kg daily; evidence of teratogenicity also was observed in 3 of 6 studies in rabbits at dosages of 40-50 mg/kg daily. Teratology studies in mice at diflunisal dosages up to 45 mg/kg daily and in rats at dosages up to 100 mg/kg daily revealed no evidence of fetal harm. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species, including rats and rabbits, at dosages ranging from 50-400 mg/kg daily (approximately 1-8 times the human dosage).

The effects of diflunisal on labor and delivery are unknown. In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, increased the incidence of dystocia, delayed parturition, and decreased pup survival.

Diflunisal is distributed into milk. Because of the potential for serious adverse reactions from diflunisal in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

No enhanced Geriatric Use information available for this drug.