FLURBIPROFEN (flurbiprofen)

There are 6 contraindications. Absolute contraindication.

Contraindication List
Aspirin exacerbated respiratory disease
Cerebrovascular accident
History of roux-en-Y gastric bypass
Post-operative from CABG surgery
Pregnancy
Renal transplant

There are 19 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute myocardial infarction
Alcohol use disorder
Chronic heart failure
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
CYp2c9 intermediate metabolizer (activity score 1)
CYp2c9 poor metabolizer
Edema
Gastrointestinal hemorrhage
Gastrointestinal perforation
Gastrointestinal ulcer
History of kidney donation
Increased risk of bleeding
Increased risk of bleeding due to coagulation disorder
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Nephrectomy
Systemic mastocytosis
Thrombotic disorder
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 54 severe adverse reactions.

More Frequent	Less Frequent
Body fluid retention Edema Urinary tract infection	Bloody stools Bloody vomit Gastritis Gastrointestinal hemorrhage Memory impairment Visual changes

Rare/Very Rare

Abnormal hepatic function tests Acute myocardial infarction Anaphylaxis Anemia Angina Angioedema Aplastic anemia Bronchospastic pulmonary disease Cardiac arrhythmia Cerebrovascular accident Chronic heart failure Corneal opacity Dyspnea Ecchymosis Eczema Eosinophilia Epistaxis Esophageal ulcer Esophagitis Exfoliative dermatitis Gastric ulcer Gastrointestinal perforation Gastrointestinal ulcer Hematuria Hemolytic anemia Hepatitis Hyperkalemia Hypertension Interstitial nephritis Jaundice Kidney disease with reduction in glomerular filtration rate (GFr) Laryngeal edema Leukopenia Lymphadenopathy Nephrotoxicity Non-infective meningitis Pancytopenia Peptic ulcer Renal failure Renal papillary necrosis Retinal hemorrhage Stevens-johnson syndrome Thrombocytopenic disorder Toxic epidermal necrolysis Urticaria

There are 36 less severe adverse reactions.

More Frequent	Less Frequent
Acute abdominal pain Diarrhea Gastric acid hypersecretory conditions Headache disorder Nausea	Blurred vision Constipation Depression Dizziness Drowsy Dyspepsia Flatulence Insomnia Nervousness Rhinitis Skin rash Symptoms of anxiety Tinnitus Tremor Vomiting

Rare/Very Rare
Abnormal vaginal bleeding Acute cognitive impairment Anorexia Ataxia Conjunctivitis Dysgeusia Fever Hearing loss Hyperhidrosis Hyperuricemia Muscle weakness Paresthesia Pruritus of skin Skin photosensitivity Stomatitis Xerostomia

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 flurbiprofen, 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.

There are no adequate and well-controlled studies of flurbiprofen in pregnant women. In animal studies, embryofetal lethality was observed in pregnant rats and rabbits receiving flurbiprofen during the period of organogenesis at exposure levels of 0.03 and 0.5

times, respectively, the exposure at the maximum recommended human dose (MRHD) of 300 mg; no evidence of malformations was observed in rats, rabbits, or mice receiving flurbiprofen at dosages of 0.8, 0.5, or 0.2

times, respectively, the MRHD. Reproduction studies revealed delayed parturition, prolonged labor, stillborn fetuses, and the presence of retained fetuses at necropsy in rats at flurbiprofen dosages that were lower than the MRHD. The effects of flurbiprofen on labor and delivery are unknown. In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased the incidence of stillbirth.

Flurbiprofen is distributed into milk in very small amounts (estimated to be 0.1 mg daily based on a daily maternal dosage of 200 mg). The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for flurbiprofen and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Geriatric patients may experience a higher incidence of adverse GI effects (e.g., ulceration, bleeding, flatulence, bloating, abdominal pain) than younger patients and are at greater risk of developing renal decompensation with NSAIAs. Use flurbiprofen with caution and at the lowest effective dosage for the shortest possible duration.