INDOMETHACIN ER (indomethacin)

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 16 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute myocardial infarction
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
Depression
Esophageal dysmotility
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 6 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Chronic heart failure
Disease of liver
Hypertension
Parkinsonism
Seizure disorder
Ulcerative colitis

There are 76 severe adverse reactions.

More Frequent	Less Frequent
Abnormal hepatic function tests Body fluid retention Edema Severe headache disorder	Gastrointestinal ulcer Hemorrhage Pruritus of skin Skin rash Syncope Tinnitus

Rare/Very Rare

Abdominal distension Abnormal vaginal bleeding Acute eruptions of skin Acute myocardial infarction Agranulocytosis Allergic dermatitis Anaphylaxis Anemia Angioedema Aplastic anemia Bloody vomit Blurred vision Bone marrow depression Bronchospastic pulmonary disease Bullous dermatitis Cardiac arrhythmia Cerebrovascular accident Chest pain Chronic heart failure Colitis Corneal deposits Diplopia Disseminated intravascular coagulation DRESS syndrome Drug-induced psychosis Dysarthria Dyspnea Ecchymosis Eosinophilia Epistaxis Erythema multiforme Esophageal ulcer Esophagitis Exfoliative dermatitis Gastric ulcer Gastroenteritis Gastrointestinal hemorrhage Gastrointestinal perforation Hematuria Hemolytic anemia Hepatitis Hyperkalemia Hypertension Hypotension Interstitial nephritis Jaundice Kidney disease with reduction in glomerular filtration rate (GFr) Leukopenia Nephrotic syndrome Nephrotoxicity Pancreatitis Peptic ulcer Peripheral neuropathy Platelet aggregation inhibition Proctitis Proteinuria Pulmonary edema Rectal bleeding Renal failure Renal papillary necrosis Seizure disorder Stevens-johnson syndrome Thrombocytopenic disorder Thrombophlebitis Toxic epidermal necrolysis Urticaria

There are 35 less severe adverse reactions.

More Frequent	Less Frequent
Dizziness Dyspepsia Headache disorder Nausea Upper abdominal pain	Anorexia Constipation Diarrhea Drowsy Flushing Hyperhidrosis Stomatitis Vomiting

Rare/Very Rare
Acute cognitive impairment Alopecia Black tarry stools Fatigue Fever Flatulence Glycosuria Gynecomastia Hearing loss Hyperglycemia Increased urinary frequency Insomnia Involuntary muscle movement Mastalgia Muscle weakness Nervousness Palpitations Petechiae Purpura Symptoms of anxiety Tachycardia Weight gain

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 indomethacin, 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.

Indomethacin has been shown to have various adverse effects in animals during reproduction studies. Dosages of 5-15 mg/kg daily have resulted in maternal toxicity and death, increased fetal resorptions, and fetal malformations in mice. Reproduction studies in mice and rats at dosages of 0.5-4

mg/kg daily have revealed no increase in fetal malformations other than retarded fetal ossification, which was observed at the highest dosage and was attributed to decreased average fetal weight. Administration of indomethacin to mice and rats during the last 3 days of gestation at a dosage of 4 mg/kg daily was associated with an increased incidence of neuronal necrosis in the diencephalon in live-born fetuses; no increase in neuronal necrosis was observed at a dosage of 2 mg/kg daily, and administration of the drug to the offspring during the first 3 days of life at a dosage of 0.5 or 4 mg/kg daily did not result in an increase in neuronal necrosis.

Indomethacin inhibits prostaglandin synthesis, which may result in prolongation of gestation and interference with labor if the drug is given late in pregnancy. When indomethacin was administered during the 27th-34th weeks of gestation to control premature uterine contractions in humans, adverse fetal reactions including constriction of the fetal ductus arteriosus, neonatal primary pulmonary hypertension, and fetal deaths have occurred. Other adverse effects associated with such use have included oligohydramnios (in the absence of premature rupture of the amniotic membrane) and neonatal edema (including hydrops), bleeding disorders, transient oliguric renal failure, and focal ileal perforation.

Reduced number and excessive muscularity of pulmonary blood vessels have occurred in offspring of rats given 2-4 mg/kg daily during the last trimester of gestation; these findings are similar to those associated with the syndrome of persistent pulmonary hypertension of the newborn. Phocomelia and agenesis of the penis in one human neonate have tentatively been attributed to fetal exposure to indomethacin. The effects of indomethacin 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.

Indomethacin is distributed into milk. Seizures occurred in one breast-fed neonate (6 days of age) after the mother had taken approximately 200 mg of indomethacin daily for about 3 days. Indomethacin should not be used in nursing women.

No enhanced Geriatric Use information available for this drug.