Indometacin

General adverse effects and adverse reactions

Adverse effects and reactions, which occur in up to 60% of patients, are closely related to indometacin’s strong anti-inflammatory potency. Gastric irritation, including ulcers, bleeding, and perforation, predominates. Nervous system complications are related to cerebral edema. Headache is common. Hematological effects are infrequently reported. Nephrotoxicity is exacerbated by pre-existing renal impairment. Ocular toxicity can follow long-term use.

Cross-reactivity with aspirin has been reported [ ]. The hazards of administering topical indometacin to asthmatic patients should be widely known [ ].

Cardiovascular

Clinical experience and reports have provided little evidence that indometacin precipitates angina or myocardial infarction. However, an individual angina-provoking effect has been documented [ ], and there are grounds for believing that it can happen.

Intravenous administration of indometacin increases blood pressure, coronary vascular resistance, and myocardial oxygen demands, decreasing coronary flow. A controlled short-term study showed that indometacin increased blood pressure in patients with mild untreated essential hypertension [ ]. In view of the increasing use of parenteral administration, the acute hemodynamic effects of indometacin may now occur more often, especially in the elderly [ ]. The mechanism is poorly understood, but apparently a direct action is exerted on the resistance vessels in various regions. This is probably independent of indometacin’s action on prostaglandin formation. The clinical relevance is largely unknown, but other NSAIDs should probably be prescribed for patients with occlusive vascular diseases affecting the cerebral and/or coronary vessels.

Other systemic cardiovascular adverse effects are due to salt and fluid retention and also to a reduction in the vasodilator action of circulating prostaglandins E ₂ and I ₂ [ ].

Unlike other NSAIDs, indometacin acts as a cerebral vasoconstrictor. It reduces cerebral flow by up to 35% and the response to hypercapnia disappears [ ]. It also reduces blood flow in the splanchnic vascular bed, by increasing local vascular resistance, but does not impair circulation in the forearm and leg muscles.

Respiratory

Inhibition of prostaglandin synthesis explains indometacin’s ability to provoke or aggravate asthma in hypersensitive patients [ ]. Indometacin in ophthalmic solution reportedly caused such deterioration in asthmatic patients as to require mechanical ventilation [ , ]. Cross-sensitivity between indometacin and aspirin has been observed.

The risk of bronchopulmonary dysplasia has been determined in 999 infants of extremely low birth weight with and without patent ductus arteriosus who survived to a postmenstrual age of 36 weeks and who were randomized to indometacin prophylaxis or placebo [ ]. The incidence of bronchopulmonary dysplasia in infants with patent ductus arteriosus was 52% (55/105) after indometacin and 56% (137/246) after placebo. In contrast, rates of bronchopulmonary dysplasia in those without a patent ductus arteriosus were 43% (170/391) after indometacin prophylaxis and 30% (78/257) after placebo. There was evidence that this difference was related to poor oxygenation and edema formation in those who developed bronchopulmonary dysplasia.

Nervous system

Adverse reactions to indometacin involving the central nervous system are frequent and come second in importance only to gastrointestinal effects. They are attributed to salt and water retention. Up to 60% of patients experience headache (often migraine-like), frontal throbbing, and vertigo. Vomiting, tinnitus, ataxia, tremor, dizziness, and insomnia follow. Somnolence, confusion, hallucinations (especially in the elderly), and psychotic symptoms have been described. Coma, clonic seizures, and myoclonic spasms [ ] can develop. Muscle weakness and paresthesia, that is, peripheral neuropathy, may develop in elderly patients, but recede after withdrawal [ , ].

Indometacin is used for non-invasive closure of symptomatic ductus arteriosus in the preterm infant. Intravenous administration causes an instant reduction in cerebral blood flow, increasing cerebral vascular resistance. The clinical significance for the nervous system of these hemodynamic changes is unknown [ , ], but they seem to be linked to the effects seen in the central nervous system. Advantage has been taken of this effect for reducing intracranial hypertension in patients with severe head injury [ ].

Indometacin is also used in preterm infants as prophylaxis against intraventricular hemorrhage. In a prospective, randomized, placebo-controlled trial in 431 preterm neonates, low-dose indometacin prevented intraventricular hemorrhage without adverse cognitive or motor outcomes at 36 months [ ].

Low-dose indometacin (0.1 mg/kg), begun in the first 24 hours of life and given every 24 hours for 6 doses, was not associated with adverse neurodevelopmental outcome at 36 months corrected age [ ].

Sensory systems

Prolonged therapy can cause a number of adverse reactions in the eyes. Trivial effects are ocular discomfort, conjunctival pain, and increased ocular tension, but mydriasis, photophobia, blurred vision, diplopia, amblyopia, and loss of vision can occur. The most serious complications are retinopathy with reduced retinal sensitivity, and corneal and retinal pigmentation. They are reversible, but improvement is slow. A report on indometacin retinopathy has added more doubt than certainty to the question of the frequency and severity of retinal toxicity [ ]. Patients taking prolonged therapy should have regular ophthalmic examinations.

Metabolism

Indometacin reduces the area under the corticotropin (ACTH) plasma concentration–time curve after insulin in normal men, possibly because of the role of prostaglandins in the control of ACTH secretion [ ].

One report has described low plasma ascorbic acid concentrations during indometacin treatment, and a case of hyperglycemia has been reported [ ].

Electrolyte balance

Hyperkalemia has been reported in patients with pre-existing renal disease treated with indometacin [ ] and in a patient with Bartter’s syndrome receiving concomitant oral potassium chloride [ ]. Indometacin caused a high serum potassium concentration in a young athlete [ ].

Mineral balance

During indometacin therapy, urinary excretion of zinc and calcium can increase significantly [ ]. The clinical relevance is not known.

Fluid balance

Salt and fluid retention is an adverse effect of indometacin, although it is less important than with the pyrazolone derivatives. Indometacin can antagonize antihypertensive agents, including beta-adrenoceptor antagonists [ , ]. The effect on blood pressure in normotensive patients has not been adequately studied.

Severe water intoxication caused by inappropriate ADH secretion has been described in an elderly woman taking indometacin [ ].

Hematologic

Anemia caused by repetitive gastrointestinal bleeding is a relatively frequent, although indirect, hematological adverse effect.

Blood dyscrasias, sometimes fatal aplastic anemia [ ], isolated granulocytopenia, and agranulocytosis have been reported [ ]. The International Agranulocytosis and Aplastic Anemia study showed that indometacin was significantly associated with agranulocytosis and aplastic anemia [ ].

Neutropenia has been reported in a preterm male infant with a patent ductus arteriosus during treatment with indometacin; this could have been coincidence, but his mother had also previously had indometacin-associated neutropenia [ ].

Since indometacin is an inhibitor of platelet aggregation, impairment of thrombocyte function is frequent, but thrombocytopenia is rare. Severe clotting defects due to inhibition of platelet aggregation in premature infants have been described [ ]. Postoperative bleeding is significantly more frequent in indometacin-treated patients. Indometacin should probably not be used postoperatively in patients at increased risk of bleeding [ ].

Gastrointestinal

Gastrotoxicity is the main adverse effect of indometacin, and symptoms range from abdominal discomfort to ulcer penetration and perforation [ ]. The phenomenon of gastric mucosal adaptation has been evoked to explain the relatively low incidence of severe adverse effects, compared with the acute gastric damage that occurs in short-term studies. In healthy volunteers, indometacin produced acute gastroduodenal damage in all cases, but resolved in almost all, despite continuing administration. The author hypothesized that the severity of mucosal damage depends on the reduction in mucosal blood flow [ ].

Small bowel ulceration with thickening of the bowel wall and stricture formation in the terminal ileum and the ileocecal junction occurred in a patient with rheumatoid arthritis taking long-term indometacin [ ]. This is one reason why prolonged courses of indometacin should be avoided whenever possible, especially in elderly women.

Osmosin®, a formulation that contained potassium bicarbonate and released indometacin osmotically, was withdrawn in 1983, not long after its launch, because of reports of intestinal irritation, bleeding, perforation, and even death. These adverse reactions were most probably caused by the very high local concentrations of indometacin and potassium in the lower part of the gastrointestinal tract produced by the tablet, which shifted the adverse reactions from the stomach to the intestine [ ].

A diaphragm-like colonic stricture occurred in a woman taking indometacin suppositories [ ]. Perforation of colonic diverticula has been described [ ].

The use of indometacin suppositories can be associated with rectal irritation, mucosal inflammation, or necrosis with bleeding [ ]. The local effect on the gastric mucosa is less important than the systemic one, and suppositories do not cause fewer gastric lesions than oral formulations [ ].

Both dexamethasone and indometacin can cause spontaneous intestinal perforation in very low birth weight neonates. In a retrospective case-control study in 16 such neonates and 32 controls matched by birth weight, those who received three or more doses of indometacin for ductal closure or intraventricular hemorrhage prophylaxis and three or more doses of dexamethasone (0.3 mg/kg cumulative dose over 3 days) for refractory hypotension during the first postnatal week were 10 times more likely to develop intestinal perforation (95% CI = 1.22, 76) [ ].

Pancreas

Two cases of acute pancreatitis have been attributed to indometacin.

• A 56-year-old man developed acute pancreatitis after taking indometacin 150 mg/day orally for 3 weeks [ ]. Other causes were ruled out. He made a complete recovery after indometacin was withdrawn.

• A 71-year-old woman developed acute pancreatitis after taking indometacin for 1 month. Other causes were ruled out [ ]. The duct of Wirsung was dilated and the pancreas hypertrophied. An abdominal CT scan showed diffuse pancreatic necrosis with fluid collections in the anterior lateral spaces of both kidneys and in the lower omental sac. She improved spontaneously after withdrawal of indometacin.

Liver

Despite reversible changes in liver enzyme tests [ ] and a fatal case of acute hepatocellular necrosis, which may have been related to indometacin, the drug is rarely hepatotoxic [ ]. Indometacin-associated cholestatic liver injury has been described. The reaction was not severe and recovery was rapid and uneventful [ ].

Urinary tract

Indometacin nephrotoxicity is rare in patients with normal renal function, but indometacin can aggravate pre-existing renal impairment, as has been observed in patients with glomerulonephritis, nephrotic syndrome, systemic lupus erythematosus, and cirrhosis complicated by ascites [ ]. Severe but reversible loss of renal function in patients with systemic lupus erythematosus in the absence of active renal disease suggests that mesangial contraction in the glomerulus could significantly reduce the capillary surface area available for filtration and hence reduce the glomerular filtration rate [ , ]. There is a significant reduction in the glomerular filtration rate and a concomitant drop in renal excretion of sodium and water in patients with compensated cirrhosis without ascites treated with indometacin [ ].

Probable indometacin-induced renal papillary necrosis has been described in two patients with chronic juvenile arthritis [ ].

Reversible acute renal insufficiency with eosinophilia has been described [ ].

The harmful effect of indometacin on renal function has been used therapeutically to induce medical nephrectomy [ ].

Skin

Reactions to indometacin range from urticaria and pruritus to fixed rashes, purpura, and maculopapular and morbilliform eruptions. Toxic epidermal necrolysis has also been described [ ]. The frequency of skin reactions is lower than with pyrazolone derivatives. There is cross-sensitivity with aspirin.

Whether indometacin exacerbates psoriasis is not certain, but one report [ ] suggests that it can.

Indometacin can exacerbate dermatitis herpetiformis [ ].