Indomethacin (Page 4 of 6)

Drug/Laboratory Test Interactions

False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day, indomethacin had no tumorigenic effect.

Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day.

Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames test and E. coli with or without metabolic activation) and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila , and the micronucleus test in mice.

Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study or a two litter reproduction study in rats.

Pregnancy

Teratogenic Effects. Pregnancy Category C

Teratogenic studies were conducted in mice and rats at dosages of 0.5, 1, 2, and 4 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. Comparable studies in rodents using high doses of aspirin have shown similar maternal and fetal effects. However, animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies in pregnant women.

Indomethacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Nonteratogenic Effects

Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

The known effects of indomethacin and other drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.

In rats and mice, 4 mg/kg/day given during the last 3 days of gestation caused a decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live born fetuses was observed. At 2 mg/kg/day, no increase in neuronal necrosis was observed as compared to the control groups. Administration of 0.5 or 4 mg/kg/day during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of indomethacin on labor and delivery in pregnant women are unknown.

Nursing Mothers

Indomethacin is excreted in the milk of lactating mothers. Indomethacin is not recommended for use in nursing mothers.

Pediatric Use

Safety and effectiveness in pediatric patients 14 years of age and younger have not been established.

Indomethacin should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk.

In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules.

If a decision is made to use indomethacin for pediatric patients 2 years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1 to 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150 to 200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 to 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions (see WARNINGS, Gastrointestinal Effects:Risk of Ulceration, Bleeding, and Perforation and DOSAGE AND ADMINISTRATION). Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS:Gastrointestinal Effects:Risk of Ulceration, Bleeding, and Perforation).

Indomethacin may cause confusion or, rarely, psychosis (see ADVERSE REACTIONS); physicians should remain alert to the possibility of such adverse effects in the elderly.

This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see WARNINGS:Renal Effects).

ADVERSE REACTIONS

The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely.

Incidence greater than 1%

GASTROINTESTINAL
nausea¹ with or without vomiting
dyspepsia¹ (including indigestion, heartburn and epigastric pain)

Diarrhea
abdominal distress or pain
constipation

CENTRAL NERVOUS SYSTEM

headache (11.7%)
dizziness¹
vertigo
somnolence
depression and fatigue (including malaise and listlessness)

SPECIAL SENSES
tinnitus

CARDIOVASCULAR
none

METABOLIC
none

INTEGUMENTARY
none

HEMATOLOGIC
none

HYPERSENSITIVITY
none

GENITOURINARY
none

MISCELLANEOUS none

________________________________________

1 Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)

Incidence less than 1%

GASTROINTESTINAL
anorexia
bloating (includes distention)
flatulence
peptic ulcer
gastroenteritis
rectal bleeding
proctitis
single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines
intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice (some fatal cases have been reported)
intestinal strictures (diaphragms)

CENTRAL NERVOUS SYSTEM

anxiety (includes nervousness)
muscle weakness
involuntary muscle movements
insomnia
muzziness
psychic disturbances including psychotic episodes
mental confusion
drowsiness
light-headedness
syncope
paresthesia
aggravation of epilepsy and parkinsonism
depersonalization
coma
peripheral neuropathy
convulsions
dysarthria

SPECIAL SENSES

ocular-corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin

blurred vision
diplopia
hearing disturbances, deafness

CARDIOVASCULAR

congestive heart failure
hypertension
hypotension
tachycardia
chest pain
arrhythmia; palpitations

METABOLIC
edema
weight gain
fluid retention
flushing or sweating
hyperglycemia
glycosuria
hyperkalemia

INTEGUMENTARY
pruritus
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson Syndrome
erythema multiforme
toxic epidermal necrolysis

HEMATOLOGIC
leucopenia
bone marrow depression
anemia secondary to obvious or occult gastrointestinal bleeding
aplastic anemia
hemolytic anemia
agranulocytosis
thrombocytopenic purpura
disseminated intravascular coagulation

HYPERSENSITIVITY
acute anaphylaxis
acute respiratory distress
rapid fall in blood pressure resembling a shock-like state
angioedema
dyspnea
asthma
purpura
angiitis
pulmonary edema
fever

GENITOURINARY

hematuria
vaginal bleeding
proteinuria, nephrotic syndrome, interstitial nephritis
BUN elevation
renal insufficiency, including renal failure

MISCELLANEOUS
epistaxis
breast changes, including enlargement and tenderness, or gynecomastia

Causal Relationship Unknown

Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians:

Cardiovascular: thrombophlebitis

Hematologic: Although there have been several reports of leukemia, the supporting information is weak.

Genitourinary: urinary frequency

A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome (see also PRECAUTIONS:General).