A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Indocin Warnings, Precautions, Pregnancy, Nursing, Abuse - Indomethacin
Indocin Warnings, Precautions, Pregnancy, Nursing, Abuse - Indomethacin
WARNINGS
General
Because of the variability
of the potential of
indomethacin to
cause adverse reactions in the individual patient,
the following are strongly recommended:
1. The lowest possible effective dose
for the individual patient
should be prescribed. Increased dosage
tends to increase adverse effects, particularly in doses over
150-200 mg/day, without corresponding
increase in clinical benefits.
2. Careful instructions to, and observations of, the individual
patient are essential
to the prevention
of serious adverse reactions. As
advancing years appear to increase the possibility of adverse
reactions, indomethacin should be used with greater care in the
aged.
3. Effectiveness of indomethacin
in children has not been established. Indomethacin should not
be prescribed for children 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 children reported in the literature or elsewhere who
were treated with indomethacin
capsules, side effects
in children were comparable to those reported in adults. Experience
in children has been confined to the use of indomethacin
capsules. If a decision is made to use indomethacin
for children two 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 children with juvenile
rheumatoid arthritis,
including fatalities.
If indomethacin
treatment is instituted,
a suggested starting dose
is 2 mg/kg/day given in divided doses. Maximum daily dosage
should not exceed 4 mg/kg/day or 150-200 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.
Gastrointestinal Effects
Single or multiple
ulcerations, including perforation
and hemorrhage of the esophagus, stomach,
duodenum or small and
large intestine, have been reported to occur with indomethacin.
Fatalities have been reported in some instances. Rarely, intestinal
ulceration has been
associated with stenosis and obstruction. Gastrointestinal bleeding
without obvious ulcer formation and perforation
of pre-existing sigmoid
lesions (diverticulum, carcinoma, etc.) have occurred. Increased
abdominal pain
in ulcerative colitis patients or the development
of ulcerative colitis
and regional ileitis have been reported to occur rarely. Because
of the occurrence, and at times severity, of gastrointestinal
reactions to indomethacin, the prescribing physician
must be continuously alert for any sign
or symptom signaling a possible gastrointestinal
reaction. The risks of continuing therapy with indomethacin
in the face of such
symptoms must be weighed against the possible benefits to the individual
patient. Indomethacin should not be given to patients with active
gastrointestinal
lesions or with a history of recurrent gastrointestinal
lesions except under circumstances which warrant the very high risk
and where patients can be monitored very closely. The gastrointestinal
effects may be reduced by giving indomethacin capsules immediately
after meals, with food, or with antacids.
Risk of GI Ulcerations,
Bleeding and Perforation with NSAID
Therapy
Serious gastrointestinal
toxicity such
as bleeding, ulceration,
and perforation, can occur at any time, with or without warning
symptoms, in patients treated chronically with NSAID
therapy. Although minor
upper gastrointestinal problems such
as dyspepsia, are
common, usually developing early in therapy, physicians should remain
alert for ulceration
and bleeding in patients
treated chronically with NSAIDs
even in the absence
of previous GI tract symptoms.
In patients observed in clinical
trials of several months to two years duration, symptomatic
upper GI ulcers, gross
bleeding or perforation
appear to occur in approximately 1% of patients treated for 3-6
months, and in about 2-4% of patients treated for one year. Physicians
should inform patients about the signs and/or symptoms of serious
GI toxicity
and what steps to take
if they occur.
Studies to date have not identified any subset of patients not
at risk of developing peptic
ulceration and bleeding.
Except for a prior history of serious GI
events and other risk factors
known to be associated with peptic ulcer
disease, such
as alcoholism, smoking,
etc., no risk
factors (e.g., age, sex) have been associated with increased risk.
Elderly or debilitated patients seem to tolerate ulceration
or bleeding less well
than other individuals and most spontaneous
reports of fatal GI
events are in this population. Studies to date are inconclusive
concerning the relative risk
of various NSAIDs in causing such
reactions. High doses of any NSAID
probably carry a greater risk
of these reactions, although controlled clinical
trials showing this do not exist in most cases. In
considering the use of relatively large doses (within the recommended
dosage range), sufficient
benefit should be anticipated
to offset the potential
increased rlsk of GI toxicity.
Renal Effects
As with other nonsteroidal anti-inflammatory
drugs, long-term administration of indomethacin
to animals has resulted in renal
papillary necrosis
and other abnormal
renal pathology. In
humans, there have been reports of acute interstitial nephritis
with hematuria, proteinuria,
and occasionally nephrotic syndrome. A second form
of renal toxicity
has been seen in patients with prerenal and renal
conditions leading to a reduction
in renal blood
flow or blood volume,
where the renal prostaglandins
have a supportive role in the maintenance of renal
perfusion. In these patients
administration of an NSAID
may cause a dose
dependent reduction
in prostaglandin
formation and may precipitate
overt renal decompensation.
Patients at greatest risk of this reaction
are those with conditions such
as renal or hepatic
dysfunction, diabetes mellitus, advanced age, extracellular
volume depletion
from any cause, congestive heart
failure, septicemia,
pyelonephritis,
or concomitant use of any nephrotoxic drug. Indomethacin or other
NSAIDs should be given
with caution and renal
function should be
monitored in any patient
who may have reduced renal
reserve. Discontinuation of NSAID
therapy is typically
followed by recovery
to the pretreatment
state. Increases in serum
potassium concentration, including hyperkalemia,
have been reported, even in some patients without renal
impairment. In patients with
normal renal
function, these effects have been attributed to a hyporeninemic-hypoaldosteronism
state (see PRECAUTIONS,DRUG INTERACTIONS).
Since indomethacin
is eliminated primarily by the kidneys, patients with significantly
impaired renal function
should be closely monitored: a lower daily dosage
should be anticipated to avoid excessive drug
accumulation.
Ocular Effects
Corneal deposits and retinal
disturbances, including those of the macula, have been observed
in some patients who had received prolonged therapy with indomethacin.
The prescribing physician
should be alert to the possible association between the changes
noted and indomethacin. It is advisable to discontinue therapy
if such changes are observed.
Blurred vision may be
a significant symptom
and warrants a thorough ophthalmological examination. Since these
changes may be asymptomatic,
ophthalmologic examination
at periodic intervals is desirable in patients where therapy
is prolonged.
Central Nervous System Effects
Indomethacin may aggravate depression
or other psychiatric
disturbances, epilepsy, and parkinsonism, and should be used with
considerable caution in patients with these conditions. If severe
CNS adverse reactions develop,
indomethacin should be discontinued. Indomethacin may cause
drowsiness; therefore, patients should be cautioned about engaging
in activities requiring mental alertness and motor
coordination, such as driving
a car. Indomethacin may also cause
headache. Headache which persists, despite dosage
reduction, requires cessation of therapy
with indomethacin.
Use in Pregnancy and the Neonatal Period
Indomethacin is not recommended for use in pregnant women, since
safety for use has not been established, and because of the known effect
of drugs of this class on the human fetal cardiovascular system (closure
of the ductus arteriosus) during the third trimester of pregnancy.
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. As
with other nonsteroidal anti-inflammatory agents which inhibit
prostaglandin synthesis, indomethacin has been found to delay parturition
in rats. In rats and mice, 4 mg/kg/day given during the last three 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 three days
of life did not cause an increase in neuronal necrosis at either dose
level.
Use in Nursing Mothers
Indomethacin is excreted in the milk of lactating mothers. Indomethacin
is not recommended for use in nursing mothers.
PRECAUTIONS
General
Indomethacin may mask
the usual signs and symptoms of infection. Therefore, the physician
must be continually on the alert for this and should use the drug
with extra care in the presence of existing controlled infection.
Fluid retention and
peripheral edema
have been observed in some patients taking indomethacin. Therefore,
as with other nonsteroidal anti- inflammatory drugs, indomethacin
should be used with caution in patients with cardiac dysfunction,
hypertension, or
other conditions predisposing
to fluid retention. In
a study of patients with severe heart
failure and hyponatremia,
indomethacin was associated with significant
deterioration
of circulatory hemodynamics,
presumably due to inhibition
of prostaglandin
dependent compensatory mechanisms. Indomethacin, like other nonsteroidal
anti-inflammatory
agents, can inhibit platelet aggregation. This effect
is of shorter duration
than that seen with aspirin
and usually disappears within 24 hours after discontinuation of
indomethacin. Indomethacin has been shown to prolong bleeding
time (but within the normal
range) in normal subjects.
Because this effect may
be exaggerated in patients with underlying hemostatic
defects, indomethacin should be used with caution in persons with
coagulation defects. As with
other nonsteroidal anti-inflammatory
drugs, borderline
elevations of one or more liver
tests may occur in up to 15% of patients. These abnormalities may
progress, may remain essentially unchanged, or may be transient
with continued therapy. The SGPT
(ALT) test is probably
the most sensitive
indicator of liver dysfunction.
Meaningful (3 times the upper limit
of normal) elevations of SGPT
or SGOT (AST) occurred
in controlled clinical
trials in less than 1% of patients. A patient
with symptoms and/or signs suggesting liver
dysfunction, or in whom an abnormal
liver test
has occurred, should be evaluated for evidence of the development
of more severe hepatic
reaction while on therapy
with indomethacin. Severe hepatic
reactions, including jaundice
and cases of fatal hepatitis,
have been reported with indomethacin
as with other nonsteroidal anti-inflammatory
drugs. Although such reactions
are rare, if abnormal
liver tests persist or
worsen, if clinical
signs and symptoms consistent with liver
disease develop, or
if systemic manifestations
occur (e.g. eosinophilia
rash, etc.) indomethacin
should be discontinued.
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 73-110
weeks) and the mouse (dosing
period 62-88 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.
Pediatric Use
Effectiveness in children 14 years of age
and younger has not been established. (See WARNINGS).
Laboratory Tests
Because serious GI tract ulceration and bleeding can occur without
warning symptoms, physicians should follow chronically treated patients for the
signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see WARNINGS,
Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).
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, General; 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, Risk of GI
Ulcerations, Bleeding and Perforation with NSAID Therapy).
Indomethacin may cause confusion or, rarely,
psychosis (seeADVERSE
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).
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