Indomethacin (Page 3 of 8)

5.9 Serious Skin Reactions

NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of indomethacin capsules at the first appearance of skin rash or any other sign of hypersensitivity.

Indomethacin capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications (4) ].

5.10 Premature Closure of Fetal Ductus Arteriosus

Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including indomethacin capsules, in pregnant women starting at 30 weeks of gestation (third trimester) [ see Use in Specific Populations (8.1) ].

5.11 Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with indomethacin capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including indomethacin capsules, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions (7) ].

5.12 Masking of Inflammation and Fever

The pharmacological activity of indomethacin capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.13 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions (5.2, 5.3, 5.6)].

5.14 Central Nervous System Effects

Indomethacin capsules may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue indomethacin capsules if severe CNS adverse reactions develop.

Indomethacin capsules may cause drowsiness; therefore, caution patients 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 capsules.

5.15 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 capsules. Be alert to the possible association between the changes noted and indomethacin capsules. 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 receiving prolonged therapy. Indomethacin capsules are not indicated for long-term treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin capsules than in the group taking indomethacin suppositories or placebo.

In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin capsules or suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group.

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 capsules and these adverse reactions, some of which have been reported only rarely.

The adverse reactions reported with indomethacin capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the capsules.

Table 1 Summary of Adverse Reactions for Indomethacin Capsules
Incidence greater than 1% Incidence less than 1%
*
Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.)

GASTROINTESTINAL

nausea * with or without vomiting dyspepsia * (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation

anorexia bloating (includes distension) 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

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

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 convulsion dysarthria

SPECIAL SENSES

tinnitus

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

blurred vision diplopia hearing disturbances, deafness

CARDIOVASCULAR

None

hypertension hypotension tachycardia chest pain

congestive heart failure arrhythmia; palpitations

METABOLIC

None

edema weight gain fluid retention flushing or sweating

hyperglycemia glycosuria hyperkalemia

INTEGUMENTARY

none

pruritus rash; urticaria petechiae or ecchymosis

exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis

HEMATOLOGIC

None

leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding

aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation

HYPERSENSITIVITY

None

acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema

dyspnea asthma purpura angiitis pulmonary edema fever

GENITOURINARY

None

hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis

BUN elevation renal insufficiency, including renal failure

MISCELLANEOUS

None

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 Aβ hemolytic streptococcus , has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome.

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