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 extended-release capsules at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin extended-release capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications (4) ].

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin extended-release capsules. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue indomethacin extended-release capsules and evaluate the patient immediately.

5.11 Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs, including indomethacin extended-release capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs, including indomethacin extended-release capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment:

Use of NSAIDs, including indomethacin extended-release capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit indomethacin extended-release capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if indomethacin extended-release capsules treatment extends beyond 48 hours. Discontinue indomethacin extended-release capsules if oligohydramnios occurs and follow up according to clinical practice [ see Use in Specific Populations (8.1) ].

5.12 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 extended-release capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including indomethacin extended-release 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) ].

5.13 Masking of Inflammation and Fever

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

5.14 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) ].

5.15 Central Nervous System Effects

Indomethacin extended-release 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 extended-release capsules if severe CNS adverse reactions develop.

Indomethacin extended-release 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 extended-release capsules.

5.16 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 extended-release capsules. Be alert to the possible association between the changes noted and indomethacin extended-release 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 extended-release 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:

  • Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1) ]
  • GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.2) ]
  • Hepatotoxicity [ see Warnings and Precautions ( 5.3) ]
  • Hypertension [ see Warnings and Precautions ( 5.4) ]
  • Heart Failure and Edema [ see Warnings and Precautions ( 5.5) ]
  • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6) ]
  • Anaphylactic Reactions [ see Warnings and Precautions ( 5.7) ]
  • Serious Skin Reactions [ see Warnings and Precautions ( 5.9) ]
  • Hematologic Toxicity [ see Warnings and Precautions ( 5.12) ]

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 immediate-release 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 immediate-release capsules or suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group.

The adverse reactions for indomethacin immediate-release 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.

The adverse reactions reported with indomethacin immediate-release 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%

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)

pancreatitis

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

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

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

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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