Indomethacin Oral Suspension is indicated for:

{ "type": "p", "children": [], "text": "Indomethacin Oral Suspension is indicated for:" }

{ "type": "ul", "children": [ "Moderate to severe rheumatoid arthritis including acute flares of chronic disease", "Moderate to severe ankylosing spondylitis", "Moderate to severe osteoarthritis", "Acute painful shoulder (bursitis and/or tendinitis)", "Acute gouty arthritis" ], "text": "" }

Carefully consider the potential benefits and risks of indomethacin and other treatment options before deciding to use indomethacin. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs.

Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient.

Dosage recommendations for active stages of the following:

Indomethacin 25 mg (5 mL) twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg (5 mL) or by 50 mg (10 mL), if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150-200 mg (30 - 40 mL) is reached. Doses above this amount generally do not increase the effectiveness of the drug.

In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg (20 mL), of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg (40 mL). In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg (5 mL) or, if required, by 50 mg (10 mL) daily.

If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely.

If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued.

Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions.

As advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly [seeUse in Specific Populations (8.5)].

Indomethacin 75-150 mg (15-30 mL) daily in 3 or 4 divided doses.

The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days.

Indomethacin 50 mg (10 mL) three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days.

Indomethacin Oral Suspension, USP 25 mg per 5 mL is an off-white suspension with cherry flavor free from extraneous particles.

{ "type": "p", "children": [], "text": "Indomethacin Oral Suspension, USP 25 mg per 5 mL is an off-white suspension with cherry flavor free from extraneous particles." }

Indomethacin is contraindicated in the following patients:

{ "type": "p", "children": [], "text": "Indomethacin is contraindicated in the following patients:" }

{ "type": "ul", "children": [ "Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]", "History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]", "In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]" ], "text": "" }

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of indomethacin in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin immediately, and perform a clinical evaluation of the patient.

NSAIDs, including indomethacin, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of indomethacin in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease. The renal effects of indomethacin may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin [see Drug Interactions (7)]. Avoid the use of indomethacin in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Both Indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.

Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When indomethacin is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. 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 at the first appearance of skin rash or any other sign of hypersensitivity.

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

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin. 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 and evaluate the patient immediately.

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDS, including indomethacin, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including indomethacin, 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, 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 use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if indomethacin treatment extends beyond 48 hours. Discontinue indomethacin if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

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 has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including indomethacin, 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)].

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

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)].

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

Indomethacin 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.

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. 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 receiving prolonged therapy. Indomethacin is not indicated for long-term treatment.

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 INDOCIN Capsules than in the group taking INDOCIN 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 INDOCIN Suppositories or Capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group.

The adverse reactions for INDOCIN 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 INDOCIN Capsules may also occur with use of the suspension.

Table 1 Summary of Adverse Reactions for INDOCIN Capsules

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="621.775"> <colgroup> <col width="33.6363636363636%"/> <col width="33.0267379679144%"/> <col width="33.3368983957219%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold"><span class="Italics">Incidence greater than 1%</span></span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold"><span class="Italics">Incidence less than 1%</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">GASTROINTESTINAL</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <ul class="Square"> <li>nausea* with or without vomiting</li> <li>dyspepsia* (including indigestion, heartburn and epigastric pain)</li> <li>diarrhea</li> <li>abdominal distress or pain constipation</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>anorexia</li> <li>bloating (includes distension)</li> <li>flatulence</li> <li>peptic ulcer</li> <li>gastroenteritis</li> <li>rectal bleeding</li> <li>proctitis</li> <li>single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines</li> <li>intestinal ulceration associated with stenosis and obstruction</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis</li> <li>ulcerative stomatitis</li> <li>toxic hepatitis and jaundice (some fatal cases have been reported)</li> <li>intestinal strictures (diaphragms)</li> <li>pancreatitis</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">CENTRAL NERVOUS SYSTEM</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <ul class="Square"> <li>headache (11.7%)</li> <li>dizziness*</li> <li>vertigo</li> <li>somnolence</li> <li>depression and fatigue (including malaise and listlessness)</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>anxiety (includes nervousness)</li> <li>muscle weakness</li> <li>involuntary muscle movements</li> <li>insomnia</li> <li>muzziness</li> <li>psychic disturbances including psychotic episodes</li> <li>mental confusion</li> <li>drowsiness</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>light-headedness</li> <li>syncope</li> <li>paresthesia</li> <li>aggravation of epilepsy and parkinsonism</li> <li>depersonalization coma</li> <li>peripheral neuropathy</li> <li>convulsion</li> <li>dysarthria</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">SPECIAL SENSES</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <ul class="Square"> <li>tinnitus</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>blurred vision</li> <li>diplopia</li> <li>hearing disturbances, deafness</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">CARDIOVASCULAR</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">None<br/> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>hypertension</li> <li>hypotension</li> <li>tachycardia</li> <li>chest pain</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>congestive heart failure</li> <li>arrhythmia; palpitations</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">METABOLIC</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">None<br/> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>edema</li> <li>weight gain</li> <li>fluid retention</li> <li>flushing or sweating</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>hyperglycemia</li> <li>glycosuria</li> <li>hyperkalemia</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">INTEGUMENTARY</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">None<br/> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>pruritus</li> <li>rash; urticaria</li> <li>petechiae or ecchymosis</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>exfoliative dermatitis</li> <li>erythema nodosum</li> <li>loss of hair</li> <li>Stevens-Johnson syndrome</li> <li>erythema multiforme</li> <li>toxic epidermal necrolysis</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">HEMATOLOGIC</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">None<br/> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>leukopenia</li> <li>bone marrow depression</li> <li>anemia secondary to obvious or occult gastrointestinal bleeding</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>aplastic anemia</li> <li>hemolytic anemia</li> <li>agranulocytosis</li> <li>thrombocytopenic purpura</li> <li>disseminated intravascular coagulation</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">HYPERSENSITIVITY</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">None<br/> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>acute anaphylaxis</li> <li>acute respiratory distress</li> <li>rapid fall in blood pressure resembling a shock-like state</li> <li>angioedema</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>dyspnea</li> <li>asthma</li> <li>purpura</li> <li>angiitis</li> <li>pulmonary edema</li> <li>fever</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">GENITOURINARY</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">None<br/> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>hematuria</li> <li>vaginal bleeding</li> <li>proteinuria</li> <li>nephrotic syndrome</li> <li>interstitial nephritis</li> </ul> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>BUN elevation</li> <li>renal insufficiency, including renal failure</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Italics">MISCELLANEOUS</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">None<br/> </td><td class="Rrule" valign="top"> <ul class="Square"> <li>epistaxis</li> <li>breast changes, including enlargement and tenderness, or gynecomastia</li> </ul> </td><td class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="3" valign="top">* Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)<br/> </td> </tr> </tbody> </table></div>

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

The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

7 DRUG INTERACTIONS

{ "type": "p", "children": [], "text": "\n7 DRUG INTERACTIONS\n" }

See Table 2 for clinically significant drug interactions with indomethacin.

{ "type": "p", "children": [], "text": "See Table 2 for clinically significant drug interactions with indomethacin." }

Table 2 Clinically Significant Drug Interactions with Indomethacin

{ "type": "p", "children": [], "text": "\nTable 2 Clinically Significant Drug Interactions with Indomethacin\n" }

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="782.04"> <colgroup> <col width="16.3265306122449%"/> <col width="83.6734693877551%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Drugs That Interfere with Hemostasis</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</li> <li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [<span class="Italics">see Warnings and Precautions (5.12)</span>].<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Aspirin</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of indomethacin and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the indomethacin alone [<span class="Italics">see Warnings and Precautions (5.2)</span>].<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [<span class="Italics">see Warnings and Precautions (5.12)</span>].<br/>Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</li> <li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>During concomitant use of indomethacin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</li> <li>During concomitant use of indomethacin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [<span class="Italics">see Warnings and Precautions (5.6)</span>]<span class="Italics">.</span> </li> <li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Diuretics</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.<br/> <br/>It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.<br/> <br/>Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Indomethacin and triamterene should not be administered together.<br/>During concomitant use of indomethacin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.<br/>Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [<span class="Italics">see Warnings and Precautions (5.6)</span>].<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Digoxin</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">During concomitant use of indomethacin and digoxin, monitor serum digoxin levels.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Lithium</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance<span class="Italics">. </span>The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">During concomitant use of indomethacin and lithium, monitor patients for signs of lithium toxicity.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Methotrexate</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="middle">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="middle">During concomitant use of indomethacin and methotrexate, monitor patients for methotrexate toxicity.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Cyclosporine</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Concomitant use of indomethacin and cyclosporine may increase cyclosporine’s nephrotoxicity.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">During concomitant use of indomethacin and cyclosporine, monitor patients for signs of worsening renal function.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">NSAIDs and Salicylates</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [<span class="Italics">see Warnings and Precautions (5.2)</span>]<span class="Italics">.</span> <br/> <br/>Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [<span class="Italics">see</span><span class="Italics">Clinical Pharmacology (12.3)</span>]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Pemetrexed</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">Concomitant use of indomethacin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">During concomitant use of indomethacin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.<br/> <br/>NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.<br/> <br/>In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Probenecid</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Clinical Impact:</span> <br/> </td><td align="justify" class="Rrule" valign="top">When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Italics">Intervention:</span> <br/> </td><td align="justify" class="Rrule" valign="top">During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.<br/> <br/> <br/> <br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"782.04\">\n<colgroup>\n<col width=\"16.3265306122449%\"/>\n<col width=\"83.6734693877551%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Drugs That Interfere with Hemostasis</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td class=\"Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</li>\n<li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [<span class=\"Italics\">see Warnings and Precautions (5.12)</span>].<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Aspirin</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of indomethacin and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the indomethacin alone [<span class=\"Italics\">see Warnings and Precautions (5.2)</span>].<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [<span class=\"Italics\">see Warnings and Precautions (5.12)</span>].<br/>Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td class=\"Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</li>\n<li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>During concomitant use of indomethacin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</li>\n<li>During concomitant use of indomethacin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [<span class=\"Italics\">see Warnings and Precautions (5.6)</span>]<span class=\"Italics\">.</span>\n</li>\n<li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Diuretics</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.<br/> <br/>It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.<br/> <br/>Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Indomethacin and triamterene should not be administered together.<br/>During concomitant use of indomethacin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.<br/>Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [<span class=\"Italics\">see Warnings and Precautions (5.6)</span>].<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Digoxin</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">During concomitant use of indomethacin and digoxin, monitor serum digoxin levels.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Lithium</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance<span class=\"Italics\">. </span>The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">During concomitant use of indomethacin and lithium, monitor patients for signs of lithium toxicity.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Methotrexate</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"middle\">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"middle\">During concomitant use of indomethacin and methotrexate, monitor patients for methotrexate toxicity.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Cyclosporine</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Concomitant use of indomethacin and cyclosporine may increase cyclosporine’s nephrotoxicity.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">During concomitant use of indomethacin and cyclosporine, monitor patients for signs of worsening renal function.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">NSAIDs and Salicylates</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [<span class=\"Italics\">see Warnings and Precautions (5.2)</span>]<span class=\"Italics\">.</span>\n<br/> <br/>Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [<span class=\"Italics\">see</span><span class=\"Italics\">Clinical Pharmacology (12.3)</span>]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Pemetrexed</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">Concomitant use of indomethacin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">During concomitant use of indomethacin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.<br/> <br/>NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.<br/> <br/>In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Probenecid</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.<br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.<br/> <br/> <br/> <br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Effects on Laboratory Tests

{ "type": "p", "children": [], "text": "\nEffects on Laboratory Tests\n" }

Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients.

{ "type": "p", "children": [], "text": "Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients." }

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.

{ "type": "p", "children": [], "text": "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." }

Risk Summary

Use of NSAIDs, including indomethacin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of indomethacin use between about 20 and 30 weeks of gestation, and avoid indomethacin use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDS, including indomethacin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg (40 mL)). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including indomethacin, can cause premature closure of the fetal ductus arteriosus (see Data).

Oligohydramnios/Neonatal Renal Impairment:

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If indomethacin treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin and follow up according to clinical practice (see Data).

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) 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, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations.

In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level.

Risk Summary

Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin and any potential adverse effects on the breastfed infant from the indomethacin or from the underlying maternal condition.

Data

In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus.

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Safety and effectiveness in pediatric patients 14 years of age and younger has 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 INDOCIN Capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of INDOCIN Capsules.

If a decision is made to use indomethacin for pediatric patients 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 pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 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.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly.

Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].

{ "type": "p", "children": [], "text": "Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]." }

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

{ "type": "p", "children": [], "text": "Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding." }

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

{ "type": "p", "children": [], "text": "For additional information about overdosage treatment contact a poison control center (1-800-222-1222)." }

Indomethacin Oral Suspension, USP is a nonsteroidal anti-inflammatory drug, available as an oral suspension containing 25 mg of indomethacin per 5 mL, alcohol 1% v/v, and sorbic acid 0.1% added as a preservative for oral administration. The chemical name is -(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4, and it has the following chemical structure.

{ "type": "p", "children": [], "text": "Indomethacin Oral Suspension, USP is a nonsteroidal anti-inflammatory drug, available as an oral suspension containing 25 mg of indomethacin per 5 mL, alcohol 1% v/v, and sorbic acid 0.1% added as a preservative for oral administration. The chemical name is -(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4, and it has the following chemical structure." }

Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. Indomethacin has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The suspension has a pH of 2.5-5.0.

{ "type": "p", "children": [], "text": "Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. Indomethacin has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The suspension has a pH of 2.5-5.0." }

Indomethacin Oral Suspension, USP 25 mg per 5 mL is an off-white suspension with cherry flavor free from extraneous particles. The inactive ingredients in Indomethacin Oral Suspension, USP include: sorbic acid, sorbitol solution, alcohol (1% v/v), simethicone emulsion, xanthan gum, sodium hydroxide to adjust pH, artificial cherry flavor (including flavoring ingredients and alcohol) and purified water.

{ "type": "p", "children": [], "text": "Indomethacin Oral Suspension, USP 25 mg per 5 mL is an off-white suspension with cherry flavor free from extraneous particles. The inactive ingredients in Indomethacin Oral Suspension, USP include: sorbic acid, sorbitol solution, alcohol (1% v/v), simethicone emulsion, xanthan gum, sodium hydroxide to adjust pH, artificial cherry flavor (including flavoring ingredients and alcohol) and purified water." }

FDA approved dissolution test specifications differ from USP.

{ "type": "p", "children": [], "text": "FDA approved dissolution test specifications differ from USP." }

Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of indomethacin, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Absorption

Following single oral doses of INDOCIN Capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered INDOCIN Capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of Indomethacin Oral Suspension was found to be bioequivalent to a 50 mg INDOCIN Capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.

Distribution

Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk.

Elimination

Metabolism

Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed.

Excretion

Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours.

Specific Populations

Pediatric: The pharmacokinetics of indomethacin has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment: The pharmacokinetics of indomethacin has not been investigated in patients with hepatic impairment.

Renal Impairment: The pharmacokinetics of indomethacin has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)].

Drug Interaction Studies

Aspirin:

In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)].

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].

Diflunisal:

In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)].

Carcinogenesis

In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), 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 (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis, respectively).

Mutagenesis

Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.

Impairment of Fertility

Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two- generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two-litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis).

Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.

{ "type": "p", "children": [], "text": "Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis." }

Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease.

{ "type": "p", "children": [], "text": "Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease." }

Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects.

{ "type": "p", "children": [], "text": "Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects." }

Indomethacin Oral Suspension, USP 25 mg per 5 mL is an off-white suspension with cherry flavor free from extraneous particles. It is supplied as follows:

{ "type": "p", "children": [], "text": "Indomethacin Oral Suspension, USP 25 mg per 5 mL is an off-white suspension with cherry flavor free from extraneous particles. It is supplied as follows:" }

NDC 70954-637-10 in bottles of 237 mL

{ "type": "p", "children": [], "text": "NDC 70954-637-10 in bottles of 237 mL" }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid temperatures above 50°C (122°F). Avoid temperatures above 50°C (122°F). Preserve in tight, light-resistant containers and protect from freezing.

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid temperatures above 50°C (122°F). Avoid temperatures above 50°C (122°F). Preserve in tight, light-resistant containers and protect from freezing." }

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin and periodically during the course of ongoing therapy.

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin and periodically during the course of ongoing therapy." }

Cardiovascular Thrombotic Events

{ "type": "p", "children": [], "text": "\nCardiovascular Thrombotic Events\n" }

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]." }

Gastrointestinal Bleeding, Ulceration, and Perforation

{ "type": "p", "children": [], "text": "\nGastrointestinal Bleeding, Ulceration, and Perforation\n" }

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]." }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity\n" }

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin and seek immediate medical therapy [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin and seek immediate medical therapy [see Warnings and Precautions (5.3)]." }

Heart Failure and Edema

{ "type": "p", "children": [], "text": "\nHeart Failure and Edema\n" }

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]." }

Anaphylactic Reactions

{ "type": "p", "children": [], "text": "\nAnaphylactic Reactions\n" }

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]." }

Serious Skin Reactions, including DRESS

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions, including DRESS\n" }

Advise patients to stop taking indomethacin immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].

{ "type": "p", "children": [], "text": "Advise patients to stop taking indomethacin immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]." }

Female Fertility

{ "type": "p", "children": [], "text": "\nFemale Fertility\n" }

Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]." }

Fetal Toxicity

{ "type": "p", "children": [], "text": "\nFetal Toxicity\n" }

Inform pregnant women to avoid use of indomethacin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform pregnant women to avoid use of indomethacin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]." }

Avoid Concomitant Use of NSAIDs

{ "type": "p", "children": [], "text": "\nAvoid Concomitant Use of NSAIDs\n" }

Inform patients that the concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

{ "type": "p", "children": [], "text": "Inform patients that the concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia." }

Use of NSAIDs and Low-Dose Aspirin

{ "type": "p", "children": [], "text": "\nUse of NSAIDs and Low-Dose Aspirin\n" }

Inform patients not to use low-dose aspirin concomitantly with indomethacin until they talk to their healthcare provider [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients not to use low-dose aspirin concomitantly with indomethacin until they talk to their healthcare provider [see Drug Interactions (7)]." }

All trademarks are the property of their respective owners.

{ "type": "p", "children": [], "text": "All trademarks are the property of their respective owners." }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

ANI Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nANI Pharmaceuticals, Inc.\n" }

Baudette, MN 56623

{ "type": "p", "children": [], "text": "Baudette, MN 56623" }

Issued: 02/2025

{ "type": "p", "children": [], "text": "\nIssued: 02/2025" }

 LB4641-01

{ "type": "p", "children": [], "text": "\n LB4641-01" }

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"> <br/> <span class="Bold">Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)</span> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?</span> <br/> <span class="Bold">NSAIDs can cause serious side effects, including:</span> <br/> <ul class="Disc"> <li> <span class="Bold">Increased risk of a heart attack or stroke that can lead to death</span>. This risk may happen early in treatment and may increase:</li> </ul> <ul class="Circle"> <li>with increasing doses of NSAIDs</li> <li>with longer use of NSAIDs</li> </ul> <span class="Bold">Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)."</span> <br/> <span class="Bold">Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.</span> <br/> <span class="Bold"> </span> <br/> <span class="Bold"> ·         <span class="Bold">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:</span></span> <br/> <ul class="Circle"> <li>anytime during use</li> <li>without warning symptoms</li> <li>that may cause death<span class="Bold">      </span> <br/> <span class="Bold">The risk of getting an ulcer or bleeding increases with:</span> <br/> </li> <li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</li> <li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”</li> <li>increasing doses of NSAIDs</li> <li>longer use of NSAIDs</li> <li>smoking</li> <li>drinking alcohol</li> <li>oolder age</li> <li>poor health</li> <li>advanced liver disease</li> <li>bleeding problems <br/> <span class="Bold">NSAIDs should only be used:</span> <br/> </li> <li>exactly as prescribed</li> <li>at the lowest dose possible for your treatment</li> <li> for the shortest time needed</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">What are NSAIDs?</span> <br/>NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  <span class="Bold">Who should not take NSAIDs?</span><span class="Bold">Do not take NSAIDs:</span> <br/> <ul class="Disc"> <li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.</li> <li>right before or after heart bypass surgery.</li> </ul> <br/> <span class="Bold">Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:</span> <br/> <ul class="Disc"> <li>have liver or kidney problems</li> <li>have high blood pressure</li> <li>have asthma</li> <li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class="Bold">You should not take NSAIDs after about 30 weeks of pregnancy.</span> </li> <li>are breastfeeding or plan to breast feed<span class="Bold">.</span> </li> </ul> <span class="Bold"> </span> <br/> <span class="Bold">Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. </span>NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class="Bold">Do not start taking any new medicine without talking to your healthcare provider first.</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"> <span class="Bold">What are the possible side effects of NSAIDs?</span><span class="Bold">NSAIDs can cause serious side effects, including:</span> <br/> <span class="Bold">See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?”</span> <br/> <ul class="Disc"> <li>new or worse high blood pressure</li> <li>heart failure</li> <li>liver problems including liver failure</li> <li>kidney problems including kidney failure</li> <li>low red blood cells (anemia)</li> <li>life-threatening skin reactions</li> <li>life-threatening allergic reactions</li> <li> <span class="Bold">Other side effects of NSAIDs include: </span>stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. <br/> <span class="Bold">Get emergency help right away if you get any of the following symptoms:</span> <br/> </li> <li>shortness of breath or trouble breathing</li> <li>chest pain</li> <li>weakness in one part or side of your body</li> <li>slurred speech</li> <li>swelling of the face or throat <br/> <span class="Bold">Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:</span> <br/> </li> <li>nausea</li> <li>more tired or weaker than usual</li> <li>diarrhea</li> <li>itching</li> <li>your skin or eyes look yellow</li> <li>indigestion or stomach pain</li> <li>flu-like symptoms</li> <li>vomit blood</li> <li>there is blood in your bowel movement or it is black and sticky like tar</li> <li>unusual weight gain</li> <li>skin rash or blisters with fever</li> <li>swelling of the arms, legs, hands and feet</li> </ul> <br/> <span class="Bold">If you take too much of your NSAID, call your healthcare provider or get medical help right away.</span> <br/>These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.<br/> <br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  <span class="Bold">Other information about NSAIDs</span> <ul class="Disc"> <li>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.</li> </ul> <ul class="Disc"> <li>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">General information about the safe and effective use of NSAIDs</span>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.<br/> <br/>If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.</td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">All trademarks are the property of their respective owners. <br/>Distributed by:<br/> <span class="Bold">ANI Pharmaceuticals, Inc.</span> <br/>Baudette, MN 56623</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\">\n<br/>\n<span class=\"Bold\">Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)</span> </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?</span>\n<br/>\n<span class=\"Bold\">NSAIDs can cause serious side effects, including:</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased risk of a heart attack or stroke that can lead to death</span>. This risk may happen early in treatment and may increase:</li>\n</ul>\n<ul class=\"Circle\">\n<li>with increasing doses of NSAIDs</li>\n<li>with longer use of NSAIDs</li>\n</ul>\n<span class=\"Bold\">Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).\"</span>\n<br/>\n<span class=\"Bold\">Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.</span>\n<br/>\n<span class=\"Bold\"> </span>\n<br/>\n<span class=\"Bold\"> ·         <span class=\"Bold\">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:</span></span>\n<br/>\n<ul class=\"Circle\">\n<li>anytime during use</li>\n<li>without warning symptoms</li>\n<li>that may cause death<span class=\"Bold\">      </span>\n<br/>\n<span class=\"Bold\">The risk of getting an ulcer or bleeding increases with:</span>\n<br/>\n</li>\n<li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</li>\n<li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”</li>\n<li>increasing doses of NSAIDs</li>\n<li>longer use of NSAIDs</li>\n<li>smoking</li>\n<li>drinking alcohol</li>\n<li>oolder age</li>\n<li>poor health</li>\n<li>advanced liver disease</li>\n<li>bleeding problems <br/>\n<span class=\"Bold\">NSAIDs should only be used:</span>\n<br/>\n</li>\n<li>exactly as prescribed</li>\n<li>at the lowest dose possible for your treatment</li>\n<li> for the shortest time needed</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">What are NSAIDs?</span>\n<br/>NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\">  <span class=\"Bold\">Who should not take NSAIDs?</span><span class=\"Bold\">Do not take NSAIDs:</span>\n<br/>\n<ul class=\"Disc\">\n<li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.</li>\n<li>right before or after heart bypass surgery.</li>\n</ul> <br/>\n<span class=\"Bold\">Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<br/>\n<ul class=\"Disc\">\n<li>have liver or kidney problems</li>\n<li>have high blood pressure</li>\n<li>have asthma</li>\n<li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class=\"Bold\">You should not take NSAIDs after about 30 weeks of pregnancy.</span>\n</li>\n<li>are breastfeeding or plan to breast feed<span class=\"Bold\">.</span>\n</li>\n</ul>\n<span class=\"Bold\"> </span>\n<br/>\n<span class=\"Bold\">Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. </span>NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class=\"Bold\">Do not start taking any new medicine without talking to your healthcare provider first.</span> <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"> <span class=\"Bold\">What are the possible side effects of NSAIDs?</span><span class=\"Bold\">NSAIDs can cause serious side effects, including:</span>\n<br/>\n<span class=\"Bold\">See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?”</span>\n<br/>\n<ul class=\"Disc\">\n<li>new or worse high blood pressure</li>\n<li>heart failure</li>\n<li>liver problems including liver failure</li>\n<li>kidney problems including kidney failure</li>\n<li>low red blood cells (anemia)</li>\n<li>life-threatening skin reactions</li>\n<li>life-threatening allergic reactions</li>\n<li>\n<span class=\"Bold\">Other side effects of NSAIDs include: </span>stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. <br/>\n<span class=\"Bold\">Get emergency help right away if you get any of the following symptoms:</span>\n<br/>\n</li>\n<li>shortness of breath or trouble breathing</li>\n<li>chest pain</li>\n<li>weakness in one part or side of your body</li>\n<li>slurred speech</li>\n<li>swelling of the face or throat <br/>\n<span class=\"Bold\">Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:</span>\n<br/>\n</li>\n<li>nausea</li>\n<li>more tired or weaker than usual</li>\n<li>diarrhea</li>\n<li>itching</li>\n<li>your skin or eyes look yellow</li>\n<li>indigestion or stomach pain</li>\n<li>flu-like symptoms</li>\n<li>vomit blood</li>\n<li>there is blood in your bowel movement or it is black and sticky like tar</li>\n<li>unusual weight gain</li>\n<li>skin rash or blisters with fever</li>\n<li>swelling of the arms, legs, hands and feet</li>\n</ul> <br/>\n<span class=\"Bold\">If you take too much of your NSAID, call your healthcare provider or get medical help right away.</span>\n<br/>These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.<br/> <br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\">  <span class=\"Bold\">Other information about NSAIDs</span>\n<ul class=\"Disc\">\n<li>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.</li>\n</ul>\n<ul class=\"Disc\">\n<li>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">General information about the safe and effective use of NSAIDs</span>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.<br/> <br/>If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Lrule Rrule\" valign=\"middle\">All trademarks are the property of their respective owners. <br/>Distributed by:<br/>\n<span class=\"Bold\">ANI Pharmaceuticals, Inc.</span>\n<br/>Baudette, MN 56623</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

Issued: 02/2025

{ "type": "p", "children": [], "text": "\nIssued: 02/2025" }

 LB4641-01

{ "type": "p", "children": [], "text": "\n LB4641-01" }

Indomethacin Oral Suspension, USP 25 mg per 5 mL - NDC 70954-637-10 - 237 mL per bottle

{ "type": "p", "children": [], "text": "Indomethacin Oral Suspension, USP 25 mg per 5 mL - NDC 70954-637-10 - 237 mL per bottle" }

Carton Label

{ "type": "p", "children": [], "text": "Carton Label" }

Container label

{ "type": "p", "children": [], "text": "Container label" }

Indomethacin for Injection is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. Clear-cut clinical evidence of a hemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly, or pulmonary plethora on chest x-ray.

{ "type": "p", "children": [], "text": "Indomethacin for Injection is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. Clear-cut clinical evidence of a hemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly, or pulmonary plethora on chest x-ray.\n" }

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles.

Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection. Benzyl alcohol as a preservative has been associated with toxicity in neonates. Therefore, do not use diluents that contain preservatives. If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL. Discard any unused portion of the solution as it does not contain a preservative. Prepare a fresh solution just prior to each administration. Once reconstituted, the indomethacin solution may be injected intravenously. While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes.

Further dilution with intravenous infusion solutions is not recommended.

Indomethacin for Injection is supplied in single dose vials containing 1 mg of indomethacin as a sterile lyophilized powder or plug for reconstitution.

{ "type": "p", "children": [], "text": "Indomethacin for Injection is supplied in single dose vials containing 1 mg of indomethacin as a sterile lyophilized powder or plug for reconstitution.\n" }

Indomethacin for Injection is contraindicated in neonates:

{ "type": "p", "children": [], "text": "Indomethacin for Injection is contraindicated in neonates:\n" }

{ "type": "ul", "children": [ "With proven or suspected infection that is untreated\n", "Who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding\n", "With thrombocytopenia or coagulation defects\n", "With or who are suspected of having necrotizing enterocolitis\n", "With significant impairment of renal function\n", "With congenital heart disease in whom patency of the ductus arteriosus is necessary for satisfactory pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta).\n" ], "text": "" }

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.

Severe hepatic reactions have been reported in adults treated chronically with oral indomethacin for arthritic disorders. [For further information, see package insert for oral indomethacin]. If clinical signs and symptoms consistent with liver disease develop in the neonate, or if systemic manifestations occur, discontinue Indomethacin for Injection.

Indomethacin for Injection may inhibit platelet aggregation. In one small study, platelet aggregation was grossly abnormal after indomethacin therapy (given orally to premature infants to close the ductus arteriosus). Platelet aggregation returned to normal by the tenth day. Observe premature infants for signs of bleeding.

In the collaborative study, major gastrointestinal bleeding was no more common in neonates receiving indomethacin than in neonates on placebo. However, minor gastrointestinal bleeding (i.e., chemical detection of blood in the stool) was more commonly noted in neonates treated with indomethacin.

Severe gastrointestinal effects have been reported in adults with various arthritic disorders treated chronically with oral indomethacin. [For further information, see package insert for oral indomethacin].

Prematurity per se is associated with an increased incidence of spontaneous intraventricular hemorrhage. Because indomethacin may inhibit platelet aggregation, the potential for intraventricular bleeding may be increased. However, in the large multicenter study of Indomethacin for Injection, the incidence of intraventricular hemorrhage in neonates treated with Indomethacin for Injection was not significantly higher than in the control neonates.

Indomethacin for Injection may cause significant reduction in urine output (50 percent or more) with concomitant elevations of blood urea nitrogen and creatinine, and reductions in glomerular filtration rate and creatinine clearance. These effects in most neonates are transient, disappearing with cessation of therapy with Indomethacin for Injection. However, because adequate renal function can depend upon renal prostaglandin synthesis, Indomethacin for Injection may precipitate renal insufficiency, including acute renal failure, especially in neonates with other conditions that may adversely affect renal function (e.g., extracellular volume depletion from any cause, congestive heart failure, sepsis, concomitant use of any nephrotoxic drug, hepatic dysfunction). When significant suppression of urine volume occurs after a dose of Indomethacin for Injection, do not give additional doses until urine output returns to normal levels.

Indomethacin for Injection in pre-term infants may suppress water excretion to a greater extent than sodium excretion. When this occurs, a significant reduction in serum sodium values (i.e., hyponatremia) may result. Monitor renal function and serum electrolyte levels during therapy with Indomethacin for Injection [see Dosage and Administration (2)].

Administer Indomethacin for Injection carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.

In a double-blind, placebo-controlled trial of 405 premature infants weighing less than or equal to 1,750 g with evidence of large ductal shunting, in those neonates treated with indomethacin (n=206), there was a statistically significantly greater incidence of bleeding problems, including gross or microscopic bleeding into the gastrointestinal tract, oozing from the skin after needle stick, pulmonary hemorrhage, and disseminated intravascular coagulopathy. There was no statistically significant difference between treatment groups in intracranial hemorrhage.

The neonates treated with Indomethacin for Injection had a significantly higher incidence of transient oliguria and elevations of serum creatinine (greater than or equal to 1.8 mg/dL) than did the neonates treated with placebo.

The incidences of retrolental fibroplasia (grades III and IV) and pneumothorax in neonates treated with Indomethacin for Injection were no greater than in placebo controls and were statistically significantly lower than in surgically-treated neonates.

The following additional adverse reactions in neonates have been reported from the collaborative study, anecdotal case reports, from other studies using rectal, oral, or intravenous indomethacin for treatment of patent ductus arteriosus or in marketed use. The rates are calculated from a database that contains experience of 849 indomethacin-treated neonates reported in the medical literature, regardless of the route of administration. One year follow-up is available on 175 neonates and shows no long-term sequelae that could be attributed to indomethacin. In controlled clinical studies, only electrolyte imbalance and renal dysfunction (of the reactions listed below) occurred statistically significantly more frequently after Indomethacin for Injection than after placebo. Reactions marked with a single asterisk (*) occurred in 3 to 9 percent of indomethacin-treated neonates; those marked with a double asterisk (**) occurred in 3 to 9 percent of both indomethacin- and placebo-treated neonates. Unmarked reactions occurred in less than 3 percent of neonates.

Renal: renal failure, renal dysfunction in 41 percent of neonates, including one or more of the following: reduced urinary output; reduced urine sodium, chloride, or potassium, urine osmolality, free water clearance, or glomerular filtration rate; elevated serum creatinine or BUN; uremia.

Cardiovascular: intracranial bleeding**, pulmonary hypertension.

Gastrointestinal: gastrointestinal bleeding*, vomiting, abdominal distention, transient ileus, gastric perforation, localized perforation(s) of the small and/or large intestine, necrotizing enterocolitis.

Metabolic: hyponatremia*, elevated serum potassium*, reduction in blood sugar, including hypoglycemia, increased weight gain (fluid retention).

Coagulation: decreased platelet aggregation [see Warnings and Precautions (5.3)].

The following adverse reactions have also been reported in neonates treated with indomethacin, however, a causal relationship to therapy with Indomethacin for Injection has not been established:

Cardiovascular: bradycardia.

Respiratory: apnea, exacerbation of pre-existing pulmonary infection.

Metabolic: acidosis/alkalosis.

Hematologic: disseminated intravascular coagulation, thrombocytopenia.

Ophthalmic: retrolental fibroplasia.**

Dermatologic: drug reaction with eosinophilia and systemic symptoms (DRESS)

A variety of additional adverse experiences have been reported in adults treated with oral indomethacin for moderate to severe rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute painful shoulder and acute gouty arthritis (see package insert for oral indomethacin for additional information concerning adverse reactions and other cautionary statements). Their relevance to the pre-term infant receiving indomethacin for patent ductus arteriosus is unknown, however, the possibility exists that these experiences may be associated with the use of Indomethacin for Injection in pre-term infants.

Because the half-life of digoxin (given frequently to pre-term infants with patent ductus arteriosus and associated cardiac failure) may be prolonged when given concomitantly with indomethacin, observe neonates receiving concomitant digoxin closely; frequent ECGs and serum digoxin levels may be required to prevent or detect digoxin toxicity early.

Indomethacin usually does not influence the hypoprothrombinemia produced by anticoagulants. When indomethacin is added to anticoagulants, monitor prothrombin time closely. In post-marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and Indomethacin for Injection.

Therapy with indomethacin may blunt the natriuretic effect of furosemide. This response has been attributed to inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs. In a study of 19 premature infants with patent ductus arteriosus treated with either Indomethacin for Injection alone or a combination of Indomethacin for Injection and furosemide, results showed that neonates receiving both Indomethacin for Injection and furosemide had significantly higher urinary output, higher levels of sodium and chloride excretion, and higher glomerular filtration rates than did those receiving Indomethacin for Injection alone. In this study, therapy with furosemide helped to maintain renal function in the premature infant when Indomethacin for Injection was added.

In one study of premature infants treated with Indomethacin for Injection and also receiving either gentamicin or amikacin, both peak and trough levels of these aminoglycosides were significantly elevated.

In some patients with compromised renal function, the co-administration of an NSAID and an ACE inhibitor or angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.

Sterile Indomethacin for Injection for intravenous administration is lyophilized indomethacin for injection. Each vial of indomethacin for injection contains 1 mg indomethacin; 0.29 mg monobasic sodium phosphate, 0.41 mg dibasic sodium phosphate and not more than 0.24 mg of sodium hydroxide (used for converting indomethacin base to the sodium salt) as a white to yellow lyophilized powder or plug. Variations in the size of the lyophilized plug and the intensity of color have no relationship to the quality or amount of indomethacin present in the vial. If necessary, hydrochloric acid (q.s.) and sodium hydroxide (q.s.) are added as pH adjusters. The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. The pH of the product does not meet the USP monograph [FD&C Act Chapter V, SEC. 501. [21USC §351](b)].

{ "type": "p", "children": [], "text": "Sterile Indomethacin for Injection for intravenous administration is lyophilized indomethacin for injection. Each vial of indomethacin for injection contains 1 mg indomethacin; 0.29 mg monobasic sodium phosphate, 0.41 mg dibasic sodium phosphate and not more than 0.24 mg of sodium hydroxide (used for converting indomethacin base to the sodium salt) as a white to yellow lyophilized powder or plug. Variations in the size of the lyophilized plug and the intensity of color have no relationship to the quality or amount of indomethacin present in the vial. If necessary, hydrochloric acid (q.s.) and sodium hydroxide (q.s.) are added as pH adjusters. The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. The pH of the product does not meet the USP monograph [FD&C Act Chapter V, SEC. 501. [21USC §351](b)].\n" }

Indomethacin is designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The structural formula is:

{ "type": "p", "children": [], "text": "Indomethacin is designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The structural formula is:\n" }

Although the exact mechanism of action through which indomethacin causes closure of a patent ductus arteriosus is not known, it is believed to be through inhibition of prostaglandin synthesis.

Indomethacin has been shown to be a potent inhibitor of prostaglandin synthesis, both in vitro and in vivo. In human newborns with certain congenital heart malformations, PGE 1 dilates the ductus arteriosus. In fetal and newborn lambs, E type prostaglandins have also been shown to maintain the patency of the ductus, and as in human newborns, indomethacin causes its constriction.

Studies in healthy young animals and in premature infants with patent ductus arteriosus indicated that, after the first dose of intravenous indomethacin, there was a transient reduction in cerebral blood flow velocity and cerebral blood flow. Similar decreases in mesenteric blood flow and velocity have been observed. The clinical significance of these effects has not been established.

In double-blind, placebo-controlled studies of Indomethacin for Injection in 460 small pre-term infants, weighing 1,750 g or less, the neonates treated with placebo had a ductus closure rate after 48 hours of 25 to 30 percent, whereas those treated with Indomethacin for Injection had a 75 to 80 percent closure rate. In one of these studies, a multicenter study, involving 405 pre-term infants, later reopening of the ductus arteriosus occurred in 26 percent of neonates treated with Indomethacin for Injection however, 70 percent of these closed subsequently without the need for surgery or additional indomethacin.

The disposition of indomethacin following intravenous administration (0.2 mg/kg) in pre-term neonates with patent ductus arteriosus has not been extensively evaluated. Even though the plasma half-life of indomethacin was variable among premature infants, it was shown to vary inversely with postnatal age and weight. In one study, of 28 neonates who could be evaluated, the plasma half-life in those less than 7 days old averaged 20 hours (range: 3 to 60 hours, n=18). In neonates older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range: 4 to 38 hours, n=10). Grouping the neonates by weight, mean plasma half-life in those weighing less than 1,000 g was 21 hours (range: 9 to 60 hours, n=10); in those neonates weighing more than 1,000 g, the mean plasma half-life was 15 hours (range: 3 to 52 hours, n=18).

Following intravenous administration in adults, indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean plasma half-life of indomethacin is 4.5 hours. In the absence of enterohepatic circulation, it is 90 minutes. Indomethacin has been found to cross the blood-brain barrier and the placenta.

In adults, about 99 percent of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. The percent bound in neonates has not been studied. In controlled trials in premature infants, however, no evidence of bilirubin displacement has been observed as evidenced by increased incidence of bilirubin encephalopathy (kernicterus).

In rats and mice, oral indomethacin 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.

{ "type": "p", "children": [], "text": "In rats and mice, oral indomethacin 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.\n" }

Pregnant rats, given 2 mg/kg/day and 4 mg/kg/day during the last trimester of gestation, delivered offspring whose pulmonary blood vessels were both reduced in number and excessively muscularized. These findings are similar to those observed in the syndrome of persistent pulmonary hypertension of the neonate.

{ "type": "p", "children": [], "text": "Pregnant rats, given 2 mg/kg/day and 4 mg/kg/day during the last trimester of gestation, delivered offspring whose pulmonary blood vessels were both reduced in number and excessively muscularized. These findings are similar to those observed in the syndrome of persistent pulmonary hypertension of the neonate.\n" }

Sterile Indomethacin for Injection is a lyophilized white to yellow powder or plug supplied as single dose vials containing indomethacin for injection, equivalent to 1 mg indomethacin.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Product</span> <br/> <span class="Bold">No.</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">NDC</span> <br/> <span class="Bold">No.</span> <br/> </td><td class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">NP605903<br/> </td><td class="Rrule" valign="middle">63323-659-09<br/> </td><td class="Rrule" valign="middle">1 mg per vial,<br/>Packaged individually. </td> </tr> </tbody> </table></div>

The container closure is not made with natural rubber latex.

Store at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F).   Protect from light.  Store container in carton until contents have been used.

Novaplus is a registered trademark of Vizient, Inc.

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Fresenius Kabi

{ "type": "p", "children": [], "text": "\nFresenius Kabi\n" }

Lake Zurich, IL 60047 www.fresenius-kabi.com/us

{ "type": "p", "children": [], "text": "Lake Zurich, IL 60047\n www.fresenius-kabi.com/us" }

451358B

{ "type": "p", "children": [], "text": "451358B" }

PACKAGE LABEL - PRINCIPAL DISPLAY - Indomethacin for Injection 1 mg Vial Label

{ "type": "p", "children": [], "text": "\nPACKAGE LABEL - PRINCIPAL DISPLAY - Indomethacin for Injection 1 mg Vial Label\n" }

NDC 63323-659-09        NP605903

{ "type": "p", "children": [], "text": "NDC 63323-659-09        NP605903" }

Indomethacin For Injection 1 mg per vial

{ "type": "p", "children": [], "text": "\nIndomethacin For Injection\n1 mg per vial\n" }

FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS

{ "type": "p", "children": [], "text": "FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS" }

Sterile     Rx only

{ "type": "p", "children": [], "text": "Sterile     Rx only" }

Single Dose Vial - Discard unused portion

{ "type": "p", "children": [], "text": "Single Dose Vial - Discard unused portion" }

PACKAGE LABEL - PRINCIPAL DISPLAY - Indomethacin for Injection 1 mg Carton Panel 

{ "type": "p", "children": [], "text": "\nPACKAGE LABEL - PRINCIPAL DISPLAY - Indomethacin for Injection 1 mg Carton Panel " }

NDC 63323-659-09        NP605903

{ "type": "p", "children": [], "text": "NDC 63323-659-09        NP605903" }

Indomethacin For Injection

{ "type": "p", "children": [], "text": "\nIndomethacin For Injection\n" }

1 mg per vial

{ "type": "p", "children": [], "text": "\n1 mg per vial\n" }

For Intravenous Use Only 

{ "type": "p", "children": [], "text": "For Intravenous Use Only \n\n" }

FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS

{ "type": "p", "children": [], "text": "FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

One vial

{ "type": "p", "children": [], "text": "One vial " }

Single Dose Vial - Discard any unused portion immediately.

{ "type": "p", "children": [], "text": "Single Dose Vial - Discard any unused portion immediately." }

Indomethacin capsules are indicated for:

{ "type": "p", "children": [], "text": "Indomethacin capsules are indicated for:" }

{ "type": "ul", "children": [ "Moderate to severe rheumatoid arthritis including acute flares of chronic disease", "Moderate to severe ankylosing spondylitis", "Moderate to severe osteoarthritis", "Acute painful shoulder (bursitis and/or tendinitis)", "Acute gouty arthritis" ], "text": "" }

Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5)].

After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs.

Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient.

Dosage recommendations for active stages of the following:

Indomethacin capsules 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 to 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug.

In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily.

If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely.

If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued.

Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions.

As advancing years appear to increase the possibility of adverse reactions, indomethacin capsules should be used with greater care in the elderly [see Use in Specific Populations (8.5)].

Indomethacin capsules 75 to 150 mg daily in 3 or 4 divided doses.

The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 to 14 days.

Indomethacin capsules 50 mg three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days.

Indomethacin Capsules, USP are available containing either 25 mg or 50 mg of indomethacin, USP.

{ "type": "p", "children": [], "text": "Indomethacin Capsules, USP are available containing either 25 mg or 50 mg of indomethacin, USP." }

The 25 mg capsule is a size ‘3’ two piece opaque green hard gelatin capsule imprinted with ‘G406’ on the body and ‘G’ on the cap, filled with white to off-white granular powder.

{ "type": "p", "children": [], "text": "The 25 mg capsule is a size ‘3’ two piece opaque green hard gelatin capsule imprinted with ‘G406’ on the body and ‘G’ on the cap, filled with white to off-white granular powder." }

Indomethacin capsules are contraindicated in the following patients:

{ "type": "p", "children": [], "text": "Indomethacin capsules are contraindicated in the following patients:" }

{ "type": "ul", "children": [ "Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product\n \n [see Warnings and Precautions (\n \n 5.7,\n \n 5.9)]\n \n .\n \n ", "History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients\n \n [see Warnings and Precautions (\n \n 5.7,\n \n 5.8)]\n \n .\n \n ", "In the setting of coronary artery bypass graft (CABG) surgery\n \n [see Warnings and Precautions (\n \n 5.1)].\n \n \n" ], "text": "" }

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions (5.2)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [ see Contraindications (4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of indomethacin capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin capsules immediately, and perform a clinical evaluation of the patient.

NSAIDs, including indomethacin capsules, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions (7)].

Avoid the use of indomethacin capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of indomethacin capsules in patients with advanced renal disease. The renal effects of indomethacin capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin capsules [ see Drug Interactions (7)] .Avoid the use of indomethacin capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Both Indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.

Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4)and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin capsules are contraindicated in patients with this form of aspirin sensitivity [ see Contraindications (4)]. When indomethacin capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. 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)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin. 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 capsules and evaluate the patient immediately.

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs, including indomethacin capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs, including indomethacin 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 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 capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if indomethacin capsules treatment extends beyond 48 hours. Discontinue indomethacin capsules if oligohydramnios occurs and follow up according to clinical practice [ see Use in Specific Populations ( 8.1) ].

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)].

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

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)].

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.

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.

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.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 1 Summary of Adverse Reactions for Indomethacin Capsules</span> </caption> <col width="30%"/> <col width="40%"/> <col width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"><span class="Italics">Incidence greater than 1%</span></span></th><th align="left" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"><span class="Italics">Incidence less than 1%</span></span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Italics">GASTROINTESTINAL</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">nausea* with or without vomiting <br/> dyspepsia* (including indigestion, heartburn and epigastric pain) <br/> diarrhea <br/> abdominal distress or pain <br/> constipation </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">anorexia <br/> bloating (includes distension) <br/> flatulence <br/> peptic ulcer <br/> gastroenteritis <br/> rectal bleeding <br/> proctitis <br/> single or multiple ulcerations, </p> <p>including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines <br/> intestinal ulceration associated with stenosis and obstruction </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis <br/> ulcerative stomatitis <br/> toxic hepatitis and jaundice (some fatal cases have been reported) <br/> intestinal strictures (diaphragms) </p> <p>pancreatitis</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">CENTRAL NERVOUS SYSTEM</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">headache (11.7%) <br/> dizziness* <br/> vertigo <br/> somnolence <br/> depression and fatigue (including malaise and listlessness) </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">anxiety (includes nervousness) <br/> muscle weakness <br/> involuntary muscle movements <br/> insomnia <br/> muzziness <br/> psychic disturbances including psychotic episodes <br/> mental confusion <br/> drowsiness </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">light-headedness <br/> syncope <br/> paresthesia <br/> aggravation of epilepsy and parkinsonism <br/> depersonalization <br/> coma <br/> peripheral neuropathy <br/> convulsion <br/> dysarthria </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">SPECIAL SENSES</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">tinnitus</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">ocular-corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">blurred vision <br/> diplopia <br/> hearing disturbances, deafness </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">CARDIOVASCULAR</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">None</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">hypertension <br/> hypotension <br/> tachycardia <br/> chest pain </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">congestive heart failure <br/> arrhythmia; palpitations </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">METABOLIC</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">None</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">edema <br/> weight gain <br/> fluid retention <br/> flushing or sweating </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">hyperglycemia <br/> glycosuria <br/> hyperkalemia </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">INTEGUMENTARY</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">none</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">pruritus <br/> rash; urticaria <br/> petechiae or ecchymosis </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">exfoliative dermatitis <br/> erythema nodosum <br/> loss of hair <br/> Stevens-Johnson syndrome <br/> erythema multiforme <br/> toxic epidermal necrolysis </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">HEMATOLOGIC</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">None</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">leukopenia <br/> bone marrow depression <br/> anemia secondary to obvious or occult gastrointestinal bleeding </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">aplastic anemia <br/> hemolytic anemia <br/> agranulocytosis <br/> thrombocytopenic purpura <br/> disseminated intravascular coagulation </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">HYPERSENSITIVITY</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">None</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">acute anaphylaxis <br/> acute respiratory distress <br/> rapid fall in blood pressure resembling a shock-like state <br/> angioedema </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">dyspnea <br/> asthma <br/> purpura <br/> angiitis <br/> pulmonary edema <br/> fever </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">GENITOURINARY</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">None</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">hematuria <br/> vaginal bleeding <br/> proteinuria <br/> nephrotic syndrome <br/> interstitial nephritis </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">BUN elevation <br/> renal insufficiency, including renal failure </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">MISCELLANEOUS</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">None</p> </td><td class="Rrule" valign="top"> <p class="First">epistaxis <br/> breast changes, including enlargement and tenderness, or gynecomastia </p> </td><td class="Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">* Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.)</p> </td> </tr> </tbody> </table></div>

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.

The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

Effects on Laboratory Tests

Indomethacin capsules reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients.

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.

Risk Summary

Use of NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of indomethacin capsules use between about 20 and 30 weeks of gestation, and avoid indomethacin capsules use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including indomethacin capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including indomethacin capsules, can cause premature closure of the fetal ductus arteriosus ( see Data).

Oligohydramnios/Neonatal Renal Impairment

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If indomethacin capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin capsules and follow up according to clinical practice ( see Data).

Labor or Delivery

There are no studies on the effects of indomethacin capsules during labor or delivery. In animal studies, NSAIDs, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal data

Reproductive 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 (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m 2basis, respectively) 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, 0.1 to 0.4 times MRHD on a mg/m 2basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations.

In rats and mice, maternal indomethacin administration of 4 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m 2basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m 2basis). Administration of 0.5 or 4 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level.

Risk Summary

Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin capsules and any potential adverse effects on the breastfed infant from the indomethacin capsules or from the underlying maternal condition.

Data

In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus.

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility.

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

Indomethacin capsules 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 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 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.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

Indomethacin may cause confusion or rarely, psychosis [ see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly.

Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [ see Clinical Pharmacology (12.3)].

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].

{ "type": "p", "children": [], "text": "Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [\n \n see\n \n Warnings and Precautions (5.1,\n \n 5.2,\n \n 5.4,\n \n 5.6)].\n\n " }

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

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For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

{ "type": "p", "children": [], "text": "For additional information about overdosage treatment contact a poison control center (1-800-222-1222)." }

Indomethacin Capsules, USP are nonsteroidal anti-inflammatory drugs, available as capsules containing 25 mg and 50 mg of indomethacin, USP, administered for oral use. The chemical name is 1-( p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid. The molecular weight is 357.79 g/mol. Its molecular formula is C 19H 16ClNO 4, and it has the following chemical structure.

{ "type": "p", "children": [], "text": "Indomethacin Capsules, USP are nonsteroidal anti-inflammatory drugs, available as capsules containing 25 mg and 50 mg of indomethacin, USP, administered for oral use. The chemical name is 1-(\n \n p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid. The molecular weight is 357.79 g/mol. Its molecular formula is C\n \n 19H\n \n 16ClNO\n \n 4, and it has the following chemical structure.\n\n " }

Indomethacin, USP is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol, chloroform, and in ether. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali.

{ "type": "p", "children": [], "text": "Indomethacin, USP is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol, chloroform, and in ether. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali." }

The inactive ingredients in Indomethacin Capsules, USP 25 mg and 50 mg include: colloidal silicon dioxide, FD&C Blue No. 1, FD&C Yellow No. 5, gelatin, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate and titanium dioxide.

{ "type": "p", "children": [], "text": "The inactive ingredients in Indomethacin Capsules, USP 25 mg and 50 mg include: colloidal silicon dioxide, FD&C Blue No. 1, FD&C Yellow No. 5, gelatin, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate and titanium dioxide." }

The imprinting ink contains: black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

{ "type": "p", "children": [], "text": "The imprinting ink contains: black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution." }

Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivoeffects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Absorption

Following single oral doses of indomethacin capsules, 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsules when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.

Distribution

Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk.

Elimination

Metabolism

Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed.

Excretion

Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours.

Specific Populations

Pediatric:The pharmacokinetics of indomethacin capsules has not been investigated in pediatric patients.

Race:Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment:The pharmacokinetics of indomethacin capsules has not been investigated in patients with hepatic impairment.

Renal Impairment:The pharmacokinetics of indomethacin capsules has not been investigated in patients with renal impairment [ see Warnings and Precautions ( 5.6)] .

Drug Interaction Studies

Aspirin:

In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [ see Drug Interactions ( 7)] .

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7) ] .

Diflunisal:

In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [ see Drug Interactions ( 7) ] .

Carcinogenesis

In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m 2basis), 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 (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m 2basis, respectively).

Mutagenesis

Indomethacin did not have any mutagenic effect in in vitrobacterial tests and a series of in vivotests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.

Impairment of Fertility

Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m 2basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m 2basis).

Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.

{ "type": "p", "children": [], "text": "Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis." }

Indomethacin capsules affords relief of symptoms; it does not alter the progressive course of the underlying disease.

{ "type": "p", "children": [], "text": "Indomethacin capsules affords relief of symptoms; it does not alter the progressive course of the underlying disease." }

Indomethacin capsules suppress inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin capsules for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin capsules may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects.

{ "type": "p", "children": [], "text": "Indomethacin capsules suppress inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin capsules for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin capsules may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects." }

Indomethacin capsules, USP are available containing either 25 mg of indomethacin, USP.

{ "type": "p", "children": [], "text": "Indomethacin capsules, USP are available containing either 25 mg of indomethacin, USP." }

The 25 mg capsule is a size ‘3’ two piece opaque green hard gelatin capsule imprinted with ‘G406’ on the body and ‘G’ on the cap, filled with white to off-white granular powder. They are available as follows:

{ "type": "p", "children": [], "text": "The 25 mg capsule is a size ‘3’ two piece opaque green hard gelatin capsule imprinted with ‘G406’ on the body and ‘G’ on the cap, filled with white to off-white granular powder. They are available as follows:" }

NDC: 70518-1458-00

{ "type": "p", "children": [], "text": "NDC: 70518-1458-00" }

PACKAGING: 30 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BLISTER PACK" }

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]." }

Protect from light.

{ "type": "p", "children": [], "text": "Protect from light." }

Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "Repackaged and Distributed By:" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "Remedy Repack, Inc." }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

{ "type": "p", "children": [], "text": "625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762" }

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin capsules and periodically during the course of ongoing therapy.

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin capsules and periodically during the course of ongoing therapy." }

Cardiovascular Thrombotic Events

{ "type": "p", "children": [], "text": "\nCardiovascular Thrombotic Events\n" }

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ see Warnings and Precautions ( 5.1) ].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ \n see Warnings and Precautions ( \n 5.1) \n ].\n " }

Gastrointestinal Bleeding, Ulceration, and Perforation

{ "type": "p", "children": [], "text": "\nGastrointestinal Bleeding, Ulceration, and Perforation\n" }

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ see Warnings and Precautions ( 5.2) ].

{ "type": "p", "children": [], "text": "Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ \n see Warnings and Precautions ( \n 5.2) \n ].\n " }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity\n" }

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin capsules and seek immediate medical therapy [ see Warnings and Precautions ( 5.3) ].

{ "type": "p", "children": [], "text": "Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin capsules and seek immediate medical therapy [ \n see Warnings and Precautions ( \n 5.3) \n ].\n " }

Heart Failure and Edema

{ "type": "p", "children": [], "text": "\nHeart Failure and Edema\n" }

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions ( 5.5) ].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ \n see Warnings and Precautions ( \n 5.5) \n ].\n " }

Anaphylactic Reactions

{ "type": "p", "children": [], "text": "\nAnaphylactic Reactions\n" }

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4) and Warnings and Precautions ( 5.7) ].

{ "type": "p", "children": [], "text": "Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ \n see Contraindications ( \n 4) and Warnings and Precautions ( \n 5.7) \n ].\n " }

Serious Skin Reactions, including DRESS

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions, including DRESS\n" }

Advise patients to stop taking indomethacin capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9, 5.10) ].

{ "type": "p", "children": [], "text": "Advise patients to stop taking indomethacin capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ \n see Warnings and Precautions ( \n 5.9, \n 5.10) \n ].\n " }

Female Fertility

{ "type": "p", "children": [], "text": "\nFemale Fertility\n" }

Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin capsules, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3) ].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin capsules, may be associated with a reversible delay in ovulation [ \n see Use in Specific Populations ( \n 8.3) \n ].\n " }

Fetal Toxicity

{ "type": "p", "children": [], "text": "\nFetal Toxicity\n" }

Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see Warnings and Precautions ( 5.11) and Use in Specific Populations ( 8.1) ].

{ "type": "p", "children": [], "text": "Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ \n see Warnings and Precautions ( \n 5.11) and Use in Specific Populations \n ( \n 8.1) \n ].\n " }

Avoid Concomitant Use of NSAIDs

{ "type": "p", "children": [], "text": "\nAvoid Concomitant Use of NSAIDs\n" }

Inform patients that the concomitant use of indomethacin capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

{ "type": "p", "children": [], "text": "Inform patients that the concomitant use of indomethacin capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see \n Warnings and Precautions ( \n 5.2) and Drug Interactions ( \n 7) \n ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.\n " }

Use of NSAIDs and Low-Dose Aspirin

{ "type": "p", "children": [], "text": "\nUse of NSAIDs and Low-Dose Aspirin\n" }

Inform patients not to use low-dose aspirin concomitantly with indomethacin capsules until they talk to their healthcare provider [ see Drug Interactions ( 7) ].

{ "type": "p", "children": [], "text": "Inform patients not to use low-dose aspirin concomitantly with indomethacin capsules until they talk to their healthcare provider [ \n see Drug Interactions ( \n 7) \n ].\n " }

Repackaged By / Distributed By: RemedyRepack Inc.

{ "type": "p", "children": [], "text": "Repackaged By / Distributed By: RemedyRepack Inc." }

625 Kolter Drive, Indiana, PA 15701

{ "type": "p", "children": [], "text": "625 Kolter Drive, Indiana, PA 15701" }

(724) 465-8762

{ "type": "p", "children": [], "text": "(724) 465-8762" }

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?\n" }

NSAIDs can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nNSAIDs can cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\nIncreased risk of a heart attack or stroke that can lead to death.This risk may happen early in treatment and may increase:\n\n\t\n \nwith increasing doses of NSAIDs\nwith longer use of NSAIDs\n\n" ], "text": "" }

Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

{ "type": "p", "children": [], "text": "\nDo not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).”\n" }

Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

{ "type": "p", "children": [], "text": "\nAvoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.\n" }

{ "type": "ul", "children": [ "\nIncreased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:\n\nanytime during use\nwithout warning symptoms\nthat may cause death\n\n" ], "text": "" }

The risk of getting an ulcer or bleeding increases with:

{ "type": "p", "children": [], "text": "\nThe risk of getting an ulcer or bleeding increases with:\n" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col width="50%"/> <col width="50%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Toprule" colspan="2" valign="top"> <ul> <li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</li> </ul> </td> </tr> <tr> <td colspan="2" valign="top"> <ul> <li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”</li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li>increasing doses of NSAIDs</li> </ul> </td><td valign="top"> <ul> <li>older age</li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li>longer use of NSAIDs</li> </ul> </td><td valign="top"> <ul> <li>poor health</li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li>smoking</li> </ul> </td><td valign="top"> <ul> <li>advanced liver disease</li> </ul> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <ul> <li>drinking alcohol</li> </ul> </td><td class="Botrule" valign="top"> <ul> <li>bleeding problems</li> </ul> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\" colspan=\"2\" valign=\"top\">\n<ul>\n<li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\" valign=\"top\">\n<ul>\n<li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>increasing doses of NSAIDs</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>older age</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>longer use of NSAIDs</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>poor health</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>smoking</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>advanced liver disease</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule\" valign=\"top\">\n<ul>\n<li>drinking alcohol</li>\n</ul>\n</td><td class=\"Botrule\" valign=\"top\">\n<ul>\n<li>bleeding problems</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>" }

NSAIDs should only be used:

{ "type": "p", "children": [], "text": "\nNSAIDs should only be used:\n" }

{ "type": "ul", "children": [ "exactly as prescribed", "at the lowest dose possible for your treatment", "for the shortest time needed" ], "text": "" }

What are NSAIDs?

{ "type": "p", "children": [], "text": "\nWhat are NSAIDs?\n" }

NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.

{ "type": "p", "children": [], "text": "NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain." }

Who should not take NSAIDs?

{ "type": "p", "children": [], "text": "\nWho should not take NSAIDs?\n" }

Do not take NSAIDs:

{ "type": "p", "children": [], "text": "\nDo not take NSAIDs:\n" }

{ "type": "ul", "children": [ "if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.", "right before or after heart bypass surgery." ], "text": "" }

Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:\n" }

{ "type": "ul", "children": [ "have liver or kidney problems", "have high blood pressure", "have asthma", "are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. \n You should not take NSAIDs after 30 weeks of pregnancy.\n", "are breastfeeding or plan to breastfeed." ], "text": "" }

Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements.NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements.NSAIDs and some other medicines can interact with each other and cause serious side effects. \n Do not start taking any new medicine without talking to your healthcare provider first.\n" }

What are the possible side effects of NSAIDs?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of NSAIDs?\n" }

NSAIDs can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nNSAIDs can cause serious side effects, including:\n" }

See “What is the most important information I should know about medicines called Non-Steroidal Anti-inflammatory Drugs (NSAIDs)?”

{ "type": "p", "children": [], "text": "\nSee “What is the most important information I should know about medicines called Non-Steroidal Anti-inflammatory Drugs (NSAIDs)?”\n" }

{ "type": "ul", "children": [ "new or worse high blood pressure", "heart failure", "liver problems including liver failure", "kidney problems including kidney failure", "low red blood cells (anemia)", "life-threatening skin reactions", "life-threatening allergic reactions", "\nOther side effects of NSAIDs include:stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.\n " ], "text": "" }

Get emergency help right away if you get any of the following symptoms:

{ "type": "p", "children": [], "text": "\nGet emergency help right away if you get any of the following symptoms:\n" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col width="50%"/> <col width="50%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> <ul> <li>shortness of breath or trouble breathing</li> </ul> </td><td class="Toprule" valign="top"> <ul> <li>slurred speech</li> </ul> </td> </tr> <tr> <td valign="top"> <ul> <li>chest pain</li> </ul> </td><td valign="top"> <ul> <li>swelling of the face or throat</li> </ul> </td> </tr> <tr class="Last"> <td class="Botrule" colspan="2" valign="top"> <ul> <li>weakness in one part or side of your body</li> </ul> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\" valign=\"top\">\n<ul>\n<li>shortness of breath or trouble breathing</li>\n</ul>\n</td><td class=\"Toprule\" valign=\"top\">\n<ul>\n<li>slurred speech</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<ul>\n<li>chest pain</li>\n</ul>\n</td><td valign=\"top\">\n<ul>\n<li>swelling of the face or throat</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule\" colspan=\"2\" valign=\"top\">\n<ul>\n<li>weakness in one part or side of your body</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:

{ "type": "p", "children": [], "text": "\nStop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:\n" }

<div class="scrollingtable"><table width="96.4%"> <colgroup> <col width="52%"/> <col width="48%"/> </colgroup> <tbody class="Headless"> <tr class="First Last"> <td class="Botrule Toprule" valign="top"> <ul> <li>nausea</li> <li>more tired or weaker than usual</li> <li>diarrhea</li> <li>itching</li> <li>your skin or eyes look yellow</li> <li>indigestion or stomach pain</li> <li>flu-like symptoms</li> </ul> </td><td class="Botrule Toprule" valign="top"> <ul> <li>vomit blood</li> <li>there is blood in your bowel movement or it is black and sticky like tar</li> <li>unusual weight gain</li> <li>skin rash or blisters with fever</li> <li>swelling of the arms, legs, hands and feet</li> </ul> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"96.4%\">\n<colgroup>\n<col width=\"52%\"/>\n<col width=\"48%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Botrule Toprule\" valign=\"top\">\n<ul>\n<li>nausea</li>\n<li>more tired or weaker than usual</li>\n<li>diarrhea</li>\n<li>itching</li>\n<li>your skin or eyes look yellow</li>\n<li>indigestion or stomach pain</li>\n<li>flu-like symptoms</li>\n</ul>\n</td><td class=\"Botrule Toprule\" valign=\"top\">\n<ul>\n<li>vomit blood</li>\n<li>there is blood in your bowel movement or it is black and sticky like tar</li>\n<li>unusual weight gain</li>\n<li>skin rash or blisters with fever</li>\n<li>swelling of the arms, legs, hands and feet</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>" }

If you take too much of your NSAID, call your healthcare provider or get medical help right away.

{ "type": "p", "children": [], "text": "\nIf you take too much of your NSAID, call your healthcare provider or get medical help right away.\n" }

These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

Other information about NSAIDs

{ "type": "p", "children": [], "text": "\nOther information about NSAIDs\n" }

{ "type": "ul", "children": [ "Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.", "Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days." ], "text": "" }

General information about the safe and effective use of NSAIDs

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of NSAIDs\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them." }

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

{ "type": "p", "children": [], "text": "If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals." }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

Repackaged By / Distributed By: RemedyRepack Inc.

{ "type": "p", "children": [], "text": "Repackaged By / Distributed By: RemedyRepack Inc." }

625 Kolter Drive, Indiana, PA 15701

{ "type": "p", "children": [], "text": "625 Kolter Drive, Indiana, PA 15701" }

(724) 465-8762

{ "type": "p", "children": [], "text": "(724) 465-8762" }

DRUG: Indomethacin

{ "type": "p", "children": [], "text": "DRUG: Indomethacin" }

GENERIC: Indomethacin

{ "type": "p", "children": [], "text": "GENERIC: Indomethacin" }

DOSAGE: CAPSULE

{ "type": "p", "children": [], "text": "DOSAGE: CAPSULE" }

ADMINSTRATION: ORAL

{ "type": "p", "children": [], "text": "ADMINSTRATION: ORAL" }

NDC: 70518-1458-0

{ "type": "p", "children": [], "text": "NDC: 70518-1458-0" }

COLOR: green

{ "type": "p", "children": [], "text": "COLOR: green" }

SHAPE: CAPSULE

{ "type": "p", "children": [], "text": "SHAPE: CAPSULE" }

SCORE: No score

{ "type": "p", "children": [], "text": "SCORE: No score" }

SIZE: 16 mm

{ "type": "p", "children": [], "text": "SIZE: 16 mm" }

IMPRINT: G406;G

{ "type": "p", "children": [], "text": "IMPRINT: G406;G" }

PACKAGING: 30 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 30 in 1 BLISTER PACK" }

ACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "ACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "INDOMETHACIN 25mg in 1" ], "text": "" }

INACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "INACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "SODIUM STARCH GLYCOLATE TYPE A POTATO", "D&C YELLOW NO. 10", "GELATIN, UNSPECIFIED", "SODIUM LAURYL SULFATE", "TITANIUM DIOXIDE", "AMMONIA", "SHELLAC", "PROPYLENE GLYCOL", "HYPROMELLOSE, UNSPECIFIED", "SILICON DIOXIDE", "ALCOHOL", "BUTYL ALCOHOL", "FERROSOFERRIC OXIDE", "MICROCRYSTALLINE CELLULOSE", "MAGNESIUM STEARATE", "LACTOSE MONOHYDRATE", "FD&C BLUE NO. 1", "ISOPROPYL ALCOHOL", "POTASSIUM HYDROXIDE" ], "text": "" }

Indomethacin suppositories are indicated for:

{ "type": "p", "children": [], "text": "Indomethacin suppositories are indicated for: " }

{ "type": "ul", "children": [ "Moderate to severe rheumatoid arthritis including acute flares of chronic disease ", "Moderate to severe ankylosing spondylitis ", "Moderate to severe osteoarthritis ", "Acute painful shoulder (bursitis and/or tendinitis) ", "Acute gouty arthritis " ], "text": "" }

Carefully consider the potential benefits and risks of indomethacin suppositories and other treatment options before deciding to use indomethacin suppositories. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs.

Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient.

SUPPOSITORIES: Indomethacin suppositories are available as 50 mg suppositories for rectal use only. Indomethacin suppositories are not for oral or intravaginal use.

THIS SECTION PREDOMINANTLY MAKES REFERENCE TO INDOMETHACIN CAPSULE, USP ORAL DOSAGE FOR GUIDANCE IN USING SUPPOSITORIES.

Indomethacin suppositories 50 mg can be substituted for indomethacin capsules, USP; however, there will be significant differences between the two dosage regimens in indomethacin blood levels [see Clinical Pharmacology (12.3)].

Oral dosage recommendations for active stages of the following:

Indomethacin capsules, USP 25 mg twice a day. or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 to 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug.

In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime, either orally or by rectal suppositories, may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily.

If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely.

If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued.

Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions.

As advancing years appear to increase the possibility of adverse reactions, indomethacin suppositories should be used with greater care in the elderly [see Use in Specific Populations (8.5)].

Indomethacin capsules, USP 75 to 150 mg daily in 3 or 4 divided doses.

The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 to 14 days.

Indomethacin capsules, USP 50 mg three times a day. Until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days.

Indomethacin suppositories, USP: 50 mg of indomethacin, USP. Yellow to white and opaque.

{ "type": "p", "children": [], "text": "Indomethacin suppositories, USP: 50 mg of indomethacin, USP. Yellow to white and opaque. " }

Indomethacin suppositories are contraindicated in the following patients:

{ "type": "p", "children": [], "text": "Indomethacin suppositories are contraindicated in the following patients: " }

{ "type": "ul", "children": [ "Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]\n", "History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]\n", "In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]\n", "In patients with a history of proctitis or recent rectal bleeding " ], "text": "" }

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of indomethacin in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin immediately, and perform a clinical evaluation of the patient.

NSAIDs, including indomethacin, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of indomethacin in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease. The renal effects of indomethacin may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin [see Drug Interactions (7)]. Avoid the use of indomethacin in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.

Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When indomethacin is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. 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 at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin. 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 and evaluate the patient immediately.

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDS, including indomethacin, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including indomethacin, 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, 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 use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if indomethacin treatment extends beyond 48 hours. Discontinue indomethacin if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

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 has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including indomethacin, 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)].

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

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)].

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

Indomethacin 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.

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. 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 receiving prolonged therapy. Indomethacin is not indicated for long-term treatment.

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 suppositories or capsules 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 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 suppositories.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="100%"/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td colspan="3"> <p class="First"> <span class="Bold">Table 1 Summary of Adverse Reactions for Indomethacin Capsules</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Bold"><span class="Italics">Incidence greater than 1%</span></span> </p> </td><td colspan="2"> <p class="First"> <span class="Bold"><span class="Italics">Incidence less than 1%</span></span> </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">GASTROINTESTINAL</span> </p> </td> </tr> <tr> <td> <p class="First">nausea* with or <br/> without vomiting <br/> dyspepsia* (including <br/> indigestion, heartburn and <br/> epigastric pain) <br/> diarrhea <br/> abdominal distress or pain <br/> constipation </p> </td><td> <p class="First">anorexia <br/> bloating (includes distension) <br/> flatulence <br/> peptic ulcer <br/> gastroenteritis <br/> rectal bleeding <br/> proctitis <br/> single or multiple ulcerations, <br/> including perforation and hemorrhage <br/> of the esophagus, stomach, <br/> duodenum or small and large <br/> intestines <br/> intestinal ulceration associated with <br/> stenosis and obstruction </p> </td><td> <p class="First">gastrointestinal bleeding without <br/> obvious ulcer formation and <br/> perforation of preexisting <br/> sigmoid lesions (diverticulum, <br/> carcinoma, etc.) development <br/> of ulcerative colitis and <br/> regional ileitis <br/> ulcerative stomatitis <br/> toxic hepatitis and jaundice <br/> (some fatal cases have been <br/> reported) <br/> intestinal strictures <br/> (diaphragms) <br/> pancreatitis </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">CENTRAL NERVOUS SYSTEM</span> </p> </td> </tr> <tr> <td> <p class="First">headache (11.7%) <br/> dizziness* <br/> vertigo <br/> somnolence <br/> depression and fatigue <br/> (including malaise and <br/> listlessness) </p> </td><td> <p class="First">anxiety (includes nervousness) <br/> muscle weakness <br/> involuntary muscle movements <br/> insomnia <br/> muzziness <br/> psychic disturbances including <br/> psychotic episodes <br/> mental confusion <br/> drowsiness </p> </td><td> <p class="First">light-headedness <br/> syncope <br/> paresthesia <br/> aggravation of epilepsy and <br/> parkinsonism <br/> depersonalization <br/> coma <br/> peripheral neuropathy <br/> convulsion <br/> dysarthria </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">SPECIAL SENSES</span> </p> </td> </tr> <tr> <td> <p class="First">tinnitus </p> </td><td> <p class="First">ocular — corneal deposits and retinal <br/> disturbances, including those of <br/> the macula, have been reported in <br/> some patients on prolonged therapy <br/> with indomethacin</p> </td><td> <p class="First">blurred vision <br/> diplopia <br/> hearing disturbances, deafness </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">CARDIOVASCULAR </span> </p> </td> </tr> <tr> <td> <p class="First">None </p> </td><td> <p class="First">hypertension <br/> hypotension <br/> tachycardia <br/> chest pain </p> </td><td> <p class="First">congestive heart failure <br/> arrhythmia; palpitations </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">METABOLIC</span> </p> </td> </tr> <tr> <td> <p class="First">None </p> </td><td> <p class="First">edema <br/> weight gain <br/> fluid retention <br/> flushing or sweating </p> </td><td> <p class="First">hyperglycemia <br/> glycosuria <br/> hyperkalemia </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">INTEGUMENTARY</span> </p> </td> </tr> <tr> <td> <p class="First">none </p> </td><td> <p class="First">pruritus <br/> rash; urticaria <br/> petechiae or ecchymosis </p> </td><td> <p class="First">exfoliative dermatitis <br/> erythema nodosum <br/> loss of hair <br/> Stevens-Johnson syndrome <br/> erythema multiforme <br/> toxic epidermal necrolysis </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">HEMATOLOGIC</span> </p> </td> </tr> <tr> <td> <p class="First">None </p> </td><td> <p class="First">leukopenia <br/> bone marrow depression <br/> anemia secondary to obvious or occult <br/> gastrointestinal bleeding </p> </td><td> <p class="First">aplastic anemia <br/> hemolytic anemia <br/> agranulocytosis <br/> thrombocytopenic purpura <br/> disseminated intravascular <br/> coagulation </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">HYPERSENSITIVITY</span> </p> </td> </tr> <tr> <td> <p class="First">None </p> </td><td> <p class="First">acute anaphylaxis <br/> acute respiratory distress <br/> rapid fall in blood pressure resembling <br/> a shock-like state <br/> angioedema </p> </td><td> <p class="First">dyspnea <br/> asthma <br/> purpura <br/> angiitis <br/> pulmonary edema <br/> fever </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">GENITOURINARY</span> </p> </td> </tr> <tr> <td> <p class="First">None </p> </td><td> <p class="First">hematuria <br/> vaginal bleeding <br/> proteinuria <br/> nephrotic syndrome <br/> interstitial nephritis </p> </td><td> <p class="First">BUN elevation <br/> renal insufficiency, including renal <br/> failure </p> </td> </tr> <tr> <td colspan="3"> <p class="First"> <span class="Italics">MISCELLANEOUS</span> </p> </td> </tr> <tr> <td> <p class="First">None </p> </td><td> <p class="First">epistaxis <br/> breast changes, including enlargement <br/> and tenderness, or gynecomastia </p> </td><td></td> </tr> <tr class="Last"> <td colspan="3"> <p class="First">* Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)</p> </td> </tr> </tbody> </table></div>

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

The following adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

See Table 2 for clinically significant drug interactions with indomethacin.

{ "type": "p", "children": [], "text": "See Table 2 for clinically significant drug interactions with indomethacin. " }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="100%"/> <col/> <tbody class="Headless"> <tr class="First"> <td colspan="2"> <p class="First"> <span class="Bold">Table 2 Clinically Significant Drug Interactions with Indomethacin</span> </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Drugs That Interfere with Hemostasis</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <ul class="Disk"> <li>Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. </li> <li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li> </ul> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class="Italics">[see <a href="#LINK_7034e0c9-1664-4377-814b-ce388590171e">Warnings and Precautions (5.12)</a>]</span>. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Aspirin</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class="Italics">[see <a href="#www.splportal.comLINK_cd557d87-e250-4d10-86cb-a9644a8e1758">Warnings and Precautions (5.2)</a>]</span>. </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class="Italics">[see <a href="#LINK_7034e0c9-1664-4377-814b-ce388590171e">Warnings and Precautions (5.12)</a>]</span>. </p> <p>Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <ul class="Disk"> <li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). </li> <li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. </li> </ul> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <ul class="Disk"> <li>During concomitant use of indomethacin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. </li> <li>During concomitant use of indomethacin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class="Italics">[see <a href="#www.splportal.comLINK_ac8484be-c3c3-4921-9637-1cfdfc69feaf">Warnings and Precautions (5.6)</a>]</span>. </li> <li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. </li> </ul> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. </p> <p>It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. </p> <p>Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels <span class="Italics">[see <a href="#www.splportal.comLINK_ac8484be-c3c3-4921-9637-1cfdfc69feaf">Warnings and Precautions (5.6)</a>]</span>. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Digoxin</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">During concomitant use of indomethacin and digoxin, monitor serum digoxin levels. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Lithium</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">During concomitant use of indomethacin and lithium, monitor patients for signs of lithium toxicity. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Methotrexate</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">During concomitant use of indomethacin and methotrexate, monitor patients for methotrexate toxicity. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Cyclosporine</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">Concomitant use of indomethacin and cyclosporine may increase cyclosporine’s nephrotoxicity. </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">During concomitant use of indomethacin and cyclosporine, monitor patients for signs of worsening renal function. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">NSAIDs and Salicylates</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class="Italics">[see <a href="#www.splportal.comLINK_cd557d87-e250-4d10-86cb-a9644a8e1758">Warnings and Precautions (5.2)</a>]</span>. </p> <p>Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin <span class="Italics">[see <a href="#www.splportal.comLINK_40da22ab-9880-419c-aac4-3222230c217b">Clinical Pharmacology (12.3)</a>]</span>. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Pemetrexed</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">Concomitant use of indomethacin and pemetrexed may increase the risk of pemetrexed-­associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">During concomitant use of indomethacin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. </p> <p>NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. </p> <p>In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Probenecid </span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Italics">Clinical Impact: </span> </p> </td><td> <p class="First">When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. </p> </td> </tr> <tr class="Last"> <td> <p class="First"> <span class="Italics">Intervention: </span> </p> </td><td> <p class="First">During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<col width=\"100%\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Table 2 Clinically Significant Drug Interactions with Indomethacin</span>\n</p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs That Interfere with Hemostasis</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<ul class=\"Disk\">\n<li>Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. </li>\n<li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class=\"Italics\">[see <a href=\"#LINK_7034e0c9-1664-4377-814b-ce388590171e\">Warnings and Precautions (5.12)</a>]</span>. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Aspirin</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_cd557d87-e250-4d10-86cb-a9644a8e1758\">Warnings and Precautions (5.2)</a>]</span>. </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class=\"Italics\">[see <a href=\"#LINK_7034e0c9-1664-4377-814b-ce388590171e\">Warnings and Precautions (5.12)</a>]</span>. </p>\n<p>Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<ul class=\"Disk\">\n<li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). </li>\n<li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<ul class=\"Disk\">\n<li>During concomitant use of indomethacin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. </li>\n<li>During concomitant use of indomethacin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_ac8484be-c3c3-4921-9637-1cfdfc69feaf\">Warnings and Precautions (5.6)</a>]</span>. </li>\n<li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. </p>\n<p>It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. </p>\n<p>Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_ac8484be-c3c3-4921-9637-1cfdfc69feaf\">Warnings and Precautions (5.6)</a>]</span>. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Digoxin</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">During concomitant use of indomethacin and digoxin, monitor serum digoxin levels. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Lithium</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">During concomitant use of indomethacin and lithium, monitor patients for signs of lithium toxicity. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Methotrexate</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">During concomitant use of indomethacin and methotrexate, monitor patients for methotrexate toxicity. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Cyclosporine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">Concomitant use of indomethacin and cyclosporine may increase cyclosporine’s nephrotoxicity. </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">During concomitant use of indomethacin and cyclosporine, monitor patients for signs of worsening renal function. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">NSAIDs and Salicylates</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_cd557d87-e250-4d10-86cb-a9644a8e1758\">Warnings and Precautions (5.2)</a>]</span>. </p>\n<p>Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_40da22ab-9880-419c-aac4-3222230c217b\">Clinical Pharmacology (12.3)</a>]</span>. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Pemetrexed</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">Concomitant use of indomethacin and pemetrexed may increase the risk of pemetrexed-­associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). </p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">During concomitant use of indomethacin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. </p>\n<p>NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. </p>\n<p>In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Probenecid </span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact: </span>\n</p>\n</td><td>\n<p class=\"First\">When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td>\n<p class=\"First\">\n<span class=\"Italics\">Intervention: </span>\n</p>\n</td><td>\n<p class=\"First\">During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Effects on Laboratory Tests

{ "type": "p", "children": [], "text": "\nEffects on Laboratory Tests \n" }

Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients.

{ "type": "p", "children": [], "text": "Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. " }

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.

{ "type": "p", "children": [], "text": "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. " }

Risk Summary

Use of NSAIDs, including indomethacin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of indomethacin use between about 20 and 30 weeks of gestation, and avoid indomethacin use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDS, including indomethacin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including indomethacin, can cause premature closure of the fetal ductus arteriosus (see Data).

Oligohydramnios/Neonatal Renal Impairment:

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If indomethacin treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin and follow up according to clinical practice (see Data).

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m2 basis, respectively) 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, 0.1 to 0.4 times MRHD on a mg/m2 basis) 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.

In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level.

Risk Summary

Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin and any potential adverse effects on the breastfed infant from the indomethacin or from the underlying maternal condition.

Data

In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight- adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus.

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Safety and effectiveness in pediatric patients 14 years of age and younger has 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 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 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.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)].

Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly.

Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].

{ "type": "p", "children": [], "text": "Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. " }

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

{ "type": "p", "children": [], "text": "Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding." }

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

{ "type": "p", "children": [], "text": "For additional information about overdosage treatment contact a poison control center (1-800-222-1222). " }

Indomethacin suppositories, USP are a nonsteroidal anti-inflammatory drug, available as a suppository containing 50 mg of indomethacin, USP administered for rectal use. The chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4, and it has the following chemical structure.

{ "type": "p", "children": [], "text": "Indomethacin suppositories, USP are a nonsteroidal anti-inflammatory drug, available as a suppository containing 50 mg of indomethacin, USP administered for rectal use. The chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4, and it has the following chemical structure." }

Indomethacin, USP is a pale yellow to yellow-tan crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol, in chloroform and in ether. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali.

{ "type": "p", "children": [], "text": "Indomethacin, USP is a pale yellow to yellow-tan crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol, in chloroform and in ether. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. " }

The inactive ingredients in indomethacin suppositories, USP include: butylated hydroxyanisole, butylated hydroxytoluene, edetic acid, glycerin, polyethylene glycol 3350, polyethylene glycol 8000, purified water and sodium chloride. Indomethacin suppositories, USP 50 mg each, are yellow to white, opaque, rectal suppositories.

{ "type": "p", "children": [], "text": "The inactive ingredients in indomethacin suppositories, USP include: butylated hydroxyanisole, butylated hydroxytoluene, edetic acid, glycerin, polyethylene glycol 3350, polyethylene glycol 8000, purified water and sodium chloride. Indomethacin suppositories, USP 50 mg each, are yellow to white, opaque, rectal suppositories." }

FDA approved drug product storage condition and dissolution specifications differs from the USP.

{ "type": "p", "children": [], "text": "FDA approved drug product storage condition and dissolution specifications differs from the USP." }

Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of indomethacin, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Absorption

Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.

The rate of absorption is more rapid from the rectal suppository than from indomethacin capsules. Ordinarily, therefore, the total amount absorbed from the suppository would be expected to be at least equivalent to the capsule. In controlled clinical trials, however, the amount of indomethacin absorbed was found to be somewhat less (80% to 90%) than that absorbed from indomethacin capsules. This is probably because some subjects did not retain the material from the suppository for the one hour necessary to assure complete absorption. Since the suppository dissolves rather quickly rather than melting slowly, it is seldom recovered in recognizable form if the patient retains the suppository for more than a few minutes.

Distribution

Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk.

Elimination

Metabolism

Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed.

Excretion

Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours.

Specific Populations

Pediatric: The pharmacokinetics of indomethacin has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment: The pharmacokinetics of indomethacin has not been investigated in patients with hepatic impairment.

Renal Impairment: The pharmacokinetics of indomethacin has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)].

Drug Interaction Studies

Aspirin: In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)].

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].

Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions (7)].

Carcinogenesis

In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m2 basis), 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 (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis, respectively).

Mutagenesis

Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.

Impairment of Fertility

Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.02 times the MRHD on a mg/m2 basis).

Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.

{ "type": "p", "children": [], "text": "Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. " }

Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease.

{ "type": "p", "children": [], "text": "Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease. " }

Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects.

{ "type": "p", "children": [], "text": "Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. " }

Indomethacin suppositories, USP 50 mg each, are yellow to white, opaque, rectal suppositories.

{ "type": "p", "children": [], "text": "Indomethacin suppositories, USP 50 mg each, are yellow to white, opaque, rectal suppositories. " }

NDC 69238-2086-3, boxes of 30 suppositories.

{ "type": "p", "children": [], "text": "NDC 69238-2086-3, boxes of 30 suppositories. " }

Storage

{ "type": "p", "children": [], "text": "\nStorage \n" }

Store refrigerated between 2° to 8°C (36° to 46°F).

{ "type": "p", "children": [], "text": "Store refrigerated between 2° to 8°C (36° to 46°F). " }

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin and periodically during the course of ongoing therapy. Indomethacin suppositories are for rectal use only. Advise patients not to use indomethacin suppositories orally or intra-vaginally.

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin and periodically during the course of ongoing therapy. Indomethacin suppositories are for rectal use only. Advise patients not to use indomethacin suppositories orally or intra-vaginally. " }

Cardiovascular Thrombotic Events

{ "type": "p", "children": [], "text": "\nCardiovascular Thrombotic Events \n" }

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. " }

Gastrointestinal Bleeding, Ulceration, and Perforation

{ "type": "p", "children": [], "text": "\nGastrointestinal Bleeding, Ulceration, and Perforation \n" }

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. " }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity \n" }

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin and seek immediate medical therapy [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop indomethacin and seek immediate medical therapy [see Warnings and Precautions (5.3)]. " }

Heart Failure and Edema

{ "type": "p", "children": [], "text": "\nHeart Failure and Edema \n" }

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. " }

Anaphylactic Reactions

{ "type": "p", "children": [], "text": "\nAnaphylactic Reactions \n" }

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. " }

Serious Skin Reactions, including DRESS

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions, including DRESS \n" }

Advise patients to stop taking indomethacin immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].

{ "type": "p", "children": [], "text": "Advise patients to stop taking indomethacin immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]." }

Female Fertility

{ "type": "p", "children": [], "text": "\nFemale Fertility \n" }

Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. " }

Fetal Toxicity

{ "type": "p", "children": [], "text": "\nFetal Toxicity \n" }

Inform pregnant women to avoid use of indomethacin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform pregnant women to avoid use of indomethacin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with indomethacin is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. " }

Avoid Concomitant Use of NSAIDs

{ "type": "p", "children": [], "text": "\nAvoid Concomitant Use of NSAIDs \n" }

Inform patients that the concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

{ "type": "p", "children": [], "text": "Inform patients that the concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. " }

Use of NSAIDs and Low-Dose Aspirin

{ "type": "p", "children": [], "text": "\nUse of NSAIDs and Low-Dose Aspirin \n" }

Inform patients not to use low-dose aspirin concomitantly with indomethacin until they talk to their healthcare provider [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients not to use low-dose aspirin concomitantly with indomethacin until they talk to their healthcare provider [see Drug Interactions (7)]. " }

Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807

{ "type": "p", "children": [], "text": "Distributed by:\nAmneal Pharmaceuticals LLC\nBridgewater, NJ 08807" }

Rev. 12-2024-02

{ "type": "p", "children": [], "text": "Rev. 12-2024-02" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td colspan="2"> <p class="First"> <span class="Bold">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span> </p> <p> <span class="Bold">NSAIDs can cause serious side effects, including: </span> </p> <ul class="Disk"> <li> <span class="Bold">Increased risk of a heart attack or stroke that can lead to death.</span> This risk may happen early in treatment and may increase: </li> </ul> <ul class="Disk"> <li>with increasing doses of NSAIDs </li> <li>with longer use of NSAIDs <p class="First"> <span class="Bold">Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. </span> </p> <ul class="Circle"> <li> <span class="Bold">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: </span> </li> </ul> </li> </ul> <ul class="Disk"> <li>anytime during use </li> <li>without warning symptoms </li> <li>that may cause death </li> </ul> <p> <span class="Bold">The risk of getting an ulcer or bleeding increases with:</span> </p> <ul class="Disk"> <li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs </li> <li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” </li> </ul> </td> </tr> <tr> <td> <ul class="Disk"> <li>increasing doses of NSAIDs </li> <li>longer use of NSAIDs </li> <li>smoking </li> <li>drinking alcohol </li> </ul> </td><td> <ul class="Disk"> <li>older age </li> <li>poor health </li> <li>advanced liver disease </li> <li>bleeding problems </li> </ul> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">NSAIDs should only be used: </span> </p> <ul class="Disk"> <li>exactly as prescribed </li> <li>at the lowest dose possible for your treatment </li> <li>for the shortest time needed</li> </ul> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">What are NSAIDs? </span> </p> <p>NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Who should not take NSAIDs? </span> </p> <p> <span class="Bold">Do not take NSAIDs: </span> </p> <ul class="Disk"> <li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. </li> <li>right before or after heart bypass surgery. </li> </ul> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: </span> </p> <ul class="Disk"> <li>have liver or kidney problems </li> <li>have high blood pressure </li> <li>have asthma </li> <li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class="Bold">You should not take NSAIDs after about 30 weeks of pregnancy.</span> </li> <li>are breastfeeding or plan to breast feed. </li> </ul> <p> <span class="Bold">Tell your healthcare provider about all of the medicines you take, including prescription or over-the­-counter medicines, vitamins or herbal supplements.</span> NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class="Bold">Do not start taking any new medicine without talking to your healthcare provider first.</span> </p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">What are the possible side effects of NSAIDs? </span> </p> <p> <span class="Bold">NSAIDs can cause serious side effects, including: </span> </p> <p> <span class="Bold">See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” </span> </p> <ul class="Disk"> <li>new or worse high blood pressure </li> <li>heart failure </li> <li>liver problems including liver failure </li> <li>kidney problems including kidney failure </li> <li>low red blood cells (anemia) </li> <li>life-threatening skin reactions </li> <li>life-threatening allergic reactions </li> <li> <span class="Bold">Other side effects of NSAIDs include:</span> stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. </li> </ul> <p> <span class="Bold">Get emergency help right away if you get any of the following symptoms:</span> </p> </td> </tr> <tr> <td> <ul class="Disk"> <li>shortness of breath or trouble breathing </li> <li>chest pain </li> <li>weakness in one part or side of your body </li> </ul> </td><td> <ul class="Disk"> <li>slurred speech </li> <li>swelling of the face or throat </li> </ul> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:</span> </p> </td> </tr> <tr> <td> <ul class="Disk"> <li>nausea </li> <li>more tired or weaker than usual </li> <li>diarrhea</li> <li>itching </li> <li>your skin or eyes look yellow </li> <li>indigestion or stomach pain </li> <li>flu-like symptoms</li> </ul> </td><td> <ul class="Disk"> <li>vomit blood </li> <li>there is blood in your bowel movement or it is black and sticky like tar </li> <li>unusual weight gain </li> <li>skin rash or blisters with fever </li> <li>swelling of the arms, legs, hands and feet </li> </ul> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">If you take too much of your NSAID, call your healthcare provider or get medical help right away. </span> </p> <p>These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. </p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">Other information about NSAIDs </span> </p> <ul class="Disk"> <li>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. </li> <li>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. </li> </ul> </td> </tr> <tr> <td colspan="2"> <p class="First"> <span class="Bold">General information about the safe and effective use of NSAIDs </span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. </p> <p>If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. </p> </td> </tr> <tr> <td colspan="2"> <p class="First">Distributed by:<br/> <span class="Bold">Amneal Pharmaceuticals LLC</span> <br/> Bridgewater, NJ 08807 <br/> For more information, go to www.amneal.com or call 1-877-835-5472 </p> </td> </tr> <tr class="Last"> <td colspan="2"> <p class="First">This Medication Guide has been approved by the U.S. Food and Drug Administration. </p> <p>Rev. 07-2023-01</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span>\n</p>\n<p>\n<span class=\"Bold\">NSAIDs can cause serious side effects, including: </span>\n</p>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">Increased risk of a heart attack or stroke that can lead to death.</span> This risk may happen early in treatment and may increase: </li>\n</ul>\n<ul class=\"Disk\">\n<li>with increasing doses of NSAIDs </li>\n<li>with longer use of NSAIDs <p class=\"First\">\n<span class=\"Bold\">Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).\" Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. </span>\n</p>\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: </span>\n</li>\n</ul>\n</li>\n</ul>\n<ul class=\"Disk\">\n<li>anytime during use </li>\n<li>without warning symptoms </li>\n<li>that may cause death </li>\n</ul>\n<p>\n<span class=\"Bold\">The risk of getting an ulcer or bleeding increases with:</span>\n</p>\n<ul class=\"Disk\">\n<li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs </li>\n<li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td>\n<ul class=\"Disk\">\n<li>increasing doses of NSAIDs </li>\n<li>longer use of NSAIDs </li>\n<li>smoking </li>\n<li>drinking alcohol </li>\n</ul>\n</td><td>\n<ul class=\"Disk\">\n<li>older age </li>\n<li>poor health </li>\n<li>advanced liver disease </li>\n<li>bleeding problems </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">NSAIDs should only be used: </span>\n</p>\n<ul class=\"Disk\">\n<li>exactly as prescribed </li>\n<li>at the lowest dose possible for your treatment </li>\n<li>for the shortest time needed</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are NSAIDs? </span>\n</p>\n<p>NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take NSAIDs? </span>\n</p>\n<p>\n<span class=\"Bold\">Do not take NSAIDs: </span>\n</p>\n<ul class=\"Disk\">\n<li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. </li>\n<li>right before or after heart bypass surgery. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: </span>\n</p>\n<ul class=\"Disk\">\n<li>have liver or kidney problems </li>\n<li>have high blood pressure </li>\n<li>have asthma </li>\n<li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class=\"Bold\">You should not take NSAIDs after about 30 weeks of pregnancy.</span>\n</li>\n<li>are breastfeeding or plan to breast feed. </li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all of the medicines you take, including prescription or over-the­-counter medicines, vitamins or herbal supplements.</span> NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class=\"Bold\">Do not start taking any new medicine without talking to your healthcare provider first.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of NSAIDs? </span>\n</p>\n<p>\n<span class=\"Bold\">NSAIDs can cause serious side effects, including: </span>\n</p>\n<p>\n<span class=\"Bold\">See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” </span>\n</p>\n<ul class=\"Disk\">\n<li>new or worse high blood pressure </li>\n<li>heart failure </li>\n<li>liver problems including liver failure </li>\n<li>kidney problems including kidney failure </li>\n<li>low red blood cells (anemia) </li>\n<li>life-threatening skin reactions </li>\n<li>life-threatening allergic reactions </li>\n<li>\n<span class=\"Bold\">Other side effects of NSAIDs include:</span> stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. </li>\n</ul>\n<p>\n<span class=\"Bold\">Get emergency help right away if you get any of the following symptoms:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<ul class=\"Disk\">\n<li>shortness of breath or trouble breathing </li>\n<li>chest pain </li>\n<li>weakness in one part or side of your body </li>\n</ul>\n</td><td>\n<ul class=\"Disk\">\n<li>slurred speech </li>\n<li>swelling of the face or throat </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td>\n<ul class=\"Disk\">\n<li>nausea </li>\n<li>more tired or weaker than usual </li>\n<li>diarrhea</li>\n<li>itching </li>\n<li>your skin or eyes look yellow </li>\n<li>indigestion or stomach pain </li>\n<li>flu-like symptoms</li>\n</ul>\n</td><td>\n<ul class=\"Disk\">\n<li>vomit blood </li>\n<li>there is blood in your bowel movement or it is black and sticky like tar </li>\n<li>unusual weight gain </li>\n<li>skin rash or blisters with fever </li>\n<li>swelling of the arms, legs, hands and feet </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">If you take too much of your NSAID, call your healthcare provider or get medical help right away. </span>\n</p>\n<p>These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. </p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Other information about NSAIDs </span>\n</p>\n<ul class=\"Disk\">\n<li>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. </li>\n<li>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of NSAIDs </span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. </p>\n<p>If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. </p>\n</td>\n</tr>\n<tr>\n<td colspan=\"2\">\n<p class=\"First\">Distributed by:<br/>\n<span class=\"Bold\">Amneal Pharmaceuticals LLC</span>\n<br/> Bridgewater, NJ 08807 <br/> For more information, go to www.amneal.com or call 1-877-835-5472 </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td colspan=\"2\">\n<p class=\"First\">This Medication Guide has been approved by the U.S. Food and Drug Administration. </p>\n<p>Rev. 07-2023-01</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }