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Contents

Indocin

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Thrombotic Events

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 .

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 .

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

Gastrointestinal Bleeding, Ulceration, And Perforation

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:

  • Use the lowest effective dosage for the shortest possible duration.
  • Avoid administration of more than one NSAID at a time.
  • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
  • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
  • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue INDOCIN until a serious GI adverse event is ruled out.
  • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding .

Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal ) 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 INDOCIN immediately, and perform a clinical evaluation of the patient.

Hypertension

NSAIDs, including INDOCIN, 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 .

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

Heart Failure And Edema

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 ) .

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

Renal Toxicity And Hyperkalemia

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 dosedependent 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 INDOCIN in patients with advanced renal disease. The renal effects of INDOCIN may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of INDOCIN . Avoid the use of INDOCIN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If INDOCIN 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. Â 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.

Anaphylactic Reactions

Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma .

Seek emergency help if an anaphylactic reaction occurs.

Exacerbation Of Asthma Related To Aspirin Sensitivity

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, INDOCIN is contraindicated in patients with this form of aspirin sensitivity . When INDOCIN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Serious Skin Reactions

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

Premature Closure Of Fetal Ductus Arteriosus

Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including INDOCIN, in pregnant women starting at 30 weeks of gestation (third trimester) .

Hematologic Toxicity

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

NSAIDs, including INDOCIN, 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 .

Masking Of Inflammation And Fever

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

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically .

Central Nervous System Effects

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

INDOCIN 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 INDOCIN.

Ocular Effects

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with INDOCIN. Be alert to the possible association between the changes noted and INDOCIN. 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. INDOCIN is not indicated for long-term treatment.

Patient Counseling Information

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 INDOCIN and periodically during the course of ongoing therapy.

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 .

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 .

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 INDOCIN and seek immediate medical therapy .

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 .

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 .

Advise patients to stop INDOCIN immediately if they develop any type of rash and to contact their healthcare provider as soon as possible .

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including INDOCIN, may be associated with a reversible delay in ovulation .

Fetal Toxicity

Inform pregnant women to avoid use of INDOCIN and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus .

Avoid Concomitant Use Of NSAIDs

Inform patients that the concomitant use of INDOCIN 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 . 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

Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to their healthcare provider .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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 and 0.07 times 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).

Use In Specific Populations

Pregnancy

Risk Summary

Use of NSAIDs, including INDOCIN, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including INDOCIN, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of INDOCIN in pregnant women.

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. 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 . 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.

Clinical Considerations

Labor or Delivery

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

Data

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 and 0.2 times 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.

Lactation

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 INDOCIN and any potential adverse effects on the breastfed infant from the INDOCIN or from the underlying maternal condition.

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 ductusarteriosus.

Females And Males Of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including INDOCIN, 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 INDOCIN, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

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

INDOCIN 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.

Geriatric Use

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 .

Indomethacin may cause confusion or rarely, psychosis ; 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 .

Acute Gout Attack

The goal of treatment during an acute gout attack is suppression of inflammation and control of pain. It is important to note, that if a patient is not on uric acid lowering therapy at the time of an acute attack – then this is not the time to initiate such therapy. However, if a patient is on uric acid lowering therapy at the time of an acute attack, it should not be discontinued.

Treatment of pain and inflammation can be achieved with NSAIDs, colchicine, or corticosteroids (systemic or intra-articular). The choice of which treatment is the right one for a particular patient should be made on the basis of the patient’s co-morbid medical conditions, other medications, and side effect profile.

  1. NSAIDS: Commonly used NSAIDs during an acute gout attack include ibuprofen 800 mg three to four times daily or indomethacin 25 to 50 mg four times daily. Treatment should be discontinued when symptoms resolve.
  2. Colchicine: Intravenous colchicine is associated with serious toxicities and side effects, so it should be used as an oral formulation only. High dose oral colchicine (1.2 mg followed by 0.6 mg every hour for 6 doses) is generally poorly tolerated because of GI side effects. Lower doses are much better received and may be used in combination with NSAIDs.
  3. Corticosteroids: In patients with contraindications to NSAID use, corticosteroids are the next choice. Corticosteroids can be administered as an injection into the effected joint (intra-articular steroids) or given systemically (orally, such as prednisone or medrol). Intra-articular steriods are useful if only one or two joints are affected and the treating physician is proficient in injecting those joints. Oral corticosteroids can be used starting at 30-40 mg daily tapering over 10-14 days.

Treatment: Uric Acid Lowering Therapy

Indications

Patients who have multiple episodes of acute gout attacks per year or who have tophi on exam are candidates for uric acid lowering therapy. Use of uric acid lowering agents will reduce the frequency of gout attacks and over time, reduce tophi formation, and diminish the risk of joint destruction. The following are indications for uric acid lowering therapy:

  • tophi or chronic arthritis on exam
  • failure of colchicine prophylaxis of acute gouty arthritis
  • renal stones
  • Prior to chemotherapy as prophylaxis of tumor lysis syndrome
  • Extremely high levels of serum uric acid (>12 mg/dl)

Uric acid is the end product of purine (nucleic acid component of DNA) metabolism and is produced normally by the body during tissue remodeling and breakdown. About 20% of uric acid is derived from purines ingested in food. Causes of hyperuricemia can be divided into two major categories: decreased clearance of uric acid from the kidney and increased synthesis of uric acid.

Decreased renal clearance – (90% of patients)

  • Intrinsic kidney disease
  • heart disease causing decreased blood flow to the kidney
  • drugs (loop diuretics, low dose aspirin, cyclosporin)
  • genetic predisposition
  • age related decrease in glomerulofiltration rate

Increased uric acid synthesis

  • Dietary indiscretions
  • Genetic predisposition
  • Increased tissue turnover–tumors, lymphoproliferative disorders
  • Stress induced increased turnover of ATP
  • Alcohol induced turnover of ATP

All patients should be encouraged to modify their lifestyle including limiting alcohol intake, encouraging weight loss where appropriate and decreasing food rich in purines. Co-morbid medical conditions should also be controlled including hypertension, diabetes and hyperlipidemia.

Foods High in Purines

Medication Options for Uric Acid Lowering

It is important to note that whenever starting a uric acid lowering treatment, there is a risk of precipitating a gout flare. A plan should be in place for management if this occurs. This generally can be avoided with the co-administration of prophylactic medications (steroids, colchicine, NSAIDs) along with the uric acid lowering therapy.

Probenecid

Probenecid may be given to patients with decreased clearance of uric acid by the kidney and normal renal function. In general its use should be limited to patients under the age of 60. Probenecid acts by inhibiting reabsorption of uric acid in the proximal tubules of the kidney. Starting dose is at 500 mg to 1000 mg daily and increased to 1500 mg to 2000 mg as needed. Occasionally higher doses are needed. Probenecid may precipitate renal stone formation and good oral hydration should be encouraged. Probenecid is contraindicated in patients with renal stones (including calcium and uric acid stones) and in patients with urate nephropathy. Probenecid given inappropriately to patients with hyperuricemia due to overproduction of uric acid can cause renal stones and urate nephropathy.

  • uricosuric
  • decreases uric acid reabsorption at the proximal renal tubules
  • useful in patients with decreased renal clearance of uric acid
  • can only be used if creatinine clearance >40 cc/min
  • must have 24 hour urine for uric acid <800 mg/dl
  • can be used in renal failure
  • increased risk of renal stones

Allopurinol

Allopurinol is a well tolerated, inexpensive, and commonly used uric acid lowering agent. Allopurinol can be started at doses as low as 100 mg daily (100 mg qod if creatinine clearance < 10 cc/min) and titrated by 100 mg every 10-14 days to achieve a serum uric acid level of 4-5 mg/dl. Liver tests, blood counts, and renal function and should be monitored while on therapy. Toxicites include rash, hepatoxicity, bone marrow suppression and severe hypersensitivity reactions. Medication interactions can occur with allopurinol, warfarin, and theophylline and levels should be monitored. Allopurinol should be avoided in patients on azathiprine, 6-mercaptopurine and cyclophosphamide because of risk for bone marrow toxicity.

  • xanthine oxidase inhibitor
  • prevents production of uric acid
  • useful in both patients with increased synthesis and decreased clearance of uric acid
  • no 24 hour urine needed
  • can be used in renal failure
  • rarely associated with bone marrow suppression, hepatotoxicity, and hypersensitivity reactions

Febuxostat

In 2009, the FDA approved the use of a new xanthine oxidase inhibitor, febuxostat, for the treatment of hyperuricemia in gout. It has demonstrated a dose-dependent decreasee in serum uric acid (daily doses 80mg or 120mg). Its efficacy has been demonstrated in patients with mild or moderate renal impairment and gout. However, it can cause abnormalities in liver function tests and routine monitoring of bloodwork is recommended. Similar to allopurinol, there are interactions of febuxostat with azathioprine, 6MP, and theophylline.

  • xanthine oxidase inhibitor
  • prevents production of uric acid
  • useful in both patients with increased synthesis and decreased clearance of uric acid
  • can be used in mild-moderate renal impairment
  • rarely associated with bone marrow suppression and hepatotoxicity

Pegloticase

Uricase is an enzyme that converts poorly soluable urate (uric acid) to the more soluable allantoin (excreted in the urine). Uricase is present in most mammals, and these mammals with uricase do not develop gout. However, humans and some primates lack uricase (because of evoluationary gene inactivation) and lack the ability to make uric acid more soluable and hence, have gout. Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who have failed conventional therapy.

Pegloticase is administered by intravenous infusion every 2 weeks. Patients should be treated prophylactically for allergic reations to the infusion with steroids and anti-histamines and monitored closely for the development of an infusion reaction. Caution should be used in prescribing this treatment in patients with a known cardiac history.

  • pegylated porcine uricase
  • useful in both patients with increased synthesis and decreased clearance of uric acid
  • increases solubility of uric acid
  • patients should be pre-medicated prior to infusions and monitored for allergic reactions
  • caution should be used in patients with known cardiac history

Treatment: Lifestyle

Nutrition / Body Composition

Avoidance of purine rich foods and alcohol may help lower uric acid levels and prevent significant fluctuations in serum uric acid that may precipitate acute attacks. Obesity and increased fat distribution are risk factors for gout.

Eating a healthy balanced diet of low-fat proteins, low-fat dairy and vegetables will help maintain a healthy weight which is beneficial for the prevention of gout attacks as well.

SIDE EFFECTS

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

  • Cardiovascular Thrombotic Events
  • GI Bleeding, Ulceration and Perforation
  • Hepatotoxicity
  • Hypertension
  • Heart Failure and Edema
  • Renal Toxicity and Hyperkalemia
  • Anaphylactic Reactions
  • Serious Skin Reactions
  • Hematologic Toxicity

Clinical Trials Experience

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

In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving 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 INDOCIN 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

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

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

Cardiovascular: Thrombophlebitis

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

Genitourinary: Urinary frequency

A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome

Read the entire FDA prescribing information for Indocin (Indomethacin)

This information from Lexicomp® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider.

Brand Names: US

Indocin; Tivorbex

Brand Names: Canada

APO-Indomethacin; MINT-Indomethacin; RATIO-Indomethacin ; SANDOZ Indomethacin; TEVA-Indomethacin

Warning

  • This drug may raise the risk of heart and blood vessel problems like heart attack and stroke. These effects can be deadly. The risk may be greater if you have heart disease or risks for heart disease. However, it can also be raised even if you do not have heart disease or risks for heart disease. The risk can happen within the first weeks of using this drug and may be greater with higher doses or long-term use. Do not use this drug right before or after bypass heart surgery.
  • This drug may raise the chance of severe and sometimes deadly stomach or bowel problems like ulcers or bleeding. The risk is greater in older people, and in people who have had stomach or bowel ulcers or bleeding before. These problems may occur without warning signs.

What is this drug used for?

  • It is used to treat some types of arthritis.
  • It is used to treat ankylosing spondylitis.
  • It is used to ease pain.
  • It may be given to you for other reasons. Talk with the doctor.

What do I need to tell my doctor BEFORE I take this drug?

All products:

  • If you have an allergy to indomethacin or any other part of this drug.
  • If you have an allergy to aspirin or NSAIDs.
  • If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had.
  • If you have ever had asthma caused by a salicylate drug like aspirin or a drug like this one like NSAIDs.
  • If you have any of these health problems: Dehydration, GI (gastrointestinal) bleeding, heart failure (weak heart), kidney disease, or liver disease.
  • If you have had a recent heart attack.
  • If you are having trouble getting pregnant or you are having your fertility checked.
  • If you are pregnant or may be pregnant. Do not take this drug if you are in the third trimester of pregnancy. You may also need to avoid this drug at other times during pregnancy. Talk with your doctor to see when you need to avoid taking this drug during pregnancy.
  • If you are taking any of these drugs: Triamterene or a salicylate drug like aspirin or diflunisal.
  • If you are taking any other NSAID.
  • If you are taking pemetrexed.

Suppository:

  • If you have had any of these health problems: Swelling of the rectum or anus, or recent rectal bleeding.

This is not a list of all drugs or health problems that interact with this drug.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take this drug?

  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this drug affects you.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • This drug may affect certain lab tests. Tell all of your health care providers and lab workers that you take this drug.
  • Talk with your doctor before you drink alcohol.
  • If you smoke, talk with your doctor.
  • Have your blood work checked if you are on this drug for a long time. Talk with your doctor.
  • High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
  • Do not take more than what your doctor told you to take. Taking more than you are told may raise your chance of very bad side effects.
  • Do not take this drug for longer than you were told by your doctor.
  • If you have asthma, talk with your doctor. You may be more sensitive to this drug.
  • The chance of heart failure is raised with the use of drugs like this one. In people who already have heart failure, the chance of heart attack, having to go to the hospital for heart failure, and death is raised. Talk with the doctor.
  • The chance of heart attack and heart-related death is raised in people taking drugs like this one after a recent heart attack. People taking drugs like this one after a first heart attack were also more likely to die in the year after the heart attack compared with people not taking drugs like this one. Talk with the doctor.
  • If you are taking aspirin to help prevent a heart attack, talk with your doctor.
  • Liver problems have happened with drugs like this one. Sometimes, this has been deadly. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • NSAIDs like this drug may affect egg release (ovulation) in women. This may cause you to not be able to get pregnant. This goes back to normal when this drug is stopped. Talk with your doctor.
  • This drug may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this drug, call your doctor right away.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

All products:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of bleeding like throwing up or coughing up blood; vomit that looks like coffee grounds; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a cause or that get bigger; or bleeding you cannot stop.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Signs of high potassium levels like a heartbeat that does not feel normal; feeling confused; feeling weak, lightheaded, or dizzy; feeling like passing out; numbness or tingling; or shortness of breath.
  • Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
  • Chest pain or pressure.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Feeling very tired or weak.
  • Change in eyesight.
  • Ringing in ears.
  • Low mood (depression).
  • Flu-like signs.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

Suppository:

  • Bleeding from rectum or rectal pain.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

All products:

  • Headache.
  • Stomach pain or heartburn.
  • Upset stomach or throwing up.
  • Diarrhea or constipation.
  • Gas.
  • Feeling dizzy, sleepy, tired, or weak.

Suppository:

  • Rectal irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to your national health agency.

How is this drug best taken?

Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.

All oral products:

  • Take with food to prevent an upset stomach.
  • Take with a full glass of water.

Liquid (suspension):

  • Shake well before use.
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.

Extended-release capsules:

  • Swallow whole. Do not chew, break, or crush.

Suppository:

  • Use suppository rectally.
  • Wash your hands before and after use.
  • If suppository is soft, chill in a refrigerator or run cold water over it.
  • Take foil off the rectal suppository and put in, pointed end first. Do not handle too much.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

How do I store and/or throw out this drug?

All oral products:

  • Store at room temperature. Do not refrigerate or freeze.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.

Suppository:

  • Store in a refrigerator. Do not freeze.

All products:

  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

General drug facts

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Last Reviewed Date

Copyright

Indomethacin capsules

What is this medicine?

INDOMETHACIN (in doe METH a sin) is a non-steroidal anti-inflammatory drug (NSAID). It is used to reduce swelling and to treat pain. It may be used for painful joint and muscular problems such as arthritis, tendinitis, bursitis, and gout.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

COMMON BRAND NAME(S): Indocin, TIVORBEX

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:

  • asthma, especially aspirin sensitive asthma

  • coronary artery bypass graft (CABG) surgery within the past 2 weeks

  • depression

  • drink more than 3 alcohol containing drinks a day

  • heart disease or circulation problems like heart failure or leg edema (fluid retention)

  • high blood pressure

  • kidney disease

  • liver disease

  • Parkinson’s disease

  • seizures

  • stomach bleeding or ulcers

  • an unusual or allergic reaction to indomethacin, aspirin, other NSAIDs, other medicines, foods, dyes, or preservatives

  • pregnant or trying to get pregnant

  • breast-feeding

How should I use this medicine?

Take this medicine by mouth with food and with a full glass of water. Follow the directions on the prescription label. Take your medicine at regular intervals. Do not take your medicine more often than directed. Long-term, continuous use may increase the risk of heart attack or stroke.

A special MedGuide will be given to you by the pharmacist with each prescription and refill. Be sure to read this information carefully each time.

Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed. While this drug may be prescribed for children as young as 15 years for selected conditions, precautions do apply.

Elderly patients over 65 years old may have a stronger reaction and need a smaller dose.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.

NOTE: This medicine is only for you. Do not share this medicine with others.

What if I miss a dose?

If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

What may interact with this medicine?

Do not take this medicine with any of the following medications:

  • cidofovir

  • diflunisal

  • ketorolac

  • methotrexate

  • pemetrexed

  • triamterene

This medicine may also interact with the following medications:

  • alcohol

  • antacids

  • aspirin and aspirin-like medicines

  • cyclosporine

  • digoxin

  • diuretics

  • lithium

  • medicines for diabetes

  • medicines for high blood pressure

  • medicines that affect platelets

  • medicines that treat or prevent blood clots like warfarin

  • NSAIDs, medicines for pain and inflammation, like ibuprofen or naproxen

  • probenecid

  • steroid medicines like prednisone or cortisone

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Tell your doctor or health care professional if your pain does not get better. Talk to your doctor before taking another medicine for pain. Do not treat yourself.

This medicine does not prevent heart attack or stroke. In fact, this medicine may increase the chance of a heart attack or stroke. The chance may increase with longer use of this medicine and in people who have heart disease. If you take aspirin to prevent heart attack or stroke, talk with your doctor or health care professional.

Do not take medicines such as ibuprofen and naproxen with this medicine. Side effects such as stomach upset, nausea, or ulcers may be more likely to occur. Many medicines available without a prescription should not be taken with this medicine.

This medicine can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Do not smoke cigarettes or drink alcohol. These increase irritation to your stomach and can make it more susceptible to damage from this medicine. Ulcers and bleeding can happen without warning symptoms and can cause death.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this medicine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells.

This medicine can cause you to bleed more easily. Try to avoid damage to your teeth and gums when you brush or floss your teeth.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:

  • allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue

  • difficulty breathing or wheezing

  • nausea, vomiting

  • signs and symptoms of bleeding such as bloody or black, tarry stools; red or dark-brown urine; spitting up blood or brown material that looks like coffee grounds; red spots on the skin; unusual bruising or bleeding from the eye, gums, or nose

  • signs and symptoms of a blood clot such as changes in vision; chest pain; severe, sudden headache; trouble speaking; sudden numbness or weakness of the face, arm, or leg; trouble walking

  • unexplained weight gain or swelling

  • unusually weak or tired

  • yellowing of eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

  • diarrhea

  • dizziness

  • headache

  • heartburn

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of the reach of children.

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Keep container tightly closed. Throw away any unused medicine after the expiration date.

NOTE: This sheet is a summary. It may not cover all possible information. If you have questions about this medicine, talk to your doctor, pharmacist, or health care provider.

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