INDOMETHACIN- indomethacin_capsule, extended release

Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of indomethacin extended-release 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 in vivo Absorption Following single oral doses of indomethacin immediate-release capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 mcg/mL and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin immediate-release 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 capsule when each was administered with food. With a typical therapeutic regimen of 25 mg 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. Indomethacin extended-release capsules 75 mg are designed to release 25 mg of the drug initially and the remaining 50 mg over approximately 12 hours (90% of dose absorbed by 12 hours). When measured over a 24-hour period, the cumulative amount and time-course of indomethacin absorption from a single indomethacin extended-release capsule are comparable to those of 3 doses of 25 mg indomethacin immediate-release capsules given at 4 hours to 6 hour intervals. Plasma concentrations of indomethacin fluctuate less and are more sustained following administration of indomethacin extended-release capsules than following administration of 25 mg indomethacin immediate-release capsules given at 4 hours to 6 hour intervals. In multiple-dose comparisons, the mean daily steady-state plasma level of indomethacin attained with daily administration of indomethacin extended-release capsules 75 mg was indistinguishable from that following indomethacin immediate-release capsules 25 mg given at 0 hour, 6 hours and 12 hours daily. However, there was a significant difference in indomethacin plasma levels between the two dosage regimens especially after 12 hours. 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. Specific Populations Pediatric The pharmacokinetics of indomethacin extended-release capsules have not been investigated in pediatric patients. Race Pharmacokinetic differences due to race have not been identified. Hepatic Impairment The pharmacokinetics of indomethacin extended-release capsules have not been investigated in patients with hepatic impairment. Renal Impairment The pharmacokinetics of indomethacin extended-release capsules have 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.

Indomethacin extended-release capsules are indicated for: 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) Indomethacin extended-release capsule is a nonsteroidal anti-inflammatory drug indicated for: 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) ( 1.

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2. 1 The dosage for moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis is one indomethacin extended-release 75 mg capsule daily ( 2. 2 The dosage for acute painful shoulder (bursitis and/or tendinitis) is one indomethacin extended-release 75 mg capsule once or twice daily ( 2. 3 Carefully consider the potential benefits and risks of indomethacin extended-release capsules and other treatment options before deciding to use indomethacin extended-release 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. THIS SECTION PREDOMINANTLY REFERENCES THE INDOMETHACIN IMMEDIATE-RELEASE CAPSULE ORAL DOSAGE AND IS INTENDED TO PROVIDE GUIDANCE IN USING INDOMETHACIN EXTENDED-RELEASE CAPSULES, 75 MG. Indomethacin extended-release capsules, 75 mg once a day can be substituted for indomethacin immediate-release capsules, 25 mg three times a day. However, there will be significant differences between the two dosage regimens in indomethacin blood levels, especially after 12 hours [ see Clinical Pharmacology ( 12 ndomethacin extended-release capsules, 75 mg twice a day can be substituted for indomethacin immediate-release capsules, USP 50 mg three times a day. Indomethacin extended-release capsules may be substituted for all the indications for indomethacin immediate-release capsules, USP except acute gouty arthritis. Dosage Recommendations for Active Stages of the Following: Indomethacin immediate-release 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 mg 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 extended-release capsules should be used with greater care in the elderly [ see Use in Specific Populations ( 8. 5 Indomethacin immediate-release capsules 75 mg to 150 mg daily in 3 or 4 divided doses. Discontinue indomethacin extended-release capsules treatment after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 days to 14 days.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5. 1 GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5. 2 Hepatotoxicity [ see Warnings and Precautions ( 5. 3 Hypertension [ see Warnings and Precautions ( 5. 4 Heart Failure and Edema [ see Warnings and Precautions ( 5. 5 Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5. 6 Anaphylactic Reactions [ see Warnings and Precautions ( 5. 7 Serious Skin Reactions [ see Warnings and Precautions ( 5. 9 Hematologic Toxicity [ see Warnings and Precautions ( 5. 12 Most common adverse reactions (incidence >= 3%) are headache, dizziness, dyspepsia and nausea. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin immediate-release capsules than in the group taking indomethacin suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin immediate-release capsules or suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin immediate-release capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with indomethacin immediate-release capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the capsules. Table 1 Summary of Adverse Reactions for Indomethacin Capsules * Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked. ) Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea * * anorexia gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc. ) development of ulcerative colitis and regional ileitis CENTRAL NERVOUS SYSTEM headache (11. 7%) anxiety (includes nervousness) light-headedness SPECIAL SENSES tinnitus ocular em dash corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin blurred vision CARDIOVASCULAR None hypertension congestive heart failure METABOLIC None edema hyperglycemia INTEGUMENTARY none pruritus exfoliative dermatitis HEMATOLOGIC None leukopenia aplastic anemia HYPERSENSITIVITY None acute anaphylaxis dyspnea GENITOURINARY None hematuria BUN elevation MISCELLANEOUS None epistaxis DERMATOLOGIC None Erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug reaction (FDE), urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity 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 Hematologic Genitourinary A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Abeta 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 post-approval 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).

Indomethacin extended-release capsules are contraindicated in the following patients: Known hypersensitivity (e. , anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [ see Warnings and Precautions ( 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. 8 In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5. 1 Known hypersensitivity to indomethacin or any components of the drug product ( 4 History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 In the setting of CABG surgery ( 4.

Infertility : 8. 3 Risk Summary Use of NSAIDs, including indomethacin extended-release 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 extended-release capsules use between about 20 and 30 weeks of gestation, and avoid indomethacin extended-release 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 extended-release 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. 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. 05 times the MRHD, respectively [ see Data 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 extended-release 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 extended-release capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin extended-release capsules 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 mg/kg/day, 1. 0 mg/kg/day, 2. 0 mg/kg/day 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/m 2 2 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/m 2 2 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 extended-release capsules and any potential adverse effects on the breastfed infant from the indomethacin extended-release 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 mg/kg 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. 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 extended-release 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 extended-release 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 extended-release 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 immediate-release 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 immediate-release 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 mg/kg/day to 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150 mg/day 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 mg/day 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. 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.

RECENT MAJOR CHANGES
Warnings and Precautions (5.9) 07/2024
DRUG INTERACTIONS
See Table 2 for clinically significant drug interactions with indomethacin. Table 2 Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact: 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. Intervention: Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e. , warfarin), antiplatelet agents (e. , aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5. 12 Aspirin Clinical Impact: 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 [ see Warnings and Precautions ( 5. 2 Intervention: Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5. 12 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). Intervention: During concomitant use of indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. see Warnings and Precautions ( 5. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e. , furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: Indomethacin and triamterene should not be administered together. 6 Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. Intervention: During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e. , neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine''s nephrotoxicity. Intervention: During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5. 2 see Clinical Pharmacology ( 12. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 mL/min to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Probenecid Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of indomethacin extended-release capsules 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. Effects on Laboratory Tests 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. Drugs that Interfere with Hemostasis (e. warfarin, aspirin, SSRIs/SNRIs) : 7 ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : 7 ACE Inhibitors and ARBs : 7 Diuretics : 7 Digoxin : 7.

OVERDOSAGE
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 grams to 100 grams in adults, 1 gram 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 times 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).
NONCLINICAL TOXICOLOGY
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 2 2 Mutagenesis Indomethacin did not have any mutagenic effect in in vitro in vivo 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 2 2
CLINICAL STUDIES
Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Indomethacin extended-release capsules afford relief of symptoms; it does not alter the progressive course of the underlying disease. Indomethacin extended-release 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 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 extended-release 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.

Zydus Pharmaceuticals USA Inc.

INDOMETHACIN- indomethacin_capsule, extended release Product manual source documgent