Indocin
Indomethacin · Suspension · Oral, Rectal
Uses
Oral Suspension is 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) Acute gouty arthritis INDOCIN 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) Acute gouty arthritis ( 1 )
Dosage and administration
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 INDOCIN 25 mg (5 mL) two or three times a day ( 2.2 ) The dosage for acute painful shoulder (bursitis and/or tendinitis) is 75-150 mg (15-30 mL) daily in 3 or 4 divided doses ( 2.3 ) The dosage for acute gouty arthritis is INDOCIN 50 mg (10 mL) three times a day ( 2.4 ) 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of INDOCIN and other treatment options before deciding to use INDOCIN. 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: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis INDOCIN 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, INDOCIN should be used with greater care in the elderly [see Use in Specific Populations ( 8.5 ) ]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) INDOCIN 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. 2.4 Acute Gouty Arthritis INDOCIN 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.
Dosage forms and strengths
(indomethacin) Oral Suspension 25 mg per 5 mL, is an off-white suspension with a pineapple coconut mint flavor. INDOCIN (indomethacin) Oral Suspension: 25 mg of indocmethacin per 5mL ( 3 )
Contraindications
4 CONTRAINDICATIONS INDOCIN is contraindicated in the following patients: 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 ) ] 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 )
Warnings and precautions
Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of INDOCIN in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of INDOCIN in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : INDOCIN is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue INDOCIN at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.10 ) Fetal Toxicity : Limit use of NSAIDs, including INDOCIN, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 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 [ 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 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. 5.2 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.
Side effects
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 Zyla Life Sciences US Inc., at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving 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) pancreatitis CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness* vertigo 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-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with 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.
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. 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. Intervention: Monitor patients with concomitant use of INDOCIN 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 [ 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 INDOCIN and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the INDOCIN alone [ see Warnings and Precautions ( 5.2 ) ]. Intervention: Concomitant use of INDOCIN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.12 ) ]. INDOCIN is not a substitute for low dose aspirin for cardiovascular protection. 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). 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. Intervention: During concomitant use of INDOCIN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of INDOCIN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 ) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: 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. It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be administered together. Both INDOCIN and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of INDOCIN 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 [ see Warnings and Precautions ( 5.6 ) ]. Digoxin Clinical Impact: The concomitant use of INDOCIN with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of INDOCIN and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: 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 Intervention: During concomitant use of INDOCIN 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.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of INDOCIN and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of INDOCIN and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of INDOCIN 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.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) ]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [ see Clinical Pharmacology ( 12.3 ) ]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Use in specific populations
Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of INDOCIN in women who have difficulties conceiving ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including INDOCIN, 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 INDOCIN use between about 20 and 30 weeks of gestation, and avoid INDOCIN 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 INDOCIN, 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 (40mL)). 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 INDOCIN, 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 INDOCIN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN 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/m 2 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/m 2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations.
Pregnancy
8.1 Pregnancy Risk Summary Use of NSAIDs, including INDOCIN, 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 INDOCIN use between about 20 and 30 weeks of gestation, and avoid INDOCIN 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 INDOCIN, 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 (40mL)). 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 INDOCIN, 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 INDOCIN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN 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/m 2 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/m 2 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/m 2 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/m 2 basis).
Pediatric use
8.4 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
8.5 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 [ 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 ) ].
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 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).
Description
(indomethacin) Oral Suspension is a nonsteroidal anti-inflammatory drug, available as an oral suspension contain 25 mg of indomethacin per 5mL, alcohol 1%, and sorbic acid 0.1% added as a preservative for oral administration. The chemical name is -(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H -indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C 19 H 16 ClNO 4 , 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 4.0-5.0. The inactive ingredients in INDOCIN include: antifoam AF emulsion, flavors, purified water, sodium hydroxide or hydrochloric acid to adjust pH, sorbitol solution, and tragacanth. INDOCIN Oral Suspension, 25 mg per 5 mL, is an off-white suspension with a pineapple coconut mint flavor. Chemical Structure
Mechanism of action
12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of INDOCIN, 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.
How supplied
(indomethacin) Oral Suspension, 25 mg per 5 mL, is an off-white suspension with a pineapple coconut mint flavor. It is supplied as follows: NDC 69344-101-01 in bottles of 237 mL Storage Store below 30°C (86°F). Avoid temperatures above 50°C (122°F). Do not freeze.
Patient 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. Cardiovascular Thrombotic Events 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 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 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 [ see Warnings and Precautions ( 5.3 ) ]. Heart Failure and Edema 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 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 Advise patients to stop taking INDOCIN 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 Advise females of reproductive potential who desire pregnancy that NSAIDs, including INDOCIN, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3 ) ]. 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. If treatment with INDOCIN 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 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 [ 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 Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ]. Manufactured by: Patheon Inc. Whitby, Ontario L1N 5Z5, Canada Distributed by: Zyla Life Sciences US Inc., Wayne, PA 19087 © 2024 Zyla Life Sciences US Inc. All rights reserved. LBL# 801.03
Label text from the FDA structured product label by Zyla Life Sciences US LLC (revised Dec 16, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Indomethacin in 2 products
Indocin NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 69344-102 | Indomethacin 50 mg/1 Suppository | Zyla Life Sciences US Inc. | ANDA |
| 69344-101 | Indomethacin 25 mg/5mL Suspension | Zyla Life Sciences US LLC | NDA |
Frequently asked questions
What is Indocin used for?
Oral Suspension is 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) Acute gouty arthritis INDOCIN is a nonsteroidal anti-inflammatory drug indicated for: Moderate to severe rheumatoid arthritis including acute flares of…
What are the side effects of Indocin?
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… See the full label for the complete list.
Who makes Indocin?
Indocin is listed by 2 labelers in the FDA NDC directory, including Zyla Life Sciences US Inc., Zyla Life Sciences US LLC.