Indomethacin

1 INDICATIONS AND USAGE Indomethacin 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) Acute gouty arthritis Indomethacin capsules are 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 )

12.1 Mechanism of Action Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro . Indomethacin concentrations reached during therapy have produced in 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.

2 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 indomethacin capsules 25 mg two or three times a day. ( 2.2 ) The dosage for acute painful shoulder (bursitis and/or tendinitis) is 75 to 150 mg daily in 3 or 4 divided doses. ( 2.3 ) The dosage for acute gouty arthritis is indomethacin capsules 50 mg three times a day. ( 2.4 ) 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient’s needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Dosage recommendations for active stages of the following: 2.2 Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin capsules 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 to 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. As advancing years appear to increase the possibility of adverse reactions, indomethacin capsules should be used with greater care in the elderly [see Use in Specific Populations (8.5) ]. 2.3 Acute painful shoulder (bursitis and/or tendinitis) Indomethacin capsules 75 to 150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 to 14 days. 2.4 Acute Gouty Arthritis Indomethacin capsules 50 mg three times a day until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions ( 5.1 )] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions ( 5.2 )] Hepatotoxicity [see Warnings and Precautions ( 5.3 )] Hypertension [see Warnings and Precautions ( 5.4 )] Heart Failure and Edema [see Warnings and Precautions ( 5.5 )] Renal Toxicity and Hyperkalemia [see Warnings and Precautions ( 5.6 )] Anaphylactic Reactions [see Warnings and Precautions ( 5.7 )] Serious Skin Reactions [see Warnings and Precautions ( 5.9 )] Hematologic Toxicity [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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 indomethacin capsules than in the group taking indomethacin suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin capsules or suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin capsules and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with indomethacin capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the capsules. Table 1 Summary of Adverse Reactions for Indomethacin Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness* vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular-corneal deposits a

5 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 indomethacin capsules 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 indomethacin capsules 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 : Indomethacin capsules are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) Serious Skin Reactions : Discontinue indomethacin capsules 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 indomethacin capsules, 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 renal 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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [ see Contraindications (4) ]. Post-MI Patients Observational st

4 CONTRAINDICATIONS Indomethacin capsules are 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 )

10 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).