Indomethacin

RECENT MAJOR CHANGES Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic Symptoms (5.10) 04/2021 Warnings and Precautions, Fetal Toxicity (5.11) 04/2021 Warnings and Precautions, Serious Skin Reactions (5.9) 07/2024

INDICATIONS & USAGE 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 dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Indomethacin extended-release capsules have been found effective in active stages of the following: 1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease. 2. Moderate to severe ankylosing spondylitis. 3. Moderate to severe osteoarthritis. 4. Acute painful shoulder (bursitis and/or tendinitis). Indomethacin extended-release capsules, USP are not recommended for the treatment of acute gouty arthritis. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. The use of indomethacin in conjunction with aspirin or other salicylates is not recommended. Controlled clinical studies have shown that the combined use of indomethacin and aspirin does not produce any greater therapeutic effect than the use of indomethacin alone. Furthermore, in one of these clinical studies, the incidence of gastrointestinal side effects was significantly increased with combined therapy. (See PRECAUTIONS,Drug Interactions ).

DOSAGE & ADMINISTRATION 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 dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Indomethacin extended-release capsules 75 mg are available for oral use. Indomethacin extended-release capsules can be administered once a day and can be substituted for indomethacin 25 mg capsules t.i.d. However, there will be significant differences between the two dosage regimens in indomethacin blood levels, especially after 12 hours (see CLINICAL PHARMACOLOGY ). In addition, indomethacin extended-release capsules 75 mg b.i.d. can be substituted for indomethacin 50 mg capsules t.i.d. Indomethacin extended-release capsules may be substituted for all the indications of indomethacin capsules except acute gouty arthritis. Adverse reactions appear to correlate with the size of the dose of indomethacin in most patients, but not all. Therefore, every effort should be made to determine the smallest effective dosage for the individual patient. Always give indomethacin extended-release capsules 75 mg with food, immediately after meals or with antacids to reduce gastric irritation. Pediatric Use : Indomethacin ordinarily should not be prescribed for children 14 years of age and under (see WARNINGS ). Adult Use : Dosage Recommendations for Active Stages of the Following: 1. Moderate to severe rheumatoid arthritis, including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis. The following information is provided as background only and refers to immediate-release indomethacin capsules (25 mg or 50 mg): Suggested Dosage : The following recommendations on dosing pertain to immediate-release indomethacin capsules, and provide important information regarding the dosage and administration of indomethacin. The prescriber should be aware of this information when considering and prescribing extended-release indomethacin. Indomethacin capsules 25 mg b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 or 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 to 200 mg is reached. DOSES ABOVE THIS AMOUNT GENERALLY DO NOT INCREASE THE EFFECTIVENESS OF THE DRUG. In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime, either orally or by rectal suppositories, may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. The following information refers to Extended-release Indomethacin Capsules (75 mg): If indomethacin extended-release capsules are used for initiating indomethacin treatment, one capsule daily should be the usual starting dose in order to observe patient tolerance since 75 mg per day is the maximum recommended starting dose for indomethacin (see above). If indomethacin extended-release capsules are used to increase the daily dose, patients should be observed for possible signs and symptoms of intolerance since the daily increment will exceed the daily increment recommended for other dosage forms. For patients who require 150 mg of indomethacin per day and have demonstrated acceptable tolerance, indomethacin extended-release capsules 75 mg may be prescribed as one capsule twice 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 repeated …

3 DOSAGE FORMS AND STRENGTHS Indomethacin Extended-Release Capsules, USP 75 mg – size “2” hard gelatin capsules with an opaque green cap and a transparent green body, imprinted with “G” on the cap and “G325” on the body in black ink, filled with off-white to yellowish colored pellets. Indomethacin Extended-Release Capsules, USP 75 mg ( 3 )

4 CONTRAINDICATIONS Indomethacin extended-release 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 )

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 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 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 immediate-release capsules 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 Immediate-Release 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 periphera …

7 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 indomethacin extended-release capsules 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 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 ( 5.11 ) ]. Indomethacin extended-release capsules are 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 indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin extended-release capsules 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 indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together. Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules 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 b …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1) Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of indomethacin extended-release capsules in women who have difficulties conceiving (8.3) Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of indomethacin extended-release capsules in women who have difficulties conceiving ( 8.3 ). 8.1 Pregnancy 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 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% 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 …

12.1 Mechanism of Action 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 . 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.

11 DESCRIPTION Indomethacin Extended-Release Capsules, USP are non-steroidal anti-inflammatory drugs, available as capsules containing 75 mg of indomethacin, USP, administered for oral use. The chemical name is 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid. The molecular weight is 357.79 g/mol. Its molecular formula is C 19 H 16 ClNO 4 . The structural formula is: Indomethacin, USP is a white to yellow crystalline powder. It is practically insoluble in water; sparingly soluble in alcohol, chloroform, and ether. A pKa of 4.5 for the carboxyl group of indomethacin, USP was calculated from the aqueous solubility data. Potentiometric titration data in 50 % methanol-water yielded pKa of 4.5 using a correction factor for the solvent. The inactive ingredients in Indomethacin Extended-Release Capsules, USP 75 mg include: black iron oxide, D&C yellow No. 10, ethylcellulose, FD&C blue No. 1, FD&C red No. 40, gelatin, hypromellose, lactose monohydrate, polyethylene glycol, potassium hydroxide, shellac, sodium lauryl sulfate, sugar spheres, talc and titanium dioxide. This product meets USP Dissolution Test 2. structure

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 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 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).

16 HOW SUPPLIED/STORAGE AND HANDLING Indomethacin extended-release capsules USP, 75 mg are size ‘2’, dark yellow cap and clear transparent body hard gelatin capsules, containing cream spherical pellets imprinted with ‘H’ on cap and ‘105’ on body. They are supplied as Bottles of 1 capsules NDC 85766-034-01 (repackaged from NDC 31722-565-XX) Bottles of 2 capsules NDC 85766-034-02 (repackaged from NDC 31722-565-XX) Bottles of 6 capsules NDC 85766-034-06 (repackaged from NDC 31722-565-XX) Bottles of 7 capsules NDC 85766-034-07 (repackaged from NDC 31722-565-XX) Bottles of 10 capsules NDC 85766-034-00 (repackaged from NDC 31722-565-XX) Bottles of 14 capsules NDC 85766-034-14 (repackaged from NDC 31722-565-XX) Bottles of 20 capsules NDC 85766-034-20 (repackaged from NDC 31722-565-XX) Bottles of 30 capsules NDC 85766-034-30 (repackaged from NDC 31722-565-XX) Bottles of 60 capsules NDC 85766-034-60 (repackaged from NDC 31722-565-XX) Bottles of 90 capsules NDC 85766-034-90 (repackaged from NDC 31722-565-XX) Bottles of 100 capsules NDC 85766-034-10 (relabeled from NDC 31722-565-01) Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture