Etodolac ER

Adverse Reactions A total of 1552 patients were exposed to etodolac extended-release tablets in controlled clinical studies of at least 4 weeks in length and using daily doses in the range of 400 to 1200 mg. In the tabulations below, adverse event rates are generally categorized based on the incidence of events in the first 30 days of treatment with etodolac extended-release tablets. As with other NSAIDs, the cumulative adverse event rates may increase significantly over time with extended therapy. In patients taking NSAIDs, including etodolac extended-release tablets, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are: gastrointestinal experiences including: abdominal pain constipation diarrhea dyspepsia flatulence GI ulcers (gastric/duodenal) * gross bleeding/perforation * nausea vomiting * Adverse events that were observed in < 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials. other events including: abnormal renal function * anemia * asthenia dizziness edema * elevated liver enzymes * headaches hypertension increased bleeding time * infection pharyngitis pruritus rashes rhinitis tinnitus * Additional NSAID Adverse Experiences Reported Occasionally with NSAIDs or Etodolac Extended-Release Tablets Include Body as a whole - allergic reaction, anaphylactic/anaphylactoid reactions (including shock), chills, fever, sepsis Cardiovascular system - congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic) Digestive system - anorexia, cholestatic hepatitis, cholestatic jaundice, dry mouth, duodenitis, eructation, esophagitis, gastritis, gastric/peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis Hemic and lymphatic system - agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia Metabolic and nutritional - hyperglycemia in previously controlled diabetic patients Nervous system - anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory system - asthma, dyspnea, pulmonary infiltration with eosinophilia Skin and appendages - angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash Special senses - blurred vision, photophobia, transient visual disturbances Urogenital system - dysuria, elevated BUN, oliguria/polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency Other NSAID Adverse Reactions, Which Occur Rarely Are Body as a whole - anaphylactic reactions, appetite changes, death Cardiovascular system - arrhythmia, cerebrovascular accident, hypotension, myocardial infarction Digestive system - colitis, esophagitis with or without stricture or cardiospasm, thirst, ulcerative stomatitis Hemic and lymphatic system - aplastic anemia, lymphadenopathy Metabolic and nutritional - change in weight Nervous system - coma, convulsions, hallucinations, meningitis Respiratory - bronchitis, pneumonia, respiratory depression, sinusitis Skin and appendages - alopecia, exfoliative dermatitis, maculopapular rash, photosensitivity, skin peeling, Stevens-Johnson syndrome, toxic epidermal necrosis Special senses - conjunctivitis, deafness, hearing impairment, taste perversion Urogenital system - cystitis, hematuria, interstitial nephritis, leukorrhea, renal calculus, uterine bleeding irregularities

Contraindications Etodolac extended-release tablets are contraindicated in patients with known hypersensitivity to etodolac. Etodolac extended-release tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, ANAPHYLACTOID REACTIONS and PRECAUTIONS, PREEXISTING ASTHMA). Etodolac extended-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Description Etodolac Extended-Release Tablets contain etodolac, which is a member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each tablet contains etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. It is a white crystalline compound, insoluble in water, but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. The chemical name is (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. The molecular weight is 287.37. Its molecular formula is C17H21NO3 and it has the following structural formula: The inactive ingredients in etodolac extended-release tablets include: HPMC 2910, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, PEG 8000, polydextrose FCC, povidone, titanium dioxide and triacetin. In addition, the 500 mg and 600 mg tablets contain Indigo Carmine Lake and the 400 mg and 600 mg tablets contain Allura Red AC Lake and Sunset Yellow F.C.F. Lake. In addition, the 500 mg tablets contain yellow iron oxide. Meets USP Dissolution Test 4. Structure

Dosage and Administration Carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with etodolac extended-release tablets, the dose and frequency should be adjusted to suit an individual patient's needs. Juvenile Rheumatoid Arthritis For the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight, according to the following table: Table 4 Body Weight Range (kg) Dose 20 to 30 400 mg Tablet × 1 31 to 45 600 mg Tablet × 1 46 to 60 400 mg Tablet × 2 >60 500 mg Tablet × 2 Rheumatoid Arthritis and Osteoarthritis For the relief of the signs and symptoms of osteoarthritis or rheumatoid arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day. As with other NSAIDs, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.

Indications and Usage Carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Etodolac extended-release tablets are indicated: For relief of signs and symptoms of juvenile arthritis For relief of the signs and symptoms of rheumatoid arthritis For relief of the signs and symptoms of osteoarthritis

Overdosage Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of the urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Clinical Pharmacology Pharmacodynamics Etodolac extended-release tablets are a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac extended-release tablets, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Absorption Etodolac extended-release tablets and etodolac tablets both contain etodolac, but differ in their release characteristics. The systemic availability of etodolac from etodolac extended-release tablets is generally greater than 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. After oral administration of etodolac extended-release tablets in doses up to 800 mg once daily, peak concentrations occur approximately 6 hours after dosing and are dose proportional for both total and free etodolac. Table 1 shows the comparison of etodolac pharmacokinetic parameters after the administration of etodolac tablets and etodolac extended-release tablets. Table 2 shows the etodolac pharmacokinetic parameters in various populations. The data from patients with renal and hepatic impairment were obtained following administration of (immediate-release) etodolac tablets. Table 1. Mean (CV)% * Pharmacokinetic Parameters Etodolac Tablets Etodolac Extended-Release Tablets Extent of Oral Absorption (Bioavailability) [F] ≥ 80% ≥ 80% Time to Peak Concentration (Tmax), h 1.4 (61%) 6.7 (47%) Oral Clearance (CL/F), mL/h/kg 49.1 (33%) 46.8 (37%) Apparent Volume of Distribution (Vd/F), mL/kg 393 (29%) 566 (26%) Terminal Half-Life (t½), h 6.4 (22%) 8.4 (30%) * % Coefficient of variation Table 2. Mean (CV%)* Pharmacokinetic Parameters of Etodolac in Normal Healthy Adults and Various Special Populations Etodolac Extended-Release Tablets Etodolac Tablets PK Parameters Normal Healthy Adults Healthy Males Healthy Females Elderly (> 65 yr) Hemodialysis † (24 to 65) (n=9) Renal Impairment † Hepatic Impairment † (18 to 44)‡ (n=116) (18 to 43) (n=102) (25 to 44) (n=14) (66 to 88) (n=24 Dialysis On Dialysis Off (46 to 73) (n=10) (34 to 60) (n=9) Tmax, h 6.7 (47%) * 6.8 (45%) 4.5 (56%) 6.2 (51%) 1.7 (88%) 0.9 (67%) 2.1 (46%) 1.1 (15%) Oral Clearance, mL/h/kg (CL/F) 46.8 (37%) 46.8 (37%) 47.2 (38%) 51.6 (40%) NA NA 58.3 (19%) 42.0 (43%) Apparent Volume of Distribution, mL/kg (Vd/F) 566 (26%) 580 (26%) 459 (28%) 552 (34%) NA NA NA NA Terminal Half-Life, h 8.4 (30%) 8.4 (29%) 7.6 (45%) 7.8 (26%) 5.1 (22%) 7.5 (34%) NA 5.7 (24%) NA = not available * % Coefficient of variation † Pharmacokinetic parameters obtained following administration of etodolac tablets ‡ Age range (years) Food/Antacid Effects Food has no significant effect on the extent of etodolac extended-release tablets absorption, however, food significantly increased Cmax (54%) following a 600 mg dose. The extent of absorption of etodolac is not affected when etodolac is administered with antacid. Coadministration, with an antacid, decreases the peak concentration reached by about 15 to 20% with no measurable effect on time-to-peak. Distribution The mean apparent volume of distribution (Vd/F) of etodolac following administration of etodolac extended-release tablets is 566 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin, and is independent of etodolac concentration over the dose range studied. It is not known whether etodolac is excreted in human milk. However, based on its physical-chemical properties, excretion into breast milk is expected. Metabolism Etodolac metabolites do not contribute significantly to the pharmacological activity of etodolac extended-release tablets. Following administration of immediate-release etodolac, several metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8- hydroxylated etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolites do not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces. Excretion The mean oral clearance of etodolac following oral etodolac extended-release tablets dosing is 47 (±17) mL/h/kg. The terminal half-life (t½) of etodolac after etodolac extended-release tablets administration is 8.4 hours compared to 6.4 hours for etodolac tablets. Approximately 1% of an etodolac tablet dose is excreted unchanged in the urine, with 72% of the dose excreted into the urine as parent drug plus metabolites: -etodolac, unchanged 1% -etodolac glucuronide 13% -hydroxylated metabolites (6-, 7-, and 8-OH) 5% -hydroxylated metabolite glucuronides 20% -unidentified metabolites 33% Fecal excretion accounted for 16% of the dose. Special Populations Geriatric In clinical studies, age was not shown to have any effect on half-life or protein binding, and demonstrated no change in expected drug accumulation. No dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics. The elderly may need dosage adjustment, however, as they may be more sensitive to antiprostaglandin effects than younger patients (see PRECAUTIONS, GERIATRIC USE). Pediatric The pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12-week clinical trial which included plasma sampling for population pharmacokinetics. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 13.3 to 21.3 mg/kg given as 400 to 1000 mg once daily. The results from a population pharmacokinetic analysis based on the 59 subjects who completed the trial are as follows: Table 3. Pharmacokinetic Parameter Estimates for Etodolac Extended-Release Tablets in Patients with Juvenile Rheumatoid Arthritis Parameter JRA * (Age: 6 to 16) † n = 59 Oral Clearance (CL/F), mL/h/kg 47.8 (38%) Apparent Volume of Distribution (Vd/F), mL/kg 78.9 (61%) Half-life (t½), h 12.1 (75%) * Mean (CV) of parameter estimates predicted from population pharmacokinetics † Age range (years) While similar, the pharmacokinetic parameters for children with juvenile rheumatoid arthritis did not directly correlate with adult pharmacokinetic data in rheumatoid arthritis. In the population pharmacokinetic analysis, body weights below 50 kg were found to correlate with CL/F (see DOSAGE AND ADMINISTRATION). Race Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion. Hepatic Insufficiency The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with hepatic insufficiency. Following administration of etodolac tablets, the plasma protein binding and disposition of total and free etodolac were unchanged in the presence of compensated hepatic cirrhosis. Although no dosage adjustment is generally required in patients with chronic hepatic diseases, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. Renal Insufficiency The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with renal insufficiency. Etodolac renal clearance following administration of etodolac tablets was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance, 37 to 88 mL/min). Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild-to-moderate renal dysfunction is generally necessary. Etodolac plasma protein binding decreases in patients with severe renal deficiency. Etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.

20221109

3

Etodolac ER Etodolac ETODOLAC ETODOLAC Bi-Convex T600

ANDA076174

Etodolac ER

Etodolac

80425-0181

HUMAN PRESCRIPTION DRUG

ORAL

Principle Display label 1

Medication Guide What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: with increasing doses of NSAIDs with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: anytime during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with: past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs Taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs" increasing doses of NSAIDs longer use of NSAIDs smoking drinking alcohol older age poor health advanced liver disease bleeding problems NSAIDs should only be used: exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT MEDICINES CALLED NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)?" new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: shortness of breath or trouble breathing chest pain weakness in one part or side of your body slurred speech swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea more tired or weaker than usual diarrhea itching your skin or eyes look yellow indigestion or stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

Clinical Studies Arthritis The use of etodolac extended-release tablets in managing the signs and symptoms of osteoarthritis of the knee and rheumatoid arthritis was assessed in double-blind, randomized, parallel, controlled clinical trials in 1552 patients. In these trials, etodolac extended-release tablets, given once daily, provided efficacy comparable to immediate-release etodolac. The safety, efficacy, and pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12-week clinical trial. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 400 to 1000 mg (13.3 to 21.3 mg/kg body weight) once daily. At these doses, etodolac extended-release tablets controlled the signs and symptoms of juvenile rheumatoid arthritis. Based on the results of this study, the safety profile of etodolac extended-release tablets (at doses not exceeding 20 mg/kg) appeared to be similar to that observed in the adult arthritic patients in clinical trials. (See PRECAUTIONS, PEDIATRIC USE).

How Supplied/Storage and Administration 600 mg tablets (grey, oval, bi-convex, film coated tablet engraved with "T600" on one side and plain on the other side). Bottles of 30 Tablets NDC: 80425-0181-01 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from excessive heat and humidity. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Mfd. by: Taro Pharmaceutical Industries Ltd. Haifa Bay, Israel 2624761 Dist. by: Taro Pharmaceuticals U.S.A., Inc. Hawthorne, NY 10532 Distributed by: Advanced Rx Pharmacy of Tennessee, LLC Nashville, TN 37211 Revised: March 2021 5201491-0321-7

Boxed Warning Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS). Etodolac extended-release tablets, 400 mg, 500 mg and 600 mg are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS). Gastrointestinal Risk NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS).