Oxaprozin

RECENT MAJOR CHANGES SECTION Warnings and Precautions, Serious Skin Reactions ( 5.9 ) 11/2024

1 INDICATIONS AND USAGE Oxaprozin tablets are indicated: • For relief of the signs and symptoms of osteoarthritis • For relief of the signs and symptoms of rheumatoid arthritis • For relief of the signs and symptoms of juvenile rheumatoid arthritis Oxaprozin is a non-steroidal anti-inflammatory drug indicated for: • Relief of signs and symptoms of Osteoarthritis (OA) (1) • Relief of signs and symptoms of Rheumatoid Arthritis (RA) (1) • Relief of signs and symptoms of Juvenile Rheumatoid Arthritis (JRA) (1)

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) OA: 1200 mg (two 600 mg tablets) given orally once a day ( 2.2 , 2.5 , 14.1 ) RA: 1200 mg (two 600 mg tablets) given orally once a day ( 2.3 , 2.5 , 14.2 ) JRA: 600 mg once daily in patients 22 to 31 kg. 900 mg once daily in patients 32 to 54 kg. 1200 mg once daily in patients ≥ 55 kg ( 2.4 , 2.5) 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of oxaprozin tablets and other treatment options before deciding to use oxaprozin tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ]. 2.2 Osteoarthritis For OA, the dosage is 1,200 mg (two 600 mg tablets) given orally once a day [ see Dosage and Administration ( 2.5 ) ]. 2.3 Rheumatoid Arthritis For RA, the dosage is 1,200 mg (two 600 mg tablets) given orally once a day [ see Dosage and Administration ( 2.5 ) ] . 2.4 Juvenile Rheumatoid Arthritis For JRA, in patients 6 to 16 years of age, the recommended dosage given orally once per day should be based on body weight of the patient as given in Table 1 [ see Dosage and Administration (2.5 ) ]. Table 1. Recommended Daily Dose of Oxaprozin Tablets by Body Weight in Pediatric Patients Body Weight Range (kg) Dose (mg) 22 to 31 600 32 to 54 900 ≥55 1200 2.5 Individualization of Dosage After observing the response to initial therapy with oxaprozin tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage should be individualized to the lowest effective dose of oxaprozin tablets to minimize adverse effects. The maximum recommended total daily dose of oxaprozin tablets in adults is 1,800 mg (26 mg/kg, whichever is lower) in divided doses. In children, doses greater than 1,200 mg have not been studied. Patients with low body weight should initiate therapy with 600 mg once daily. Patients with severe renal impairment or on dialysis should also initiate therapy with 600 mg once daily. If there is insufficient relief of symptoms in such patients, the dose may be cautiously increased to 1,200 mg, but only with close monitoring [ see Clinical Pharmacology ( 12.3 ) ]. In adults, in cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allows therapy to be started with a one-time loading dose of 1,200 mg to 1,800 mg (not to exceed 26 mg/kg). Doses larger than 1,200 mg/day on a chronic basis should be reserved for patients who weigh more than 50 kg, have normal renal and hepatic function, are at low risk of peptic ulcer, and whose severity of disease justifies maximal therapy. Physicians should ensure that patients are tolerating doses in the 600 mg to 1,200 mg/day range without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to the larger doses. Most patients will tolerate once-a-day dosing with oxaprozin tablets, although divided doses may be tried in patients unable to tolerate single doses.

3 DOSAGE FORMS AND STRENGTHS Oxaprozin tablets USP, 600 mg are yellow, oval shaped, scored, film-coated tablets debossed “C” on one side and “01|70” on the other side. Oxaprozin tablets: 600 mg (3)

4 CONTRAINDICATIONS Oxaprozin is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to oxaprozin 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 oxaprozin 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 (>3 %) are: constipation, diarrhea, dyspepsia, nausea, rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy's Laboratories Inc., at 1-888-375-3784 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 practice. Adverse reaction data were derived from patients who received oxaprozin in multidose, controlled, and open-label clinical trials. Rates for events from clinical trial experience are based on 2,253 patients who took 1,200 mg to 1,800 mg oxaprozin per day in clinical trials. Of these, 1,721 patients were treated for at least 1 month, 971 patients for at least 3 months, and 366 patients for more than 1 year. Incidence Greater than 1%: : In clinical trials of oxaprozin or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%. Cardiovascular system: edema. Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting. Hematologic system: anemia, increased bleeding time. Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache. Skin and appendages: pruritus, rash. Special senses: tinnitus. Urogenital system: abnormal renal function, dysuria or frequency. Incidence Less than 1%: : The following adverse reactions were reported in clinical trials or in patients taking other NSAIDs. Body as a whole: appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis. Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis. Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including liver failure, stomatitis, hemorrhoidal or rectal bleeding. Hematologic system: aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, purpura, thrombocytopenia, leukopenia. Metabolic system: hyperglycemia, weight changes. Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness. Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression. Skin: alopecia, angioedema, urticaria, photosensitivity, sweat. Special senses: blurred vision, conjunctivitis, hearing decrease. Urogenital: cystitis, hematuria, increase in menstrual flow, oliguria/ polyuria, proteinuria, renal insufficiency, decreased menstrual flow. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxaprozin. Because these reactions are reported v …

7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with oxaprozin [see Clinical Pharmacology (12.3) ]. Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis Clinical Impact: Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin 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 oxaprozin with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions ( 5.11 )]. 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 ( 5.12 )] . Intervention: Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.12 ) ]. Oxaprozin 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 ACE inhibitors, 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 oxaprozin and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin 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. Intervention: During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5.6) ]. Digoxin Clinical Impact: The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of oxaprozin 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 oxaprozin and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomi …

8.1 Pregnancy Risk Summary Use of NSAIDs, including oxaprozin, 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 oxaprozin use between about 20 and 30 weeks of gestation, and avoid oxaprozin 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 oxaprozin, 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, oral administration of oxaprozin to pregnant rabbits at doses 0.1-times the maximum daily human dose (based on body surface area) resulted in evidence of teratogenicity; however, oral administration of oxaprozin to pregnant mice and rats during organogenesis at doses equivalent to the maximum recommended human dose revealed no evidence of teratogenicity or embryotoxicity. In rat reproduction studies in which oxaprozin was administered through late gestation failure to deliver and a reduction in live birth index was observed at doses equivalent to the maximum recommended human dose. 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 oxaprozin, 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 oxaprozin, 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 oxaprozin treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue oxaprozin and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of oxaprozin during labor or delivery. In animal studies, NSAIDS, including oxaprozin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. 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 olig …

12.1 Mechanism of Action Oxaprozin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of oxaprozin, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Oxaprozin is a potent inhibitor of prostaglandin synthesis in vitro. Oxaprozin 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 oxaprozin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

11 DESCRIPTION Oxaprozin is a nonsteroidal anti-inflammatory drug, available as tablets of 600 mg for oral administration. The chemical name is 4,5-diphenyl-2-oxazole-propionic acid. The molecular weight is 293. Its molecular formula is C 18 H 15 NO 3 , and it has the following chemical structure. Oxaprozin is a white to yellowish-white crystalline powder. It is sparingly soluble in methanol and in ethanol, slightly soluble in ether and practically insoluble in water. The inactive ingredients in oxaprozin include: corn starch, D&C Yellow No. 10, FD&C Yellow No. 6, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, methylcellulose, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium starch glycolate, titanium dioxide and triacetin. 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 acute NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), 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 an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxaprozin tablets USP, 600 mg are yellow, oval shaped, scored, film-coated tablets debossed “C” on one side and “01|70” on the other side. NDC: 71335-0393-1 30 TABLET, FILM COATED in a BOTTLE NDC: 71335-0393-2 20 TABLET, FILM COATED in a BOTTLE NDC: 71335-0393-3 14 TABLET, FILM COATED in a BOTTLE NDC: 71335-0393-4 60 TABLET, FILM COATED in a BOTTLE NDC: 71335-0393-5 90 TABLET, FILM COATED in a BOTTLE NDC: 71335-0393-6 6 TABLET, FILM COATED in a BOTTLE NDC: 71335-0393-7 120 TABLET, FILM COATED in a BOTTLE Storage Keep bottles tightly closed. Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504