Oxaprozin

1 INDICATIONS AND USAGE OXAPROZIN is 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 CAPSULES 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 (four 300 mg caplets) given orally once a day ( 2.2, 2.5, 14.1) RA: 1200 mg (four 300 mg caplets) given orally once a day ( 2.3, 2.5, 14.2) JRA: 600 mg (two 300 mg capsules) once daily in patients 22 to 31 kg. 900 mg (three 300 mg capsules) once daily in patients 32 to 54 kg. 1,200 mg (four 300 mg capsules) once daily in patients 55 kg or greater ( 2.4, 2.5) Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2.1) OA: 1200 mg (four 300 mg caplets) given orally once a day ( 2.2, 2.5, 14.1) RA: 1200 mg (four 300 mg caplets) given orally once a day ( 2.3, 2.5, 14.2) JRA: 600 mg (two 300 mg capsules) once daily in patients 22 to 31 kg. 900 mg (three 300 mg capsules) once daily in patients 32 to 54 kg. 1,200 mg (four 300 mg capsules) once daily in patients 55 kg or greater ( 2.4, 2.5) 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of OXAPROZIN CAPSULES and other treatment options before deciding to use OXAPROZIN CAPSULES. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS AND PRECAUTIONS (5)]. Different dose strengths and formulations (e.g., capsules, tablets) of oral oxaprozin are not interchangeable. This difference should be taken into consideration when changing strengths or formulations [see Dosage and Administration (2.2, 2.3, 2.4), Cinical Pharmacology (12.3)]. The highest daily dose for OXAPROZIN CAPSULES is 1,200 mg a day. 2.2 Osteoarthritis For OA, the dosage is 1,200 mg (four 300 mg capsules) given orally once a day [see DOSAGE AND ADMINISTRATION (2.5)]. 2.3 Rheumatoid Arthritis For RA, the dosage is 1,200 mg (four 300 mg capsules) 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 CAPSULES by Body Weight in Pediatric Patients Body Weight Range (kg) Dose (mg) Number of Capsules 22 to 31 kg 600mg Two capsules 32 to 54 kg 900mg Three capsules 2 to 54 kg 1,200mg Four capsules 2.5 Individualization of Dosage After observing the response to initial therapy with OXAPROZIN CAPSULES, 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 CAPSULES to minimize adverse effects. The maximum recommended total daily dose of OXAPROZIN CAPSULES in adults and pediatric patients is 1,200 mg. 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)]. Physicians should ensure that patients are tolerating lower doses without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to larger doses. Most patients will tolerate once-a-day dosing with OXAPROZIN CAPSULES, although divided doses may be tried in patients unable to tolerate single doses.

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 OXAPROZIN 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 OXAPROZIN 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: OXAPROZIN CAPSULES is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) Serious Skin Reactions: Discontinue OXAPROZIN 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 OXAPROZIN 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 cyclooxygenase-2 (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 oxaprozin, 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 studies conducted in the Danish National Regi…

4 CONTRAINDICATIONS SECTION OXAPROZIN CAPSULES 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 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)

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 CAPSULES with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and 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 OXAPROZIN CAPSULES and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS (5.12) ]. OXAPROZIN CAPSULES 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 CAPSULES and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of OXAPROZIN 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. Intervention: During concomitant use of OXAPROZIN CAPSULES 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 CAPSULES 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 CAPSULES and lithium, monitor patients for si…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elswhere in 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: constipation, diarrhea, dyspepsia, nausea, rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Solubiomix, LLC at 1-844-551-9911 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, the active component of OXAPROZIN CAPSULES, in multidose, controlled, and open-label clinical trials. Rates for events from clinical trial experience are based on 2253 patients who took 1,200 mg to 1800 mg of the active component of OXAPROZIN CAPSULES per day in clinical trials. Of these, 1721 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, the active component of OXAPROZIN CAPSULES, 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 Greater 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. Adverse Reactions in Pediatric Patients with Juvenile Rheumatoid Arthritis…