VYSCOXA

1. INDICATIONS AND USAGE VYSCOXA is indicated In adults for the management of the signs and symptoms of: VYSCOXA contains celecoxib, a nonsteroidal anti-inflammatory drug, and is indicated: In adults for • Osteoarthritis (OA) ( 1.1 ) • Rheumatoid Arthritis (RA) ( 1.2 ) • Ankylosing Spondylitis (AS) ( 1.3 ) In pediatric patients two years and older for • Juvenile Rheumatoid Arthritis (JRA) ( 1.4 ) Limitations of Use VYSCOXA must be administered on an empty stomach at least 2 hours before or 1 hour after food. Taking VYSCOXA with food results in plasma exposures of celecoxib up to 50% higher than intended. If patients cannot tolerate VYSCOXA in the fasted state, discontinue use of VYSCOXA ( 2.1 , 5 , 12 ) 1.1 Osteoarthritis (OA) [ see Clinical Studies (14.1) ]. 1.2 Rheumatoid Arthritis (RA) [ see Clinical Studies (14.2) ]. 1.3 Ankylosing Spondylitis (AS) [ see Clinical Studies (14.3) ]. In pediatric patients two years of age and older for the management of the signs and symptoms of: 1.4 Juvenile Rheumatoid Arthritis (JRA) [ see Clinical Studies (14.4) ]. Limitations of Use VYSCOXA must be administered on an empty stomach at least 2 hours before or 1 hour after food. Taking VYSCOXA with food results in plasma exposures of celecoxib up to 50% higher than intended. If patients cannot tolerate VYSCOXA in the fasted state, discontinue use of VYSCOXA (reference Sections 2.1 , 5 , 12 ). VYSCOXA is NOT indicated for the management of acute pain or treatment of primary dysmenorrhea.

2. DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. ( 2.1 ) • OA: 200 mg (20 mL) once daily or 100 mg (10 mL) twice daily. ( 2.2 , 14.1 ) • RA: 100 mg (10 mL) to 200 mg (20 mL) twice daily. ( 2.3 , 14.2 ) • AS: 200 mg (20 mL) once daily single dose or 100 mg (10 mL) twice daily. If no effect is observed after 6 weeks, a trial of 200 mg (20 mL) twice daily may be of benefit. ( 2.4 , 14.3 ) • JRA: 50 mg (5 mL) twice daily in patients 10 kg to 25 kg. 100 mg (10 mL) twice daily in patients more than 25 kg. ( 2.5 , 14.4 ) Important: VYSCOXA is not recommended at a single dose greater than 200 mg (20 mL). Single doses of the suspension greater than 200 mg (20 mL) may result in celecoxib concentrations higher than expected. For patients who require a single dose over 200 mg (20 mL), use a different celecoxib formulation ( 2.1 , 12.3 ) Hepatic Impairment: Reduce daily dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class B). ( 2.6 , 8.6 , 12.3 ) Poor Metabolizers of CYP2C9 Substrates: Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers. ( 2.6 , 8.8 , 12.3 ). 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of VYSCOXA and other treatment options before deciding to use VYSCOXA. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ]. The maximum single dose of VYSCOXA is 200 mg (20 mL). Administering more than 200 mg (20 mL) in a single dose of the VYXCOXA suspension may result in higher than intended plasma concentrations of celecoxib. In patients requiring a single dose greater than 200 mg (20 mL), use a different product. VYSCOXA must be taken on an empty stomach at least 2 hours before or 1 hour after food [ see Clinical Pharmacology (12.3) ]. For patients who cannot tolerate dosing with VYSCOXA on an empty stomach, discontinue the use of this product. Do not advise the patient to take VYSCOXA with food. 2.2 Osteoarthritis For OA, the dosage is 200 mg (20 mL) per day administered as a single dose or as 100 mg (10 mL) twice daily. 2.3 Rheumatoid Arthritis For RA, the dosage is 100 mg (10 mL) to 200 mg (20 mL) twice daily. 2.4 Ankylosing Spondylitis For AS, the dosage is 200 mg (20 mL) daily in single (once per day) dose or 100 mg (10 mL) twice daily. If no effect is observed after 6 weeks, a trial of 200 mg (20 mL) twice daily may be worthwhile. If no effect is observed after 6 weeks on 200 mg (20 mL) twice daily, a response is not likely and consideration should be given to alternate treatment options. 2.5 Juvenile Rheumatoid Arthritis For JRA, the dosage for pediatric patients (age 2 years and older) is based on weight. For patients weighing 10 kg to 25 kg the recommended dose is 50 mg (5 mL) twice daily. For patients greater than 25 kg the recommended dose is 100 mg (10 mL) twice daily. 2.6 Special Populations Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh Class B), reduce the dose by 50%. The use of VYSCOXA in patients with severe hepatic impairment is not recommended [ see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . Poor Metabolizers of CYP2C9 Substrates In adult patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin), initiate treatment with half of the lowest recommended dose. In patients with JRA who are known or suspected to be poor CYP2C9 metabolizers, consider using alternative treatments [ see Use in Specific populations (8.8) and Clinical Pharmacology (12.5) ].

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 VYSCOXA 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 VYSCOXA 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 : VYSCOXA is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) • Serious Skin Reactions : Discontinue VYSCOXA 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 VYSCOXA, 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. In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [ see Clinical Studies (14.6) ]. A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and ibuprofen. Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists' Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke [ see Clinical Studies (14.5) ]. To minimize the poten…

4. CONTRAINDICATIONS VYSCOXA is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, 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) ]. • In patients who have demonstrated allergic-type reactions to sulfonamides [ see Warnings and Precautions (5.7) ]. • Known hypersensitivity to celecoxib, or any components of the drug product or sulfonamides. ( 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 3 for clinically significant drug interactions with celecoxib. Table 3: Clinically Significant Drug Interactions with Celecoxib Drugs That Interfere with Hemostasis Clinical Impact: • Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib 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 VYSCOXA 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) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 mg to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 mg to 325 mg). Intervention: Concomitant use of VYSCOXA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.12) ]. VYSCOXA 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 VYSCOXA and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VYSCOXA 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 VYSCOXA 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 Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of VYSCOXA 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%. T…

8.1 Pregnancy Risk Summary Use of NSAIDs, including VYSCOXA, 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 VYSCOXA use between about 20 and 30 weeks of gestation and avoid VYSCOXA 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 VYSCOXA, 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, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose (MRHD) of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the MRHD ( 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 celecoxib, 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 background risk of major birth defects and miscarriage for the indicated population 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 VYSCOXA, 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 VYSCOXA treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue VYSCOXA and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of celecoxib during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data The available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib. 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 dysfunct…

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 in arthritis trials (>2% and >placebo) are: abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Carwin Pharmaceutical Associates, LLC at 1-844-700-5011 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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Of the celecoxib-treated patients in the pre-marketing controlled clinical trials of another formulation of celecoxib, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more. Pre-marketing Controlled Arthritis Trials Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence. Table 1: Adverse Events Occurring in >2% of Celecoxib Patients from Pre-marketing Controlled Arthritis Trials CEL N=4146 Placebo N=1864 NAP N=1366 DCF N=387 IBU N=345 CEL = Celecoxib 100 mg to 200 mg twice daily or 200 mg once daily; NAP = Naproxen 500 mg twice daily; DCF = Diclofenac 75 mg twice daily; IBU = Ibuprofen 800 mg three times daily. Gastrointestinal Abdominal Pain 4.1% 2.8% 7.7% 9.0% 9.0% Diarrhea 5.6% 3.8% 5.3% 9.3% 5.8% Dyspepsia 8.8% 6.2% 12.2% 10.9% 12.8% Flatulence 2.2% 1.0% 3.6% 4.1% 3.5% Nausea 3.5% 4.2% 6.0% 3.4% 6.7% Body as a whole Back Pain 2.8% 3.6% 2.2% 2.6% 0.9% Peripheral Edema 2.1% 1.1% 2.1% 1.0% 3.5% Injury-Accidental 2.9% 2.3% 3.0% 2.6% 3.2% Central, Peripheral Nervous system Dizziness 2.0% 1.7% 2.6% 1.3% 2.3% Headache 15.8% 20.2% 14.5% 15.5% 15.4% Psychiatric Insomnia 2.3% 2.3% 2.9% 1.3% 1.4% Respiratory Pharyngitis 2.3% 1.1% 1.7% 1.6% 2.6% Rhinitis 2.0% 1.3% 2.4% 2.3% 0.6% Sinusitis 5.0% 4.3% 4.0% 5.4% 5.8% Upper Respiratory Infection 8.1% 6.7% 9.9% 9.8% 9.9% Skin Rash 2.2% 2.1% 2.1% 1.3% 1.2% In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for disconti…