Celecoxib

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.

3. DOSAGE FORMS AND STRENGTHS Oral suspension: 10 mg/mL of celecoxib as a white, opaque, unflavored suspension. Oral suspension: 10 mg/mL ( 3 )

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 )

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 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 celecoxib, 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 Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of VYSCOXA in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If VYSCOXA is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including celecoxib cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with VYSCOXA. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [ see Clinical Studies (14.6) ]. Strategies to Minimize the GI Risks in NSAID-treated patients:

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time. […]

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 discontinuation due to adverse events in the celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain. The following adverse reactions occurred in 0.1% to 1.9% of patients treated with celecoxib (100 mg to 200 mg twice daily or 200 mg once daily): Gastrointestinal: Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting Cardiovascular: Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction General: Hypersensitivity, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain Central, peripheral nervous system: Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo Hearing and vestibular: Deafness, tinnitus Heart rate and rhythm: Palpitation, tachycardia Liver and biliary: Hepatic enzyme increased (including SGOT increased, SGPT increased) Metabolic and nutritional: blood urea nitrogen (BUN) increased, creatine phosphokinase (CPK) increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased Musculoskeletal: Arthralgia, arthrosis, myalgia, synovitis, tendinitis Platelets (bleeding or clotting): Ecchymosis, epistaxis, thrombocythemia, Psychiatric: Anorexia, anxiety, appetite increased, depression, nervousness, somnolence Hemic: Anemia Respiratory: Bronchitis, bronchospasm, bronchospasm aggravated, cough, dyspnea, laryngitis, pneumonia Skin and appendages: Alopecia, dermatitis, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria Application site disorders: Cellulitis, dermatitis contact Urinary: Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus The following serious adverse events (causality not evaluated) occurred in <0.1% of patients : Cardiovascular: Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis Gastrointestinal: I ntestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus General: Sepsis, sudden death Liver and biliary: Cholelithiasis Hemic and lymphatic: Thrombocytopenia Nervous: Ataxia, suicide [see Drug Interactions (7) ] Renal: Acute renal failure The Celecoxib Long-Term Arthritis Safety Study [ see Clinical Studies (14.6) ] Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with celecoxib was maintained with or without aspirin use [ see Clinical Pharmacology (12.2) ]. Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively). […]

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%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VYSCOXA and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. Intervention: During concomitant use of VYSCOXA and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of celecoxib and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of VYSCOXA and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ] . Intervention: The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of VYSCOXA and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. CYP2C9 Inhibitors or inducers Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of celecoxib. Intervention Evaluate each patient's medical history when consideration is given to prescribing VYSCOXA. A dosage adjustment may be warranted when VYSCOXA is administered with CYP2C9 inhibitors or inducers [ see Clinical Pharmacology (12.3) ]. CYP2D6 substrates Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. Intervention Evaluate each patient's medical history when consideration is given to prescribing VYSCOXA. A dosage adjustment may be warranted when VYSCOXA is administered with CYP2D6 substrates [ see Clinical Pharmacology (12.3) ]. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. Intervention Monitor patients with concomitant use of VYSCOXA with corticosteroids for signs of bleeding [ see Warnings and Precautions (5.2) ] .
• Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]) : Monitor patients for bleeding who are concomitantly taking VYSCOXA with drugs that interfere with hemostasis. Concomitant use of VYSCOXA and analgesic doses of aspirin is not generally recommended. […]

8. USE IN SPECIFIC POPULATIONS Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of VYSCOXA in women who have difficulties conceiving. ( 8.3 )

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 dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by AUC 0–24h ), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6 times human exposure based on the AUC 0–24h at 200 mg twice daily for RA) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 6 times human exposure based on the AUC 0–24h at 200 mg twice daily for RA). Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC 0–24h at 200 mg twice daily). The effects of celecoxib on labor and delivery in pregnant women are unknown.

8.2 Lactation Risk Summary Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when VYSCOXA is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VYSCOXA and any potential adverse effects on the breastfed infant from the VYSCOXA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including VYSCOXA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including VYSCOXA, in women who have difficulties conceiving or who are undergoing investigation of infertility. […]

Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of COX-2. Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro . Celecoxib 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. Since celecoxib is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.