Celecoxib

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 celecoxib 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 celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)] . Celecoxib 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 celecoxib and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of celecoxib 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 celecoxib 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 celecoxib 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 celecoxib 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 celecoxib 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 celecoxib 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 celecoxib 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. Co­administration 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 celecoxib. A dosage adjustment may be warranted when celecoxib 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 celecoxib. A dosage adjustment may be warranted when celecoxib 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 celecoxib 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 celecoxib with drugs that interfere with hemostasis. Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended. ( 7 ) • Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with celecoxib may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ( 7 ) • ACE Inhibitors and ARBs: Concomitant use with celecoxib in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. ( 7 ) • Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. ( 7 ) • Digoxin: Concomitant use with celecoxib can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. ( 7 )

Celecoxib is indicated for: - "Osteoarthritis (OA)" - "Rheumatoid Arthritis (RA)" - "Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older" - "Ankylosing Spondylitis (AS)" - "Acute Pain (AP)" - "Primary Dysmenorrhea (PD)."

2 DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. ( 2.1 ) • OA: 200 mg once daily or 100 mg twice daily. ( 2.2 , 14.1 ) • RA: 100 mg to 200 mg twice daily. ( 2.3 , 14.2 ) • JRA: 50 mg twice daily in patients 10 kg to 25 kg. 100 mg twice daily in patients more than 25 kg. ( 2.4 , 14.3 ) • AS: 200 mg once daily single dose or 100 mg twice daily. If no effect is observed after 6 weeks, a trial of 400 mg (single or divided doses) may be of benefit. ( 2.5 , 14.4 ) • AP and PD: 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg twice daily as needed. ( 2.6 , 14.5 ) Hepatic Impairment: Reduce daily dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class B). ( 2.7 , 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. ( 2.7 , 8.8 , 12.3 ) 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of celecoxib and other treatment options before deciding to use celecoxib. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)] . These doses can be given without regard to timing of meals. 2.2 Osteoarthritis For OA, the dosage is 200 mg per day administered as a single dose or as 100 mg twice daily. 2.3 Rheumatoid Arthritis For RA, the dosage is 100 mg to 200 mg twice daily. 2.4 Juvenile Rheumatoid Arthritis For JRA, the dosage for pediatric patients (age 2 years and older) is based on weight. For patients ≥10 kg to ≤25 kg the recommended dose is 50 mg twice daily. For patients >25 kg the recommended dose is 100 mg twice daily. For patients who have difficulty swallowing capsules, the contents of a celecoxib capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2°C to 8°C/ 35°F to 45°F). 2.5 Ankylosing Spondylitis For AS, the dosage of celecoxib is 200 mg daily in single (once per day) or divided (twice per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options. 2.6 Management of Acute Pain and Treatment of Primary Dysmenorrhea For management of Acute Pain and Treatment of Primary Dysmenorrhea, the dosage is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed. 2.7 Special Populations Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh Class B), reduce the dose by 50%. The use of celecoxib 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)] .

In arthritis trials, adverse reactions occurring at ≥2% incidence versus placebo included "abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash."