Celecoxib (Page 5 of 11)

Other Pre-Approval Studies

Adverse Events from Ankylosing Spondylitis Studies

A total of 378 patients were treated with celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RA studies.

Adverse Events from Analgesia and Dysmenorrhea Studies

Approximately 1,700 patients were treated with celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of celecoxib capsules were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies.

The APC and PreSAP Trials

Adverse reactions from long-term, placebo-controlled polyp prevention studies

Exposure to celecoxib in the APC and PreSAP trials was 400 mg to 800 mg daily for up to 3 years. [see Special Studies Adenomatous Polyp Prevention Studies (14.7)].

Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from celecoxib pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with celecoxib were greater as compared to the arthritis pre-marketing trials were as follows:

	Celecoxib Capsules (400 to 800 mg daily) N = 2285	Placebo N=1303
Diarrhea	10.5%	7.0%
Gastroesophageal reflux disease	4.7%	3.1%
Nausea	6.8%	5.3%
Vomiting	3.2%	2.1%
Dyspnea	2.8%	1.6%
Hypertension	12.5%	9.8%
Nephrolithiasis	2.1%	0.8%

The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking celecoxib capsules, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies:

Nervous system disorders:

Cerebral infarction

Eye disorders:

Vitreous floaters, conjunctival hemorrhage

Ear and labyrinth:

Labyrinthitis

Cardiac disorders :

Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy

Vascular disorders:

Deep vein thrombosis

Reproductive system and breast disorders:

Ovarian cyst

Investigations :

Blood potassium increased, blood sodium increased, blood testosterone decreased

Injury, poisoning, and procedural complications:

Epicondylitis, tendon rupture

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of celecoxib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure

Cardiovascular

Vasculitis, deep venous thrombosis

General

Anaphylactoid reaction, angioedema

Liver and biliary

Liver necrosis, hepatitis, jaundice, hepatic failure

Hemic and lymphatic

Agranulocytosis, aplastic anemia, pancytopenia, leucopenia

Metabolic

Hypoglycemia, hyponatremia

Nervous

Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage

Renal

Interstitial nephritis

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 (5.11)].
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 (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib capsules (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 (5.11)]. Celecoxib capsules are 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 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 capsules 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. 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 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 capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.2)].