June 25, 2016
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Celebrex

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Celebrex




Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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 CELEBREX-treated patients in the pre-marketing controlled clinical trials, 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 CELEBREX 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 CELEBREX 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 CELEBREX 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 CELEBREX Patients from Pre-marketing Controlled Arthritis Trials

  CBX
N=414 6
Placebo
N=1864
NAP
N=1366
DCF
N=387
IBU
N=345
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
  Rhinitis 2.3% 1.1% 1.7% 1.6% 2.6%
  Sinusitis 2.0% 1.3% 2.4% 2.3% 0.6%
  Upper Respiratory 5.0% 4.3% 4.0% 5.4% 5.8%
  Infection 8.1% 6.7% 9.9% 9.8% 9.9%
Skin
  Rash 2.2% 2.1% 2.1% 1.3% 1.2%
CBX = CELEBREX 100 – 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.

In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving CELEBREX and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the CELEBREX treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of CELEBREX 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 - 1.9% of patients treated with CELEBREX (100 - 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 Leg cramps, hypertonia, hypoesthesia, nervous system: 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: BUN increased, 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: Intestinal 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]

Renal: Acute renal failure

The Celecoxib Long-Term Arthritis Safety Study

[see Special Studies]

Hematological Events: The incidence of clinically significant decreases in hemoglobin ( > 2 g/dL) was lower in patients on CELEBREX 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 CELEBREX was maintained with or without aspirin use [see CLINICAL PHARMACOLOGY].

Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for CELEBREX, 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).

Juvenile Rheumatoid Arthritis Study

In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg twice daily, 82 patients were treated with celecoxib 6 mg/kg twice daily, and 83 patients were treated with naproxen 7.5 mg/kg twice daily. The most commonly occurring ( ≥ 5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring ( ≥ 5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups.

In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg twice daily. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged.

Table 2: Adverse Events Occurring in ≥ 5% of JRA Patients in Any Treatment Group, by System Organ Class (% of patients with events)

System Organ Class Preferred Term Celecoxib 3 mg/kg
N=77
Celecoxib 6 mg/kg
N=82
Naproxen 7.5 mg/kg
N=83
Any Event 64 70 72
Eye Disorders 5 5 5
Gastrointestinal 26 24 36
  Abdominal pain NOS 4 7 7
  Abdominal pain upper 8 6 10
  Vomiting NOS 3 6 11
  Diarrhea NOS 5 4 8
  Nausea 7 4 11
General 13 11 18
  Pyrexia 8 9 11
Infections 25 20 27
  Nasopharyngitis 5 6 5
Injury and Poisoning 4 6 5
Investigations* 3 11 7
Musculoskeletal 8 10 17
  Arthralgia 3 7 4
Nervous System 17 11 21
  Headache NOS 13 10 16
  Dizziness (excl vertigo) 1 1 7
Respiratory 8 15 15
  Cough 7 7 8
Skin & Subcutaneous 10 7 18
* Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin time, Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis abnormal NOS

Other Pre-Approval Studies

Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with CELEBREX 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 CELEBREX 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 CELEBREX 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 CELEBREX in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [see Special Studies: Adenomatous Polyp Prevention Studies].

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 CELEBREX pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with CELEBREX were greater as compared to the arthritis pre-marketing trials were as follows:

  CELEBREX (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 CELEBREX, 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

Postmarketing Experience

The following adverse reactions have been identified during post approval use of CELEBREX. 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

Read the Celebrex (celecoxib) Side Effects Center for a complete guide to possible side effects

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 CELEBREX with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS].
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].
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention: Concomitant use of CELEBREX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS].
CELEBREX 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 angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (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 CELEBREX and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
  • During concomitant use of CELEBREX 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].
  • 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 CELEBREX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS].
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 CELEBREX 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 CELEBREX 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). Celebrex has no effect on methotrexate pharmacokinetics.
Intervention: During concomitant use of CELEBREX and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of CELEBREX and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention: During concomitant use of CELEBREX 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].
Intervention: The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of CELEBREX and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of CELEBREX 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].
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].
Corticosteroids
Clinical Impact: Concomitant use of corticosteroids with CELEBREX may increase the risk of GI ulceration or bleeding.
Intervention Monitor patients with concomitant use of CELEBREX with corticosteroids for signs of bleeding [see WARNINGS AND PRECAUTIONS].

Read the Celebrex Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/7/2016

Side Effects
Interactions

Celebrex - User Reviews

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