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CELEBREX (celecoxib) Adverse Reactions

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Adverse Reactions

Adverse Drug Reaction Overview

Of the CELEBREX (celecoxib) treated patients in controlled 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 have received a total daily dose of CELEBREX of 200 mg (100 mg BID or 200 mg QD) or more, including more than 400 treated at 800 mg (400 mg BID). Approximately 3,900 patients have 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.

CELEBREX has been studied in elderly patients. Of the total number of patients who received CELEBREX in clinical trials, more than 3,300 patients were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. While the incidence of adverse experiences tended to be higher in elderly patients, no substantial differences in safety and effectiveness were observed between these subjects and younger patients. In GI endoscopy studies involving over 800 elderly patients, the rate of gastroduodenal ulceration was not different in elderly patients compared to the young. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In clinical studies comparing renal function as measured by the GFR, urea and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers.

Clinical Trial Adverse Drug Reactions - New Drug Submission (NDS) Arthritis Trials

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1 lists all adverse events, regardless of causality, occurring in >2% of patients receiving CELEBREX from 12 controlled studies conducted in patients with osteoarthritis and rheumatoid arthritis that included a placebo and/or a positive control group.

Table 1 Events Occurring in ≥2% of CELEBREX Patients From Original NDS Arthritis Trials
 

CELEBREX

100-200mg BID

and 200mg QD

(n=4146)

Placebo

(n=1864)

Naproxen

500mg BID

(n=1366)

Ibuprofen

800mg TID

(n=387)

Diclofenac

75mg BID

(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 and 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 tract 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 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 adverse event profile from the long-term outcomes trial (at 4- and 2-fold the recommended doses for OA and RA, respectively) is similar to those reported in the arthritis-controlled trials. In the arthritis-controlled trials, the CELEBREX endoscopic gastroduodenal ulceration rate was consistently less than what was seen with the NSAID comparators. In the long-term outcome study however, there was no statistically significant difference for the incidence of complicated ulcers (perforation, obstruction, or bleeding) among the CELEBREX 400 mg BID and NSAID comparators (see CLINICAL TRIALS - Special Studies). The major differences in study design and patient populations preclude direct comparison between the GI endpoint results in the arthritis controlled and the long-term outcome trials.

The incidences of withdrawals due to adverse events and the incidences of selected serious adverse events (i.e., those causing hospitalization or felt to be life-threatening or otherwise medically significant) observed in this trial are shown in Table 2. No significant differences were seen across treatment groups in the incidences of serious adverse events (see Table 2).

Table 2 Summary of Withdrawal and Serious Cardiovascular Adverse Event Data From the CLASS Trial
Incidence Rates (%) in all OA and RA Patients and in Patients Without ASA

All Patients

Celecoxib

400 mg BID

(n=3987)

Diclofenac

75 mg BID

(n=1996)

Ibuprofen
800 mg TID

(n=1985)

All withdrawals

22.4

26.5*

23.0

Withdrawals for GI

Symptoms

12.2

16.6*

13.4

Serious adverse events

6.8

5.6

6.0

Myocardial infarction (fatal and non-fatal)

Deep vein thrombosis

Cardiac failure

Unstable angina

Cerebrovascular disorder

0.5

0.2

0.2

0.2

0.1

0.2

0.3

0.1

0.2

0.3

0.5

0.0

0.5

0.0

0.3

    

Patients Without ASA

(n=3105)

(n=1551)

(n=1573)

All withdrawals

21.2

25.4*

22.5

Withdrawals for GI

Symptoms

11.5

15.4*

13.2

Serious adverse events

5.0

4.2

4.3

Myocardial infarction (fatal and non-fatal)

0.2

0.1

0.1

Deep vein thrombosis

0.2

0.2

0.0

Cardiac failure

0.1

<0.1

0.3

Unstable angina

<0.1

0.0

0.0

Cerebrovascular disorder

<0.1

0.3

0.1

*p<0.05 vs. celecoxib

The following adverse events occurred in 0.1 - 1.9% of patients regardless of causality:

CELEBREX

(100 – 200 mg BID or 200 mg QD)

Gastrointestinal:

Constipation, diverticulitis, dry mouth, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, stomatitis, tenesmus, tooth disorder, vomiting

Cardiovascular:

Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction

General:

Allergy aggravated, allergic reaction, asthenia, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain

Resistance Mechanism

Disorders:

Herpes simplex, herpes zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media

Central, Peripheral Nervous System:

Leg cramps, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, vertigo

Female Reproductive:

Breast fibroadenosis, breast neoplasm, breast pain, dysmenorrhea, menstrual disorder, vaginal hemorrhage, vaginitis

Male Reproductive:

Prostatic disorder

Hearing and Vestibular:

Deafness, ear abnormality, earache, tinnitus

Heart Rate and Rhythm:

Palpitation, tachycardia

Liver and Biliary System:

ALT increased, AST increased, hepatic function abnormal

Metabolic and Nutritional:

Urea increased, CPK increased, diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increase, creatinine increased, alkaline phosphatase increased, weight increase

Musculoskeletal:

Arthralgia, arthrosis, bone disorder, fracture accidental, myalgia, neck stiffness, synovitis, tendinitis

Platelets

(bleeding or clotting):

Ecchymosis, epistaxis, thrombocythemia

Psychiatric:

Anorexia, anxiety, appetite increased, depression, nervousness, somnolence

Hemic:

Anemia

Respiratory:

Bronchitis, bronchospasm, bronchospasm aggravated, coughing, dyspnea, laryngitis, pneumonia

Skin and Appendages:

Alopecia, dermatitis, nail disorder, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria

Application Site Disorders:

Cellulitis, dermatitis contact, injection site reaction, skin nodule

Special Senses:

Taste perversion

Urinary System:

Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus, urinary incontinence, urinary tract infection

Vision:

Blurred vision, cataract, conjunctivitis, eye pain, glaucoma

Adverse Events From Ankylosing Spondylitis Studies

A total of 896 patients were treated with CELEBREX in placebo- and active-controlled ankylosing spondylitis studies for a maximum duration of 12 weeks. CELEBREX was also studied in one long-term open label extension study up to 2 years in 215 patients with ankylosing spondylitis. The average daily dose was 200 mg. The types of adverse events reported in the ankylosing spondylitis studies were generally similar to those reported in the arthritis studies. The percentage of patients with hypertension (6.1%) and serious GI adverse events (3.7%) in the 2­year, open­label extension study, were greater than those reported in the 12­week studies, respectively of 0.7% and 0.0%. The most common GI disorders reported in the 2-year extension study compared to those reported in the 12­week studies include Diarrhea (15.0% vs. 4.5%), Abdominal Pain upper (13.6 % vs. 3.8%), Dyspepsia (9.8% vs. 3.7%), Nausea (5.6% vs. 2.8%) and Abdominal Pain (5.6% vs. 1.5%). The percentage of patients with cardio-vascular events (1.4%) in the 2-year, open-label extension study was similar to that observed in the CLASS trials.

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 (up to 400 mg) of study medication. Doses up to 600 mg/day of CELEBREX were studied in primary dysmenorrhea and post-orthopaedic surgery pain studies. The types of adverse experiences in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only new adverse event reported was alveolar osteitis (dry socket) in the post-oral surgery pain studies.

In approximately 700 patients treated with CELEBREX in the post-general and orthopaedic surgery pain studies, the most commonly reported adverse experiences were nausea, vomiting, headache, dizziness and fever.

Other serious adverse reactions which occur rarely (estimated <0.1%) regardless of causality: the following adverse events have occurred rarely in patients taking CELEBREX.

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, cholelithiasis, ileus

Hemic and

Lymphatic:

Thrombocytopenia

Liver and Biliary System:

Cholelithiasis, hepatitis, jaundice, liver failure

Metabolic:

Hypoglycemia

Nervous System:

Ataxia

Renal:

Acute renal failure

General:

Sepsis, sudden death

Serious Cardiovascular Adverse Events: Long-term Studies Involving Patients with Sporadic Adenomatous Polyps

Two studies involving patients with sporadic adenomatous polyps were conducted with celecoxib: the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Colorectal Sporadic Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint, as shown below:

Serious Cardiovascular Adverse Events in the APC and PreSAP Trials

Number (%) of Subjects [Hazards Ratioa (95% Confidence Interval) Compared to Placebo]

 

APC Trial

PreSAP Trial

 

Placebo

N = 679

Celecoxib 200 mg BID

N = 685

Celecoxib 400 mg BID

N = 671

Placebo

N = 628

Celecoxib 400 mg QD

N = 933

Adjudicated Endpointb

      

CV death              

1 (0.1)

5 (0.7)

[4.9 (0.6, 42.2)]

6 (0.9)

[6.2 (0.7, 51.4)]

4 (0.6)

4 (0.4)

[0.7 (0.2, 2.7)]

 

 

  

 

 

CV death or MI  

4 (0.6)

14 (2.0)

[3.5 (1.1, 10.6)]

15 (2.2)

[3.9 (1.3, 11.7)]

7 (1.1)

13 (1.4)

[1.3 (0.5, 3.2)]

 

 

  

 

 

CV death, MI, or stroke (APTC endpoint)

6 (0.9)

17 (2.5)

[2.8 (1.1, 7.2)]

20 (3.0)

[3.4 (1.4, 8.5)]

12 (1.9)

21 (2.3)

[1.2 (0.6, 2.4)]

 

 

  

 

 

BID = Twice daily; QD = Once daily; N = Number of subjects treated; CV = Cardiovascular; MI = Myocardial infarction; APTC = Antiplatelet Trialists’ Collaboration; HF = Heart failure.

a     Hazards ratios are based on event rates per subject-year of exposure to study medication.

b    Includes only serious adverse events, for all randomized subjects, adjudicated and categorized according to a pre‑specified scheme by an independent Cardiovascular Safety Committee blinded to randomized treatment assignments.

Investigator Reports of Adverse Reaction from Long-term, Placebo-controlled Polyp Prevention Studies

Indications and dosages of the PreSAP and APC trials are not approved in Canada. Exposure to CELEBREX in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years. Among adverse reactions that occurred in higher percentages of patients than in the arthritis pre- marketing trials (treatment durations up to 12 weeks (see ADVERSE REACTIONS – Clinical Trial Adverse Drug Reactions), hypertension was reported at an incidence of 12.5% in the celecoxib group (400-800 mg daily dose) compared to 9.8% in the placebo group.

Abnormal Hematologic and Clinical Chemistry Findings

During the controlled clinical trials, there was an increased incidence of hyperchloremia in patients receiving celecoxib compared with patients on placebo. Other laboratory abnormalities that occurred more frequently in the patients receiving celecoxib included hypophosphatemia, and elevated urea. These laboratory abnormalities were also seen in patients who received comparator NSAIDs in these studies. The clinical significance of these abnormalities has not been established.

Post-Market Adverse Drug Reactions

Additional reports of serious adverse events temporally associated with CELEBREX during worldwide post-marketing experience are included below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to CELEBREX exposure.

Blood and Lymphatic System Disorders:

Pancytopenia, agranulocytosis, aplastic anemia, leukopenia*

Serious bleeding events (some of them fatal) have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin or similar agents (see DRUG INTERACTIONS)

Immune System Disorders:

Serious allergic reactions, anaphylactic shock

Psychiatric Disorders:

Confusion*, hallucination

Nervous System Disorders:

Aggravated epilepsy, aseptic meningitis, ageusia, anosmia

Ear and Labyrinth Disorders:

Decreased hearing

Eye Disorders:

Conjunctivitis

Cardiac Disorders:

Congestive heart failure, heart failure, myocardial infarction, arrhythmia**, syncope**, arterial thrombotic events

Vascular Disorders:

Vasculitis, cerebral hemorrhage, pulmonary embolism (some with fatal outcome), flushing**

Respiratory, Thoracic and Mediastinal Disorders:

Bronchospasm, pneumonitis

Gastrointestinal Disorders:

Gastrointestinal hemorrhage, acute pancreatitis, gastric ulcer**, duodenal ulcer**, esophageal ulcer**

Hepatobiliary Disorders:

Liver failure (with fatal outcome), fulminant hepatitis (with fatal outcome), liver necrosis, cholestasis, cholestatic hepatitis (with fatal outcome), hepatitis, jaundice

Skin and Subcutaneous Tissue Disorders:

Angioedema, isolated reports of skin exfoliation including: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS, or hypersensitivity syndrome), acute generalized exanthematous pustulosis (AGEP), bullous eruption, dermatitis bullous**

Reproductive System and Breast Disorders:

Menstrual disorder, female fertility decreased (see WARNINGS AND PRECAUTIONS Sexual Function/Reproduction), reduction of amniotic fluid volume, reduction of fetal urine production

Musculoskeletal and Connective Tissue Disorders:

Myositis

Renal and Urinary Disorders:

Acute renal failure, interstitial nephritis, nephrotic syndrome, acute glomerulonephritis, minimal change disease, hyponatremia

General Disorders and Administration Site Conditions:Chest pain

Serious Cardiovascular Adverse Events:

Meta-analyses and pharmacoepidemiological data point towards an increased risk of arteriothrombotic events associated with the use of CELEBREX, particularly at doses of >200 mg/day (see WARNINGS AND PRECAUTIONS – Serious Warnings and Precautions)

* Noted in both cumulative review of clinical trial data set and post-market adverse drug reactions
** Identified in cumulative review of clinical trial data set

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