Side Effects of Celebrex (celecoxib)

Celebrex (celecoxib) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat arthritis, pain, menstrual cramps, and colonic polyps.

Prostaglandins are chemicals that are important contributors to the inflammation of arthritis that causes pain, fever, swelling and tenderness. 

Celebrex blocks the enzyme that makes prostaglandins (cyclooxygenase 2), resulting in lower concentrations of prostaglandins. As a consequence, inflammation and its accompanying pain, fever, swelling and tenderness are reduced. 

Celebrex differs from other NSAIDs in that it causes less inflammation and ulceration of the stomach and intestine (at least with short-term use) and does not interfere with the clotting of blood. NSAIDs have been found to prevent the formation and reduce the size of polyps in patients with the genetic disease, familial adenomatous polyposis (FAP). 

In FAP, patients develop large numbers of polyps in their colons, and the polyps invariably become malignant. The only cure of FAP is removal of the entire colon. Celebrex is approved as an adjunctive (secondary) treatment among patients with FAP. 

Common side effects of Celebrex include headache, abdominal pain, indigestion, diarrhea, nausea, gas (flatulence), and insomnia.

Serious side effects of Celebrex include fainting, vomiting, kidney failure, heart failure, worsening high blood pressure (hypertension), chest pain, ringing in the ears, deafness, stomach and intestinal ulcers, bleeding, blurred vision, anxiety, photosensitivity, weight gain, water retention, flu-like symptoms, fever, cough, gastrointestinal reflux disease (GERD), rash, drowsiness, weakness, allergic reactions; and increased risk of heart attacks, stroke, and related conditions (which can be fatal). 

Drug interactions of Celebrex include aspirin or other NSAIDs (for example, ibuprofen, naproxen, etc.), which may increase the occurrence of stomach and intestinal ulcers. It may be used with low-dose aspirin.

• Fluconazole increases the concentration of Celebrex in the body by preventing the elimination of Celebrex in the liver. 
• Celebrex increases the concentration of lithium in the blood by 17% and may promote lithium toxicity.
• Persons taking the anticoagulant (blood thinner) warfarin should have their blood tested when initiating or changing Celebrex treatment, particularly in the first few days, for any changes in the effects of the anticoagulant.
• NSAIDs may reduce the blood-pressure-lowering effects of drugs that are given to reduce blood pressure. This may occur because prostaglandins play a role in the regulation of blood pressure.
• Persons who drink more than three alcoholic beverages per day may be at increased risk of developing stomach ulcers when taking NSAIDs, and this also may be true with Celebrex.

Celebrex has not been studied in pregnant women. It should not be used in late pregnancy because there is a risk of heart defects in the newborn. Celebrex should only be used in pregnant women when the benefits outweigh the potential risk to the fetus. 

Available evidence suggests Celebrex is secreted in breast milk. Nursing mothers should avoid Celebrex or discontinue breastfeeding.

WARNING

RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

Cardiovascular Thrombotic Events

• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use.
• Celebrex is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Bleeding, Ulceration, and Perforation

• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious (GI) events.

What are the common side effects of Celebrex?

The most common side effects of celecoxib include:

• Headache
• Abdominal pain
• Indigestion (dyspepsia)
• Diarrhea
• Nausea
• Flatulence (gas)
• Insomnia

What are the serious side effects of Celebrex?

Other and more serious side effects of celecoxib include:

• Fainting
• Vomiting
• Kidney failure
• Heart failure
• Aggravation of hypertension
• Chest pain
• Ringing in the ears
• Deafness
• Stomach and intestinal ulcers
• Bleeding
• Blurred vision
• Anxiety
• Photosensitivity
• Weight gain
• Water retention
• Flu-like symptoms
• Fever
• Cough
• GERD (gastrointestinal reflux disease)
• Rash
• Drowsiness
• Weakness

Celecoxib, like other NSAIDs may cause serious stomach and intestinal ulcers that may occur at any time during treatment. Celecoxib does not interfere with the function of the blood platelets and, as a result, does not reduce clotting and lead to increased bleeding time like other NSAIDs.

Allergic reactions can occur with celecoxib. Individuals who have developed allergic reactions (rash, itching, difficulty breathing) from sulfonamides (for example, sulfamethoxazole and trimethoprim [Bactrim]), aspirin or other NSAIDs may experience an allergic reaction to celecoxib and should not take celecoxib.

NSAIDs (except for low-dose aspirin) may increase the risk of heart attacks, stroke, and related conditions, which can be fatal. This risk may increase with duration of use and in patients who have underlying risk factors for heart and blood vessel conditions. NSAIDs should not be used for the treatment of pain resulting from coronary artery bypass graft (CABG) surgery.

NSAIDs cause an increased risk of serious, even fatal, stomach and intestinal adverse reactions such as bleeding, ulcers, and perforation of the stomach or intestines. These events can occur at any time during treatment and without warning symptoms. Elderly patients are at greater risk for these types of reactions.

See Table 3 for clinically significant drug interactions with celecoxib.

Table 3: Clinically Significant Drug Interactions with Celecoxib

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

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

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

• 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% To 1.9% Of Patients Treated With Celebrex (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: 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
• Renal: Acute renal failure

The Celecoxib Long-Term Arthritis Safety Study

See prescribing information.

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.

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)

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 mg to 800 mg daily for up to 3 years.
• 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:

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