Celebrex (Celecoxib) Adverse Reactions
- abdominal pain
- agranulocytosis
- anaphylactoid reactions
- anemia
- angina
- angioedema
- anorexia
- aplastic anemia
- aseptic meningitis
- ataxia
- azotemia
- back pain
- bleeding
- blurred vision
- bronchospasm
- chest pain (unspecified)
- cholelithiasis
- cholestasis
- confusion
- constipation
- cyanosis
- diarrhea
- dyspepsia
- dysphagia
- dysuria
- edema
- elevated hepatic enzymes
- erythema
- erythema multiforme
- esophageal stricture
- esophageal ulceration
- esophagitis
- exfoliative dermatitis
- flatulence
- gastritis
- gastroesophageal reflux
- GI bleeding
- GI obstruction
- GI perforation
- headache
- hearing loss
- heart failure
- hematuria
- hemorrhoids
- hepatic failure
- hepatitis
- hypertension
- ileus
- interstitial nephritis
- intracranial bleeding
- jaundice
- leukopenia
- maculopapular rash
- melena
- methemoglobinemia
- myocardial infarction
- nausea/vomiting
- odynophagia
- pancreatitis
- pancytopenia
- peptic ulcer
- peripheral edema
- phlebitis
- proteinuria
- pruritus
- pulmonary embolism
- pyrosis (heartburn)
- rash (unspecified)
- renal failure (unspecified)
- renal papillary necrosis
- Stevens-Johnson syndrome
- stomatitis
- stroke
- syncope
- thrombocytopenia
- tinnitus
- toxic epidermal necrolysis
- urticaria
- vasculitis
- ventricular fibrillation
- visual impairment
- xerostomia
Celebrex Adverse Reactions
Nonsteroidal anti-inflammatory drugs, including celecoxib, cause an increased risk of serious gastrointestinal (GI) adverse effects 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. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. A trend exists for an increased likelihood of serious GI event development at some point during therapy with longer NSAID duration of use. Celecoxib premarketing clinical trials demonstrate that the incidence of endoscopically observed GI ulceration is lower than that observed for nonselective NSAIDs. Five endoscopic trials, two of which were placebo-controlled, compared celecoxib (50 to 400 mg twice daily) and a comparator NSAIDs (naproxen 500 mg twice daily; ibuprofen 800 mg three times daily; and diclofenac 75 mg twice daily) over 3—6 months in over 4500 rheumatoid arthritis and osteoarthritis patients. Four of these trials reported a statistically lower incidence of endoscopically observed peptic ulcer ranging from 1.5—5.9% for celecoxib relative to the 9.6—17.6% reported for the comparator NSAIDs. There was no statistical difference between diclofenac (2.9%) and celecoxib (1.8%) in one study. In contrast to the comparator NSAIDs, celecoxib did not alter platelet aggregation or bleeding time. Prospective, long-term outcome trials will be required to determine the actual incidence of serious, clinically significant upper GI events with celecoxib therapy. Fatal intracranial bleeding has been reported rarely (< 0.1%), but the causality to celecoxib has not been established. Among 4146 patients who took celecoxib 100—200 mg twice daily or 200 mg daily in clinical trials, the most common GI-related adverse reactions to celecoxib were mild to moderate gastrointestinal complaints: dyspepsia (8.8%), diarrhea (5.6%), abdominal pain (4.1%), nausea/vomiting (3.5%), and flatulence (2.2%). Less common GI effects (0.1—1.9% incidence) that occurred with celecoxib regardless of causality included: anorexia, constipation, diverticulitis, gastritis, gastroenteritis, gastroesophageal reflux disease (GERD), hemorrhoids, hiatal hernia, melena, stomatitis and xerostomia. Rare (< 0.1%) GI adverse effects occurring with celecoxib therapy (regardless of causality) in pre-marketing trials included GI obstruction, GI perforation, GI bleeding, colitis with bleeding, and ileus. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3—6 months, and in about 2—4% of patients treated for one year. It is unclear, how the these rates apply to celecoxib. Among 5285 patients who received celecoxib (>= 200 mg/day) in controlled, pre-marketing clinical trials of 1 to 6 months duration, two patients (0.04%) experienced significant upper GI bleeding, at 14 and 22 days after initiation of dosing. Approximately 40% of patients were in studies that required them to be free of ulcers by endoscopy at study entry. Thus, it is unclear if this study population is representative of the general population. Patients receiving celecoxib and their health care providers should monitor for the signs and symptoms of ulceration and bleeding, even in the absence of previous GI tract symptoms. Experience with chronic NSAID therapy in debilitated patients suggest greater potential for serious GI adverse events. Elderly patients are at a greater risk for serious gastrointestinal events. In patients with familial adenomatous polyposis (FAP), the adverse reactions reported during clinical trials were similar to those seen in the arthritis trials. Intestinal anastomotic ulceration was the only new adverse event reported in the FAP trial, regardless of causality. It was observed in 3 of 58 patients (one at 100 mg PO twice daily and two at 400 mg PO twice daily) who had prior intestinal surgery.
Rare cases of esophagitis have been reported in patients receiving NSAIDs, including celecoxib. NSAID-induced esophagitis is characterized by sudden onset odynophagia, pyrosis (heartburn), retrosternal pain, and dysphagia. Severe complications such as esophageal ulceration, esophageal stricture, bleeding, and perforation have been reported rarely. Risk factors for NSAID-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication.
In controlled clinical trials of celecoxib, the incidence of borderline elevated hepatic enzymes (1.2—3 times the upper limit of normal) was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST (approximately three or more times the upper limit of normal). Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST have been reported in approximately 1% of patients in clinical trials with NSAIDs. Elevated hepatic enzymes may progress, may remain unchanged, or may be transient with continuing therapy. Pancreatitis and cholelithiasis occurred in < 0.1% of patients during clinical trials. Additionally, hepatitis, jaundice and hepatic failure thought to be due to celecoxib have been reported to the manufacturer through their postmarketing surveillance program. Rare cases of severe hepatic reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (some with fatal outcome) have been reported with other NSAIDs. Patients with signs or symptoms of liver dysfunction or increases in liver function tests need to be carefully monitored for the development of a severe hepatic reaction. If signs or symptoms of liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur, celecoxib should be discontinued.
Anemia is sometimes seen in patients receiving celecoxib. In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Celecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not appear to inhibit platelet aggregation at indicated dosages. In pre-marketing studies of platelet dysfunction, celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration had no effect on platelet aggregation and bleeding time. Comparator NSAIDs (naproxen 500 mg twice daily, ibuprofen 800 mg three times daily, diclofenac 75 mg twice daily) significantly reduced platelet aggregation and prolonged bleeding time.
Anaphylactoid reactions and angioedema have been observed in association with celecoxib through the manufacturer’s postmarketing surveillance program. Anaphylactoid reactions have occurred in patients without known prior exposure to celecoxib. In clinical trials, 0.1—1.9% of patients developed urticaria and/or bronchospasm. Patients with hypersensitivity to salicylates (aspirin triad), other NSAIDs, or sulfonamides are at higher risk for allergic reactions to celecoxib. Celecoxib is not recommended for patients with the aspirin triad . Allergic reactions to celecoxib were reported in 33% of patients tested who had previous cutaneous reactions to other NSAIDs. There has been one case of Sweet’s syndrome described in association with celecoxib.
The most common dermatological adverse effect of celecoxib is a rash (unspecified), which occurred in 2.2% of 4146 patients in clinical trials. Erythema and/or pruritus may be present and a maculopapular rash has been described. Stevens-Johnson syndrome (SJS), erythema multiforme, exfoliative dermatitis, and toxic epidermal necrolysis (TEN) have been reported to the manufacturer through their postmarketing surveillance program and in the literature and may occur in patients without prior known sulfa allergy. A 57 year-old man without a documented sulfonamide allergy experienced possible erythema multiforme, an acute inflammatory skin reaction, and throat swelling thought to be due to celecoxib. Although the skin reaction resolved with celecoxib discontinuation, a similar reaction occurred with the introduction of glyburide. Toxic epidermal necrolysis from celecoxib was diagnosed in a 41 year-old woman that developed an erythematous rash that progressed to exfoliative dermatitis. An apparent case of fatal TEN from an idiosyncratic reaction to celecoxib occurred in a 85 year-old woman that presented with nausea, vomiting, and blanching erythematous macules on her back. The erythematous macules developed dusky centers and evolved into flaccid vesicles and bullae involving approximately 40% of her body surface. She had extensive mucosal erosions throughout her gastrointestinal tract, cholestasis, elevated liver enzymes, and hyperbilirubinemia. She began taking celecoxib 100 mg daily 18 days before rash development. All of her other medications (labetalol, atorvastatin, isosorbide mononitrate, amiodarone, warfarin, ranitidine, furosemide, phenytoin, thyroxine and occasional acetaminophen, propoxyphene, and hydrocodone) were taken for at least 1 year at stable dosages. In addition to an idiosyncratic reaction as an etiology for either SJS or TEN, a hypersensitivity syndrome that consists of fever, rash, and internal organ involvement may occur. The exact mechanism of severe skin reactions to celecoxib, which does not contain an aromatic amine, is unknown but is likely different than the mechanism associated with sulfonamide antibiotics, as these drugs are much more commonly associated with SJS and TEN. Sulfonamide antibiotics have an aromatic amine moiety whereas celecoxib, furosemide, and thiazide diuretics have a sulfonamide component but not an aromatic amine. Further support for a different mechanism of action is obtained from the observation of a lack of cross-sensitivity between sulfamethoxazole and celecoxib in 6 adults. Discontinue celecoxib at the first appearance of a skin rash or any other sign of hypersensitivity.
Renal effects of celecoxib appear to be similar to the effects observed with other NSAIDs. Serious or life-threatening renal failure (unspecified) has been reported in patients with normal or impaired renal function after short-term therapy with celecoxib. Additionally, interstitial nephritis has been associated with celecoxib. With some NSAIDS, renal papillary necrosis has been reported. Vasodilatory renal prostaglandins and the potent vasoconstrictor angiotensin II work in concert to maintain renal blood flow. Inhibition of renal prostaglandins by NSAIDs can cause renal insufficiency and thus, fluid retention. Overt renal decompensation due to a dose-dependent reduction in prostaglandin formation and thus, renal blood flow is usually reversed with NSAID discontinuation. Edema (peripheral edema) was observed in 2.1% of 4146 patients who took 100—200 mg twice daily or 200 mg daily of celecoxib. Aggravated hypertension occurred in 0.1—1.9% of patients whereas congestive heart failure occurred in < 0.1% of patients. As with all NSAIDs, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension. Both diclofenac 75 mg twice daily and celecoxib 200 mg once daily raised the systolic and diastolic blood pressure of Hispanic or African American patients with normal renal function who received each drug in a randomized, crossover fashion after stabilization of their blood pressure with trandolapril and hydrochlorothiazide and clonidine, if necessary. During the study, no antihypertensive drug dosage changes or additions were allowed. Although not a prespecified outcome measure, the mean increase in systolic pressure between the hours of 11 A.M. and 4 P.M was 4.16 ± 1.84 and 3.6 ± 0.04 with celecoxib and diclofenac, respectively. The respective mean increases in diastolic pressure were 4.32 ± 0.89 and 2 ± 0.89. The morning dose of each drug was given between the hours of 7 and 9. Receipt of celecoxib did not affect the mean systolic blood pressure over 24 hours (128 ± 11 at baseline to 129 ± 9 after 4 weeks of celecoxib). Conversely, the mean systolic blood pressure over 24 hours went from 130 ± 14 mm Hg at baseline to 134 ± 15 mm Hg after 4 weeks of diclofenac 75 mg twice daily. Similar results of each treatment on diastolic blood pressure were found. Thus, NSAID drug administration frequency and timing of blood pressure measurement are important considerations. In another study, the mean change from baseline in average 24-hour systolic and diastolic blood pressure was -0.1 ± 0.6—1 mmHg after 6 weeks of celecoxib 200 mg daily in adults (76% White, 14% Black) with stable hypertension (systolic <150 mmHg) and normal renal function. Blood pressure was measured every 20 minutes during 24-hour ambulatory monitoring, and no antihypertensive drug changes were allowed (all patients took at least an angiotensin converting enzyme inhibitor or an angiotensin-2 receptor blocker). Similar findings were obtained when blood pressure was measured in a clinic between 7 and 11 in the morning. Of the 114 patients, an increase in the systolic blood pressure of 0—10 mmHg occurred in 32%, an increase in 10—20 mmHg occurred in 14%, and a greater than 20 mmHg increase occurred in 3%. Furthermore, of 68 patients who had a baseline ambulatory systolic blood pressure less than 135 mmHg, 11 had a reading of 135 mmHg or higher at week 6. Renal function should be closely monitored for any signs of potential nephrotoxicity after initiating therapy with celecoxib, especially in high-risk patients. Signs such as hematuria, proteinuria, dysuria, and azotemia may be present. Monitoring of the patient’s fluid status, and serum creatinine and blood urea nitrogen concentrations is recommended.
Celecoxib may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. The risk may increase with duration of use, and patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Of 4146 patients who took 100—200 mg twice daily or 200 mg daily of celecoxib for arthritis, 0.1—1.9% had angina pectoris, chest pain (unspecified), or myocardial infarction. Less than 0.1% had syncope, ventricular fibrillation, pulmonary embolism, stroke, vasculitis, peripheral gangrene, or thrombophlebitis. Due to data from an interim analysis, celecoxib administration was halted 33 months into a 3-year, randomized, double-blind, placebo-controlled, multicenter study designed to investigate whether celecoxib could prevent colon cancer in people with a history of colon polyps. Of 679 patients who received placebo, 7 had myocardial infarction, stroke, heart failure, or death from cardiovascular causes. In contrast, 16 of 685 patients who received celecoxib 200 mg twice daily and 23 of 671 patients who received celecoxib 400 mg twice daily met the composite cardiovascular end point. Interestingly, the estimated probability of the composite endpoint began to diverge among the placebo and celecoxib groups around 12 months after the first dose. The potential confounding factors of aspirin usage, gender, age, lipid-lowering drug usage, or baseline cardiovascular risk factors were not found to be significantly associated with the composite end point. Cardiovascular safety data were assessed retrospectively by an independent committee. About half of patients in each group had a history of myocardial infarction, cerebrovascular disease, congestive heart failure, angina, or hypertension and about a third of patients used aspirin. There is no consistent evidence that concurrent aspirin use mitigates the increased risk of serious cardiovascular thrombotic events associated with NSAID use. Interim analyses of data from 2 other ongoing celecoxib prevention trials have not yielded an increased rate of adverse cardiovascular events. Rofecoxib, another COX-2 inhibitor, has been pulled from the U.S. market due to an observed increased risk for serious cardiovascular events, such as myocardial infarction and strokes. Although not designed to determine cardiovascular risk, data on certain events that occurred in patients taking celecoxib 400 mg twice daily over a 6-month period is available. Of 833 patients who took aspirin up to 325 mg daily and celecoxib, 23 events of a cerebrovascular accident, of a myocardial infarction, or of angina occurred. A similar number of events (n=27) occurred in 812 patients that took aspirin up to 325 mg daily and either ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily. In contrast, of patients not taking aspirin, 16 events occurred in patients taking celecoxib as compared with 14 events in patients taking ibuprofen or diclofenac. Patients with cardiac or cerebrovascular disease were not excluded. Despite numerous re-analyses and meta-analyses of available data, a properly designed randomized controlled study is needed to determine what risk, if any, celecoxib presents to patients with and without cardiovascular disease in the presence and absence of aspirin for cardiovascular prophylaxis. Use of the lowest celecoxib effective dose for the shortest duration possible is recommended to minimize the potential for an adverse cardiovascular event.
Although both headache and back pain were reported in clinical trials, the incidence of these adverse reactions did not exceed that seen in patients treated with placebo. Overuse of celecoxib by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. In this case, overuse of celecoxib (i.e., simple analgesic) has been defined as taking 3 or more doses per day more often than 5 days per week. The frequency of use may be more important than the dose. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement. Analgesic overuse may be responsible for the transformation of episodic migraine or episodic tension headache into daily headache and may perpetuate the syndrome.
Serious adverse reactions which occurred rarely (< 0.1%) during celecoxib clinical trials, without establishment of a causal relationship and not related to the known pharmacology of celecoxib included: syncope, ventricular fibrillation, pulmonary embolism, thrombophlebitis, stroke, peripheral gangrene, ataxia, sepsis, thrombocytopenia, and sudden death. Agranulocytosis, aplastic anemia, pancytopenia, and leukopenia have been reported through the manufacturer’s postmarketing surveillance program.
Aseptic meningitis has been reported rarely with NSAID therapy. Ibuprofen has been the most common NSAID implicated in this adverse reaction; however, cases have been reported with sulindac, naproxen, tolmetin, diclofenac, ketoprofen, rofecoxib, and piroxicam. Aseptic meningitis has been reported through postmarketing surveillance (< 0.1%) but the causality to celecoxib has not been established. Aseptic meningitis from one NSAID does not preclude use of another NSAID; most patients can be treated with another drug without incident. However, one patient with Sjogren’s syndrome experienced aseptic meningitis after receipt of naproxen, ibuprofen, and rofecoxib at different times; aseptic meningitis developed about a week after each drug exposure, and the symptoms abated roughly 2 days following each drug cessation. The occurrence of aseptic meningitis is not related to NSAID chemical class or prostaglandin inhibition. A Type III or IV immunological hypersensitivity reaction is the proposed mechanism of action. Drug-induced aseptic meningitis usually occurs shortly after drug initiation but can occur after years of drug usage. Although NSAID-induced aseptic meningitis is primarily reported in patients with systemic lupus erythematosus (SLE), healthy patients and patients with other disease states such as ankylosing spondylitis, connective tissue disease, osteoarthritis, and rheumatoid arthritis have developed NSAID-induced aseptic meningitis. Symptoms of aseptic meningitis include confusion, drowsiness, general feeling of illness, severe headache, nausea, nuchal rigidity, and photophobia. As aseptic meningitis is a diagnosis of exclusion, the suspected drug should be discontinued and not restarted unless a rechallenge is desired.
Otic effects, such as tinnitus and hearing loss have occurred with celecoxib (0.1—1.9%). Visual impairment, such as blurred vision and glaucoma also occurred in the same percentage of patients in clinical trials.
Celecoxib is chemically designated as a benzene sulfonamide. Methemoglobinemia is known to be associated with sulfonamides and with benzene derivatives. A case report of methemoglobinemia due to celecoxib has been reported. A healthy man developed a severe headache and progressive confusion and agitation while taking celecoxib 100 mg twice daily for osteoarthritis; celecoxib had been started 1 month prior to the development of symptoms. Due to a serum methemoglobin fraction of 9% (reference range 0—0.2) on admission, the patient received methylene blue treatment. Within 5 minutes, his cyanosis significantly improved. Repeat administration of methylene blue was needed 4 hours later. The serum methemoglobin concentrations decreased to 0.7% and 0.4% after the first and second methylene blue treatments, respectively. Celecoxib was discontinued and the patient received methylene blue (100 mg PO tid), ascorbic acid (300 mg PO tid), and riboflavin (20 mg PO qd) for 3 days. He was discharged and remained symptom-free. Although a rechallenge was not feasible, celecoxib as the cause of the event was thought probable via use of the Naranjo probability scale.
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