Summary Of Exposure |
A) USES: Cyclooxygenase-2 (COX-2) inhibitors are nonsteroidal anti-inflammatory drugs (NSAIDs), antipyretics, analgesics, and inhibitors of thrombocyte aggregation. Celecoxib (Celebrex) is used to treat rheumatoid arthritis and osteoarthritis and is the only remaining COX-2 inhibitor on the market in the US. Rofecoxib (Vioxx) was removed from the market in 2004 due to concerns for increased risk of myocardial infarction and stroke, and valdecoxib (Bextra) was removed in 2005 for similar reasons. Etoricoxib (Arcoxia), lumiracoxib (Prexige), and parecoxib (Dynastat) [a prodrug of valdecoxib] are not approved for use in the US, but are available in other countries.
B) PHARMACOLOGY: The cyclooxygenase (COX) enzyme (prostaglandin synthase H) consists of 2 isoforms, COX-1 and COX-2. COX-2 inhibitors decrease the synthesis of prostaglandin H2 by selectively inhibiting COX-2 (from 30- to 433-fold more potent towards COX-2 in vitro) with little or no inhibition of COX-1 at therapeutic doses. Although similar to traditional NSAIDs, selective inhibition of COX-2 may result in fewer gastrointestinal adverse effects usually associated with NSAIDs.
C) TOXICOLOGY: At supratherapeutic doses, selective inhibition of COX-2 is lost, and the usual COX-1 effects may manifest in the GI tract as gastritis, and in the renal system as hypertension, decreased renal perfusion, decreased glomerular filtration rate, edema, and interstitial nephritis.
D) EPIDEMIOLOGY: COX-2 inhibitors are an uncommon cause of poisoning, are usually unintentional, and rarely result in severe manifestations.
E) WITH THERAPEUTIC USE
1) ADVERSE EFFECTS: COMMON: GI effects occur most commonly and include dyspepsia, nausea, diarrhea, abdominal pain, pancreatitis, and flatulence. Other fairly common findings include headache and fever.
2) SEVERE: Celecoxib is rarely associated with cardiac or renal events. GI bleeding may occur with chronic use. Methemoglobinemia is a rare event. Rofecoxib was voluntarily withdrawn from the market in 2004, due to an increased risk of severe dysrhythmias (ventricular fibrillation, cardiac arrest and sudden death), renal events, and associated with aseptic meningitis.
F) WITH POISONING/EXPOSURE
1) OVERDOSE: Little data are available. Significant poisonings result in symptoms similar to those observed with typical NSAIDs, such as GI upset, vomiting, abdominal pain. Rarely hypertension, acute renal failure, respiratory depression, drowsiness, dizziness, confusion, and coma may occur.
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) CASE REPORT: A 79-year-old woman developed visual disturbance (described as orange-colored spots within both visual fields), within 2 months of starting a regimen of twice-daily celecoxib 100 mg for the treatment of back pain caused by spinal stenosis. The visual disturbance resolved within 3 days of discontinuing celecoxib (Lund & Neiman, 2001).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) EDEMA 1) WITH THERAPEUTIC USE a) Edema has been reported as an adverse effect in patients receiving rofecoxib 12.5 to 25 mg ((Anon, 1998a); Cameron, 1998). In clinical trials, lower extremity edema was reported in 3.7% of patients receiving rofecoxib 12.5 mg to 25 mg compared to 1.1% receiving placebo. In patients receiving 50 mg rofecoxib daily, lower extremity edema incidence was 6.3% (Prod Info Vioxx(R), rofecoxib, 1999).
b) Edema was reported in 2.1% of patients receiving celecoxib during clinical trials (Prod Info CELEBREX(R) oral capsules, 2006).
B) HEART FAILURE 1) WITH THERAPEUTIC USE a) CASE SERIES: Five elderly patients developed COX-2 inhibitor (celecoxib, rofecoxib) -associated renal dysfunction, complicated by hyperkalemia, metabolic acidosis, hyponatremia, and heart failure. Hemodialysis was required in 3 patients to treat severe hyperkalemia or heart failure (Perazella & Tray, 2001).
C) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) In clinical trials of rofecoxib at doses of 12.5 mg or 25 mg daily, hypertension was reported in 3.5% of patients compared to 1.3% for placebo. In patients taking 50 mg rofecoxib daily, hypertension was reported in 8.2% of patients (Prod Info Vioxx(R), rofecoxib, 1999).
2) WITH POISONING/EXPOSURE a) The product manufacturer speculates that a significant poisoning may result in hypertension (Prod Info CELEBREX(R) oral capsules, 2006).
D) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) In a large, randomized study of 8076 patients receiving long-term, daily treatment for rheumatoid arthritis with either rofecoxib 50 mg/day or naproxen 1000 mg/day (Vioxx Gastrointestinal Outcomes Research Study (VIGOR); aspirin not permitted), patients receiving rofecoxib had a relative risk of 2.38 (95% confidence interval, 1.39 to 4.0; p less than 0.001) for developing serious, thrombotic, cardiovascular adverse events (MI, ischemic stroke, unstable angina, cardiac thrombus, sudden or unexplained death, transient ischemic attack, resuscitated cardiac arrest) compared with patients treated with naproxen(Mukherjee et al, 2001). These results may be due to prothombotic effects of rofecoxib or antithrombotic effects of naproxen.
b) Additionally, in a comparative analysis of VIGOR patients and patients receiving placebo in an aspirin primary prevention meta-analysis, the annualized rate for acute myocardial infarction was significantly higher in patients receiving rofecoxib compared with meta-analysis patients receiving placebo (0.74% versus 0.52%, respectively; p=0.04) (Mukherjee et al, 2001).
c) ROFECOXIB: DRUG WITHDRAWN FROM MARKET: As of September 30, 2004, Merck, Inc., has voluntarily withdrawn rofecoxib (Vioxx(R)) from the market after drug safety monitoring of a long-term study indicated that the drug may increase the risk of serious cardiovascular events, including myocardial infarctions and strokes among patients receiving rofecoxib, compared to patients receiving placebo. Although the risk appeared small among individual users, the overall risk of a heart attack was twice the risk, compared to placebo-treated patients. the FDA reported that other drugs in this class would be closely monitored for similar side effects (Anon, 2004; FDA, 2004).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) ACUTE RESPIRATORY INSUFFICIENCY 1) WITH POISONING/EXPOSURE a) The product manufacturer speculates that a significant poisoning may result in respiratory depression (Prod Info CELEBREX(R) oral capsules, 2006). However, this effect has not yet been reported.
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) Headache has been reported in osteoarthritis patients receiving rofecoxib 12.5 to 50 mg daily in unpublished studies; incidence/severity data are unavailable ((Anon, 1998a); Cameron, 1998).
b) Headache was reported in 16% to 30% of patients receiving celecoxib during clinical trials (Prod Info CELEBREX(R) oral capsules, 2006; Simon et al, 1999; Emery et al, 1999).
B) INSOMNIA 1) WITH THERAPEUTIC USE a) Insomnia was reported in osteoarthritis patients receiving 12.5 to 50 mg rofecoxib daily in unpublished studies; incidence/severity data are unavailable ((Anon, 1998a); Cameron, 1998).
b) Insomnia was reported in 2% of patients receiving celecoxib during clinical trials (Prod Info CELEBREX(R) oral capsules, 2006).
C) LETHARGY 1) WITH POISONING/EXPOSURE a) The product manufacturer speculates that a significant poisoning may result in rare effects of respiratory depression and coma (Prod Info CELEBREX(R) oral capsules, 2006). However, these effects have not yet been reported.
b) CELECOXIB: In a series of 632 poison center cases with exposure to celecoxib alone, 15 (2.7%) patients developed drowsiness, 6 (1.1%) became dizzy, 4 (0.7%) developed confusion and 2 (0.4%) developed coma (Forrester, 2006).
c) VALDECOXIB: In a series of 179 poison center cases with exposure to valdecoxib alone, 3 patients became drowsy or lethargic, 2 had numbness, and 2 became dizzy (Forrester, 2006a).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) GASTROINTESTINAL IRRITATION 1) WITH THERAPEUTIC USE a) In clinical trials, adverse gastric events were reported in association with celecoxib therapy. Complaints included dyspepsia (8.8%), diarrhea (5.6%), abdominal pain (4.1%), nausea (3.5%), and flatulence (2.2%) (Prod Info CELEBREX(R) oral capsules, 2006).
b) In rofecoxib clinical trials, doses of 12.5 mg to 25 mg daily resulted in gastrointestinal complaints including dyspepsia (3.5%), diarrhea (6.5%), epigastric discomfort (3.8%), heartburn (4.2%), and nausea (5.2%). Doses of rofecoxib 50 mg daily were associated with a higher incidence of these symptoms (Prod Info Vioxx(R), rofecoxib, 1999).
2) WITH POISONING/EXPOSURE a) CELECOXIB: In a series of 632 poison center cases of exposure to celecoxib alone, 10 patients (1.8%) developed vomiting, 8 (1.4%) had abdominal pain, and 6 (1.1%) reported nausea (Forrester, 2006).
b) VALDECOXIB: In a series of 179 poison center cases of exposure to valdecoxib alone, 5 patients developed vomiting, 2 had diarrhea, 2 had nausea and one had abdominal pain (Forrester, 2006).
B) GASTRIC ULCER 1) WITH THERAPEUTIC USE a) In various controlled trials, COX-2 inhibitors have been associated with a decreased incidence of gastrointestinal side effects and increased GI tolerability compared to traditional nonsteroidal antiinflammatory drugs (NSAID's) (Prod Info CELEBREX(R) oral capsules, 2006; Dequeker et al, 1998; Simon, 1998; Hawkey et al, 1998; (Anon, 1998); Simon et al, 1999; Emery et al, 1999; Langman et al, 1999). However, the COX-2 inhibitors are not without gastric side effects, and the amount of safety afforded by selective inhibition of COX-2 has been questioned (Yeomans et al, 1998) (Wallace et al, 1998).
b) CASE REPORT: A 69-year-old woman developed gastric erosions in association with celecoxib therapy at 100 mg twice daily for 6 weeks. The patient had severe epigastric pain and endoscopy revealed severe, erosive gastropathy comparable to NSAID-induced gastropathy. After discontinuation of celecoxib and treatment with omeprazole, abdominal pain resolved (Mohammed & Croom, 1999).
c) In a series of randomized, controlled trials with over 4500 rheumatoid and osteoarthritis patients, celecoxib 50 mg twice daily up to 400 mg twice daily was associated with a lower incidence of ulcers observed via endoscopy after 12 to 24 weeks of treatment compared to naproxen 500 mg twice daily or ibuprofen 800 mg three times daily (Prod Info Celebrex (TM), celecoxib, 1999).
d) In 2 studies comparing celecoxib to diclofenac, data regarding ulcer incidence was conflicting. In one study, there was no difference in observation of endoscopic ulcers after treatment with celecoxib or diclofenac 75 mg twice daily after 1, 2, and 3 months while in another study, there was a statistically significant difference in the incidence of endoscopic ulcers between treatment groups after 6 months (Prod Info Celebrex (TM), celecoxib, 1999).
e) In 5,285 patients receiving celecoxib in clinical trials at a daily dose of 200 mg or greater, only 2 patients experienced upper gastrointestinal bleeding. Bleeding occurred after 14 and 22 days of therapy, respectively (Prod Info Celebrex (TM), celecoxib, 1999).
f) In a series of phase II clinical trials comparing the safety and efficacy of celecoxib to naproxen in rheumatoid and osteoarthritis, approximately 6 of 32 patients (19%) receiving naproxen 500 mg twice daily developed gastric ulcers confirmed by endoscopy compared to zero patients receiving placebo or celecoxib. No duodenal ulcers were observed in any treatment group (Simon, 1998).
g) In 2 studies involving 1,516 patients, rofecoxib 25 mg and 50 mg daily was compared to ibuprofen 2400 mg daily and placebo for the development of gastroduodenal ulcers. Treatment with either dose of rofecoxib was associated with a significantly lower percentage of endoscopically confirmed ulcers compared to ibuprofen (Prod Info Vioxx(R), rofecoxib, 1999).
h) In short-term placebo-controlled studies involving healthy subjects, no significant gastrointestinal blood loss (over 28 days) or changes in intestinal permeability (over one week) were observed with rofecoxib 25 or 50 mg once daily ((Anon, 1998)).
i) In healthy volunteers, fecal blood loss was not increased after 4 weeks of treatment with rofecoxib 25 mg daily, rofecoxib 50 mg daily, or placebo. However, ibuprofen 2400 daily was associated with a significant increases in fecal blood loss (Prod Info Vioxx(R), rofecoxib, 1999).
C) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea has been reported as an adverse effect of rofecoxib use in patients taking rofecoxib 12.5 to 50 mg daily; incidence/severity data are unavailable ((Anon, 1998a); Cameron, 1998). In clinical trials, the incidence of diarrhea in patients taking celecoxib was 5.6%, compared to 3.8% in patients taking placebo (Prod Info CELEBREX(R) oral capsules, 2006).
D) PANCREATITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: An 84-year-old woman presented with severe abdominal pain 2 days after she began taking celecoxib for knee pain. There was a history of mild hypertriglyceridemia and hypertension and her medications included estrogen and a thiazide diuretic. Initial laboratory values included an amylase of 318 Units/L, lipase 905 Units/L, AST 724 Units/L, ALT 210 Units/L, and normal total bilirubin and serum calcium levels. Celecoxib was discontinued and the patient's symptoms and laboratory values improved with bowel rest and parenteral nutrition. Celecoxib may have caused or contributed to acute pancreatitis and hepatitis (Carrillo-Jimenez & Nurnberger, 2000).
E) GASTROINTESTINAL HEMORRHAGE 1) WITH THERAPEUTIC USE a) As of October 2000, approximately 1300 cases of GI events (eg bleeding, obstruction, perforation, or stenosis) and 73 fatalities have been reported to the United States FDA (Weaver et al, 2001).
b) ROFECOXIB: Severe upper gastrointestinal bleeding occurred in a 77-year-old woman three weeks after beginning rofecoxib 25 mg daily for osteoarthritis. The patient initially presented with complaints of hematemesis and melena; she was found to be hypotensive and anemic (nadir hemoglobin of 8 grams/deciliter). Upper gastrointestinal endoscopy revealed multiple, large gastric erosions, with the stigmata of recent hemorrhage. The patient was transfused with 3 units of blood, and treated with omeprazole; she recovered without incident (Caroli & Monica, 2001).
c) CASE SERIES: Gastrointestinal bleeding occurred in 2 patients several weeks after starting rofecoxib. The first patient's esophagogastroduodenoscopy (EGD) revealed diffuse erosive gastritis throughout the stomach, including an erosion with adherent blood clot, while the second revealed active chronic gastritis and two duodenal ulcers with no active bleeding (Foral et al, 2002).
d) CASE REPORT: A 52-year-old woman with a temporary colostomy after resection of a sigmoid tumor, developed acute hemorrhagic colitis 5 days after starting rofecoxib 25 mg/day for low back pain. A colonoscopy (via patient's stoma) revealed a large portion of the transverse colon with hemorrhage, nodularity, superficial exudate, and mucosal edema. She recovered following symptomatic treatment and was discharged (Freitas et al, 2002).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) HEPATIC FAILURE 1) WITH THERAPEUTIC USE a) Nimesulide, a nonsteroidal antiinflammatory drug with selective COX-2 inhibitory action, was associated with fulminant hepatic failure in a 58-year-old woman. The patient had increasing jaundice over a 10-day period in addition to confusion, nausea, and vomiting. Despite liver transplantation, the patient died due to multi-organ failure (McCormick et al, 1999).
b) CASE REPORT: A 63-year-old woman, who had been taking nimesulide 200 mg daily for the past 7 months, presented with a 3-week history of pruritus, nausea and vomiting, dark urine, and progressive jaundice. Laboratory analysis revealed elevated liver enzyme concentrations and hyperbilirubinemia. A liver biopsy, performed 8 days post-presentation, showed extensive parenchymal necrosis and severe cholestasis primarily within the hepatocytes. The patient also developed hemolytic anemia refractory to treatment with blood transfusions, intravenous steroids, and plasmapheresis. Approximately 23 days post-admission, the patient developed hepatic encephalopathy necessitating liver transplantation (Rodrigo et al, 2002).
B) TOXIC HEPATITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: An 84-year-old woman presented with severe abdominal pain 2 days after she began taking celecoxib for knee pain. There was a history of mild hypertriglyceridemia and hypertension and her medications included estrogen and a thiazide diuretic. Initial laboratory values included an amylase of 318 Units/L, lipase 905 Units/L, AST 724 Units/L, ALT 210 Units/L, and normal total bilirubin and serum calcium levels. Celecoxib was discontinued and the patient's symptoms and laboratory values improved with bowel rest and parenteral nutrition. Celecoxib may have caused or contributed to acute pancreatitis and hepatitis (Carrillo-Jimenez & Nurnberger, 2000).
b) CASE REPORT: A 55-year-old woman with a history of sulfa allergy developed cholestatic hepatitis within 3 weeks of beginning treatment with oral celecoxib 200 mg/day to treat radicular pain. Laboratory analysis revealed elevations in serum alanine and aspartate aminotransferases; a peripheral eosinophilia was also evident. Liver biopsy revealed marked intrahepatocyte cholestasis with eosinophil-rich inflammation of the portal tracts. Celecoxib had been discontinued prior to hospitalization; the patient was not rechallenged with the agent, and experienced full resolution of symptoms and laboratory abnormalities at 4 months follow-up (Galan et al, 2001).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) In a randomized, controlled trial, creatinine values decreased slightly (Simon et al, 1999).
b) Several authors have reported cases of acute renal failure with therapeutic dosing of COX-2 inhibitors (celecoxib, rofecoxib) (Ahmad et al, 2002; Alkhuja et al, 2002; Woywodt et al, 2001; Perazella & Tray, 2001; Perazella & Eras, 2000).
c) CASE REPORT: Acute renal failure and volume overload caused by celecoxib were reported in a 63-year-old man with a history of hypertension, coronary artery disease, left ventricular hypertrophy with preserved ventricular function, osteoarthritis, and chronic renal insufficiency. Laboratory values included a serum creatinine of 4.9 mg/dL, BUN 73 mg/dL, sodium 134 mEq/L, potassium 5.1 mEq/L, chloride 96 mEq/L, and total CO2 20 mEq/L. Discontinuation of celecoxib and treatment with intravenous furosemide resulted in the resolution of acute renal failure and volume overload (Perazella & Eras, 2000).
d) CASE REPORT: Acute renal insufficiency complicated by congestive heart failure and mild hyperkalemia was reported in a 68-year-old man after taking celecoxib 200 mg orally twice daily for gout. There was a history of coronary artery disease, cardiomyopathy, anemia, type 2 diabetes mellitus, hypertension, gout, hyperlipidemia, and diabetic nephropathy. Symptoms resolved upon discontinuation of celecoxib and treatment with intravenous furosemide (Perazella & Eras, 2000).
e) CASE REPORT: A 43-year-old woman with a history of rheumatoid arthritis developed nonoliguric acute renal failure (BUN 90 mg/dL, creatinine 7.4 mg/dL) after receiving celecoxib 200 mg/day for 14 days. Celecoxib was discontinued, and 7 days after admission, she was discharged. Although renal function improved, it had not returned to normal 30 days after presentation (BUN 52 mg/dL, creatinine 3.8 mg/dL) (Alkhuja et al, 2002).
f) CASE SERIES: Five elderly patients developed renal dysfunction (mean increase in serum creatinine level of 2.4 mg/dL) following the use of COX-2 inhibitors for 6 to 21 days celecoxib 200 mg/day (n=3), rofecoxib 25 mg (n=1), and rofecoxib 50 mg (n=1). Reversal of renal impairment to baseline occurred 2 to 8 days after discontinuation of therapy. In addition, these patients developed hyperkalemia (serum potassium, 5.6 to 8.5 mEq/L), metabolic acidosis (serum bicarbonate, 12 to 18 mEq/L), hyponatremia (serum sodium, 126 to 132 mEq/L), and heart failure. Hemodialysis was required in 3 patients to treat severe hyperkalemia or heart failure (Perazella & Tray, 2001).
2) WITH POISONING/EXPOSURE a) The product manufacturer speculates that a significant poisoning may result in acute renal failure (Prod Info CELEBREX(R) oral capsules, 2006).
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Acid-Base |
3.11.2) CLINICAL EFFECTS
A) METABOLIC ACIDOSIS 1) WITH THERAPEUTIC USE a) CASE SERIES: Five elderly patients developed COX-2 inhibitor (celecoxib, rofecoxib)-associated renal dysfunction, complicated by hyperkalemia, metabolic acidosis (serum bicarbonate, 12 to 18 mEq/L), hyponatremia, and heart failure (Perazella & Tray, 2001).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) PLATELET AGGREGATION 1) WITH THERAPEUTIC USE a) LACK OF EFFECT 1) CELECOXIB: In a series of phase II clinical trials, celecoxib did not affect platelet aggregation or thromboxane B2 levels compared to predose measurements. In the same subjects, thromboxane B2 levels and platelet aggregation were significantly inhibited after a single dose of aspirin 650 mg (Simon, 1998).
2) CELECOXIB: In a study of healthy volunteers, celecoxib 400 mg twice daily did not affect platelet aggregation after 7 days, while aspirin rapidly inhibited platelet aggregation (Lipsky & Isakson, 1997). In another study, supratherapeutic celecoxib (600 mg twice daily) did not affect platelet aggregation, serum thromboxane levels, or bleeding time significantly (Leese et al, 2000).
3) ROFECOXIB: Single doses of rofecoxib of 500 mg to 1000 mg or multiple rofecoxib doses up to 375 mg daily for 12 days did not affect bleeding time compared to placebo (Prod Info Vioxx(R), rofecoxib, 1999).
B) METHEMOGLOBINEMIA 1) WITH THERAPEUTIC USE a) CASE REPORT: A 72-year-old man developed methemoglobinemia (methemoglobin fraction 9%) and confusion after using celecoxib (100 mg PO twice daily) for one month. He was treated with methylene blue with resolution of his methemoglobinemia and his confusion. (Kaushik et al, 2004).
C) HEMOLYTIC ANEMIA 1) WITH THERAPEUTIC USE a) CASE REPORT: A 63-year-old woman, who had been taking nimesulide 200 mg daily for the past 7 months, developed acute liver failure and hemolytic anemia resistant to treatment with blood transfusions, intravenous steroids, and plasmapheresis. The patient clinically deteriorated, necessitating liver transplantation. Following transplantation and with discontinuation of nimesulide therapy, she recovered uneventfully with no evidence of hemolysis at her 2-year follow-up (Rodrigo et al, 2002).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) DISORDER OF SKIN 1) WITH THERAPEUTIC USE a) A 57-year-old man developed acute neutrophilic dermatosis (Sweet's syndrome) within 1 week of beginning therapy with celecoxib 100 mg twice daily for shoulder bursitis. The patient initially developed multiple, painful erosions of the nasal mucosa, accompanied by wrist and knee arthralgias, and painful, erythematous plaques on his hands, neck, legs, and perianal area. Skin biopsy from a hand lesion revealed a dense, nodular, neutrophilic infiltrate with abundant leukocytoclasis within the superficial dermis, and spongiform, pustular, epidermal dermatitis. Significant clearing of lesions occurred after the patient was treated with prednisone 20 mg/day, following the discontinuation of celecoxib (Fye et al, 2001).
b) Pseudoporphyria developed in a 12-year-old girl receiving celecoxib to treat juvenile rheumatoid arthritis. Within several weeks of starting treatment with celecoxib, the girl presented with blisters and crusted erosions on her face and dorsum of her hands. The lesions cleared, leaving superficial residual scarring, within 2 weeks of discontinuing treatment with celecoxib. Porphyrin levels were normal on assays of blood, stool, and urine. Similar eruptions had occurred earlier in the course of her disease after receiving naproxen and nabumetone (Cummins et al, 2000).
B) STEVENS-JOHNSON SYNDROME 1) A 58-year-old man developed Stevens-Johnsons syndrome after receiving celecoxib treatment (dose unspecified) for an unspecified period of time. The patient initially presented with abdominal pain associated with diarrhea. Within 24 hours, he developed severe, bullous, erosive mucositis accompanied by fever, rectal bleeding, dysphasia, and a violaceous rash on his abdomen. Celecoxib was apparently discontinued, and the patient was sufficiently recovered for hospital discharge. One month later, the patient again presented with diarrhea, a red and elevated rash, and bilateral conjunctivitis that he developed 1 day after ingesting 1 dose of celecoxib. The drug was discontinued, and the symptoms were fully resolved 1 week later (Gill & Hermolin, 2001).
C) DRUG-INDUCED TOXIC PUSTULODERMA 1) WITH THERAPEUTIC USE a) CASE REPORT: A 35-year-old woman developed erythematous facial swelling with pruritus and a burning sensation of the face and neck approximately 4 hours after beginning nimesulide therapy, 200 mg twice daily, for treatment of neck pain. Within 24 hours postingestion, the swelling decreased, however pruritic non-follicular pinhead-sized pustules developed on her face and neck. The pustuloderma spontaneously resolved within 4 days after onset of symptoms, with no scarring and only mild desquamation. Six months later, patch testing, using 1% and 5% nimesulide preparations, was positive with both concentrations (Lateo & Boffa, 2002).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ACUTE ALLERGIC REACTION 1) Celecoxib is contraindicated in patients with a hypersensitivity to sulfonamides (Prod Info CELEBREX(R) oral capsules, 2006). The relative reporting rate of sulfonamide-type adverse drug reactions with celecoxib was 80% higher than with rofecoxib (Wiholm, 2001).
2) CASE SERIES: Urticaria and angioedema developed in 3 patients treated with celecoxib over varying lengths of time (Kelkar et al, 2001).
3) CASE REPORT: A 55-year-old woman experienced an anaphylactic reaction after ingesting a single dose of celecoxib, following a 3-month period without exposure to the drug. The patient had previously received a month-long course of celecoxib to treat Achilles tendonitis, approximately 6 months earlier (Levy & Fink, 2001).
4) CASE REPORT: After taking celecoxib, an adult patient suffered fatal allergic vasculitis with diffuse necrotic purpura. It is suggested that such a reaction could have been triggered by an allergic reaction linked to the chemical structure of celecoxib or an interaction of the drug with synthesis of endothelial eiconasoids leading to an imbalance between vasoactive end products, resulting in widespread rise to local thrombosis (Schneider et al, 2002).
5) CASE REPORT: Delayed cutaneous hypersensitivity reaction occurred in 2 patients receiving celecoxib to treat different arthropathic disorders. Both patients (a 76-year-old man and a 64-year-old woman), received celecoxib 200 mg daily, without prior exposure to the drug. Fourteen and 11 days, respectively, after starting treatment, both patients developed erythematous, maculopapular rashes without mucous membrane involvement. The distribution and type of skin eruption were congruent with a cell-mediated (type IV) hypersensitivity skin reaction, confirmed by celecoxib patch testing in the man, and drug-specific lymphocyte transformation testing in the woman. Both patients recovered following withdrawal of celecoxib and combined treatment with oral antihistamine and topical corticosteroid (Grob et al, 2000).
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Reproductive |
3.20.1) SUMMARY
A) Celecoxib is rated FDA pregnancy category C at less than 30 weeks of gestation and D at 30 weeks of gestation and longer. Rofecoxib is rated as FDA pregnancy category C. Irreversible end-stage renal failure associated with maternal ingestion of the cyclooxygenase type-2 selective inhibitor nimesulide as a tocolytic was reported in a newborn. Severe oligohydramnios occurred in a pregnant woman after the administration of oral nimesulide. Celecoxib is excreted into human breast milk. Rofecoxib was excreted into the milk of lactating rats. It is unknown whether rofecoxib is excreted into human milk.
3.20.2) TERATOGENICITY
A) NIMESULIDE 1) Severe oligohydramnios occurred in a 27-year-old pregnant woman after receiving oral nimesulide for postoperative preterm labor prophylaxis during a twin pregnancy. The patient received 25 days of nimesulide 100 mg twice daily prior to receiving ultrasound confirmation of severe oligohydramnios at 27 weeks of gestation; the amniotic fluid index measured 1.9 and 2 cm in the two sacs. Amniotic fluid levels slowly increased after the discontinuation of nimesulide (Holmes & Stone, 2000).
2) Irreversible end-stage renal failure associated with maternal ingestion of the cyclooxygenase type-2 selective inhibitor nimesulide as a tocolytic was reported in a newborn (Peruzzi et al, 1999).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Celecoxib is rated FDA pregnancy category C at less than 30 weeks of gestation and D at 30 weeks of gestation and longer. It is recommended that the use of celecoxib and other NSAIDs be avoided after 30 weeks of gestation due to the risk of premature closure of the ductus arteriosus (Prod Info CELEBREX(R) oral capsules, 2016).
2) Rofecoxib is rated FDA pregnancy category C (Prod Info Vioxx(R), rofecoxib, 1999).
B) ANIMAL STUDIES 1) CELECOXIB a) Ventricular septal defects (rarely) and fetal alterations (eg, fused ribs, fused or misshapen sternebrae) were reported in rabbits administered oral celecoxib throughout organogenesis at doses approximately 2-fold the human exposure at 200 mg twice daily. A dose-dependent increase in diaphragmatic hernias was observed in rats administered oral celecoxib throughout organogenesis at doses approximately 6-fold the human exposure at 200 mg twice daily. Pre- and postimplantation losses and reduced embryofetal survival were observed in rats administered oral celecoxib at doses approximately 6-fold the human exposure at 200 mg twice daily (Prod Info CELEBREX(R) oral capsules, 2016).
b) In rats given doses approximately 7 times the maximum recommended human dose, no evidence of delayed labor or birth was observed (Prod Info CELEBREX(R) oral capsules, 2016). In one study involving fetal lambs, celecoxib appeared to affect the ductus arteriosus both in vitro and in vivo (Takahashi et al, 2000).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF EFFECT 1) CELECOXIB a) According to limited data from 3 published reports of 12 breastfeeding women, low levels of celecoxib were found in human breast milk at an average infant dose of 10 to 40 mcg/kg/day (less than 1% of a 2-year-old child's weight-based therapeutic dose). No adverse events were reported in 2 of the breastfed infants at 17 and 22 months of age (Prod Info CELEBREX(R) oral capsules, 2016).
b) Celecoxib is excreted into human milk but in quantities not clinically significant for the infant(Gardiner et al, 2005; Knoppert et al, 2003). A nursing mother was treated with 100 mg celecoxib twice daily for 4 doses. Four samples of milk were hand-expressed from each breast over 24 hours. Additionally, samples were expressed from the right breast only over 48 hours. The infant's daily exposure to celecoxib was estimated to be 20 mcg/kg based upon the maximum milk concentration of 133 ng/mL and an average milk intake of 150 mL/kg (Knoppert et al, 2003).
B) ANIMAL STUDIES 1) ROFECOXIB a) Rofecoxib was excreted into the milk of lactating rats at concentrations similar to that observed in plasma. At doses between 6 and 18 times the human exposures, there was increased pup mortality and decreased body weight following exposure to milk. It is unknown whether rofecoxib is excreted into human milk (Prod Info Vioxx(R), rofecoxib, 1999).
3.20.5) FERTILITY
A) LACK OF EFFECT 1) Fertility was not impaired in male and female rats given oral celecoxib at doses approximately 11 times the normal human dose (Prod Info CELEBREX(R) oral capsules, 2016).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) LACK OF EFFECT 1) No carcinogenic effects were found in rats administered oral doses of celecoxib up to 200 mg/kg for males and 10 mg/kg for females (approximately 2 to 4 times normal human exposure) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately equal to normal human doses) for 2 years (Prod Info CELEBREX(R) oral capsules, 2008).
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Genotoxicity |
A) Celecoxib mutagenicity studies have found negative results in an Ames test and a mutation assay in Chinese hamster ovary cells. It was not clastogenic in a chromosome aberration assay in CHO cells and in an in vivo micronucleus test in rat bone marrow (Prod Info CELEBREX(R) oral capsules, 2008).
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