Rofecoxib Side Effects
Applies to rofecoxib: oral suspension, oral tablet
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation of the stomach, small or large intestine, can occur at any time, with or without symptoms, in patients treated with nonsteroidal anti-inflammatories. The incidence of upper GI adverse events (perforations, ulcers, and bleed) was shown to be significantly lower (1.3% vs 1.8%) in patients with osteoarthritis receiving rofecoxib 12.5, 25, or 50 mg/day than in those receiving ibuprofen, diclofenac, or nabumetone. Risk factors for NSAID-induced GI bleeding include a prior history of peptic ulcer disease or gastrointestinal bleeding, treatment with oral corticosteroids, anticoagulation therapy, smoking, alcoholism, older age, poor general health status, and longer duration of NSAID therapy.
Rofecoxib (50 mg a day) has also been shown to have a lower incidence of serious upper gastrointestinal adverse events such as major bleeding, perforation, and obstruction compared to naproxen (1000 mg a day). The reduction in risk was about 50% in cumulative rates for rofecoxib (0.52%) compared to naproxen (1.22%) in the Vioxx Gastrointestinal Outcomes Research (VIGOR) study.[Ref]
Gastrointestinal side effects have included diarrhea, dyspepsia, epigastric discomfort, heartburn, and nausea. These were the most frequently reported gastrointestinal adverse events occurring in greater than 2% of patients. Other reported adverse events occurring in less than 2% of patients studied have included acid reflux, aphthous stomatitis, constipation, dental caries, dental pain, digestive gas symptoms, dry mouth, duodenal disorder, dysgeusia, esophagitis, flatulence, gastric disorder, gastritis, gastroenteritis, hematochezia, hemorrhoids, infectious gastroenteritis, oral infection, oral lesion, oral ulcer, vomiting, colitis, colonic malignant neoplasm, cholecystitis, duodenal ulcer, gastrointestinal bleeding, intestinal obstruction, and pancreatitis.
Rofecoxib 50 mg/day has been associated with a higher incidence of gastrointestinal symptoms (abdominal pain, epigastric pain, heartburn, nausea and vomiting) than that seen with either 12.5 or 25 mg/day dosage.[Ref]
General side effects have included asthenia, fatigue, dizziness, influenza-like disease, lower extremity edema, sinusitis and upper respiratory infection. Other general side effects have included abscess, chest pain, chills, contusion, cyst, diaphragmatic hernia, fever, fluid retention, flushing, fungal infection, infection, laceration, pain, pelvic pain, peripheral edema, postoperative pain, syncope, trauma, upper extremity edema, viral syndrome, cerumen impaction, epistaxis, dry throat, otic pain, otitis, otitis media, pharyngitis, tinnitus, and tonsillitis.[Ref]
Hepatic side effects have included borderline elevations of one or more liver tests that may occur in up to 15% of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, elevations of ALT or AST greater than three times normal have been reported in 1% of patients in clinical trials with NSAIDs. Patients with signs and/or symptoms of liver disease or with abnormal liver tests should be monitored carefully while on rofecoxib for evidence of worsening disease. If signs and symptoms consistent with liver disease develop, rofecoxib should be discontinued. Use of rofecoxib is not recommended in patients with severe hepatic insufficiency.[Ref]
In controlled clinical trials of rofecoxib, the incidence of borderline elevation of liver tests was comparable to the incidence observed with ibuprofen and lower than that observed with diclofenac. In placebo controlled trials, approximately 0.5% of patients taking rofecoxib and 0.1% of patients taking placebo had noticeable elevations of ALT or AST.[Ref]
Cardiovascular side effects have included hypertension in greater than 2% of patients. Other cardiovascular side effects have included angina pectoris, atrial fibrillation, bradycardia, hematoma, irregular heart beat, palpitation, premature ventricular contraction, tachycardia, cerebrovascular accident, congestive heart failure, deep venous thrombosis, myocardial infarction, pulmonary edema, pulmonary embolism, transient ischemic attack, unstable angina and venous insufficiency.[Ref]
The cumulative rate of serious cardiovascular thromboembolic adverse events (heart attacks, angina pectoris, and peripheral vascular events) was reported to occur in a higher percentage of patients receiving rofecoxib (1.8%) compared to patients receiving naproxen (0.6%) in the Vioxx Gastrointestinal Outcomes Research (VIGOR) study. The relationship of the cardiovascular findings to the use of rofecoxib is not known.
Patients being treated for rheumatoid arthritis with rofecoxib at a dose of 25 mg a day have been reported to have a higher incidence of hypertension compared to patients treated with naproxen at a dose of 1000 mg a day.
Lower extremity edema and hypertension have been reported to occur less often with the 12.5 and 25 mg/day dosage than with the 50 mg/day dosage.[Ref]
In two separate studies, a similar reduction in glomerular filtration rate to nonselective nonsteroidal anti-inflammatory drugs was observed.
Sudden reduction in urine output and rise in serum creatinine levels were observed in a 65-year-old woman, with a history of mild renal failure (Clcr = 57 mL/min), hyperuricemia, mitral valve regurgitation and heart failure, after receiving a single dose of rofecoxib 25 mg because of lower back pain. Over the course of her hospital stay, her renal laboratory parameters slowly returned to her baseline levels.
Acute interstitial nephritis has been reported in a 63-year-old man diagnosed with third-degree burns, on 70% of body surface area, that had been receiving for 3 weeks rofecoxib 25 mg daily for arthritis. Patient underwent one hemodialysis treatment. Creatinine and potassium levels returned to baseline levels a month later.[Ref]
Renal side effects have included a decrease in glomerular filtration rate. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Acute renal failure after a single dose of rofecoxib has been reported. Interstitial nephritis has been diagnosed in a patient 3 weeks after the start of treatment with rofecoxib.[Ref]
Cases of neutrophilic dermatosis have been reported to occur within one to two weeks of initiation of rofecoxib treatment for joint pains. Patients presented with multiple subcutaneous nodules over both legs, anterior and posterior areas, and areas of ulceration. The patient's leg lesions disappeared after discontinuation of rofecoxib.
A 46-year-old woman who had previously developed psoriasis after exposure to a nonselective NSAID developed a severe case of psoriasis 5 days after she started taking rofecoxib for neck strain. It took several months for symptoms to abate.[Ref]
Dermatologic side effects have included alopecia, atopic dermatitis, basal cell carcinoma, contact dermatitis, herpes simplex, herpes zoster, nail unit disorder, perspiration, pruritus, rash, skin erythema, urticaria, and xerosis. Acute onset of neutrophilic dermatosis has been reported shortly after initiation of rofecoxib therapy. A severe case of psoriasis has been reported to have developed 5 days after the start of treatment with rofecoxib.
Pseudoporphyria has been reported in a 60-year-old woman 2 weeks after the start of rofecoxib treatment for pain control. The skin lesions cleared within 1 month after discontinuation of therapy.[Ref]
Nervous system side effects have included headache, hypesthesia, insomnia, median nerve neuropathy, migraine, muscular spasm, paresthesia, sciatica, somnolence, and vertigo. In the postmarketing phase of rofecoxib, aseptic meningitis has been reported to the Spontaneous Reporting System of the FDA.[Ref]
Musculoskeletal side effects have included back pain, arm pain, arthralgia, bursitis, cartilage trauma, joint swelling, muscle cramps, muscle weakness, musculoskeletal pain, musculoskeletal stiffness, myalgia, osteoarthritis, tendonitis, traumatic arthropathy, and wrist fracture.[Ref]
Breast malignant neoplasm, prostate malignant neoplasm and urolithiasis have been reported in less than 0.1% of patients.[Ref]
Genitourinary side effects have included urinary tract infections, cystitis, dysuria, menopausal symptoms, menstrual disorder, nocturia, urinary retention, vaginitis, breast mass, and urolithiasis.[Ref]
Hematologic side effects have included reports of lymphoma in less than 0.1% of patients.[Ref]
1. Caroli A, Monica F "Severe upper gastrointestinal bleeding during treatment with rofecoxib for osteoarthritis." Am J Gastroenterol 96 (2001): 1663-5
2. Hunt RH, Bowen B, Mortensen ER, Simon TJ, James C, Cagliola A, Quan H, Bolognese JA "A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects." Am J Med 109 (2000): 201-6
3. Ehrich EW, Schnitzer TJ, McIlwain H, Levy R, Wolfe F, Weisman M, Zeng Q, Morrison B, Bolognese J, Seidenberg B, Gertz BJ "Effect of specific COX-2 inhibition in osteoarthritis of the knee: A 6 week double blind, placebo controlled pilot study of rofecoxib." J Rheumatol 26 (1999): 2438-47
4. "Product Information. Vioxx (rofecoxib)." Merck & Co, Inc, West Point, PA.
5. Simon LS, Smolen JS, Abramson SB, et al. "Controversies in COX-2 selective inhibition." J Rheumatol 29 (2002): 1501-10
6. Mamdani M, Rochon PA, Juurlink DN, et al. "Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs." BMJ 325 (2002): 624
7. Schnitzer TJ, Truitt K, Fleischmann R, Dalgin P, Block J, Zeng Q, Bolognese J, Seidenberg B, Ehrich EW "The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis." Clin Ther 21 (1999): 1688-702
8. Gornet JM, Hassani Z, Modiglian R, Lemann M "Exacerbation of Crohn's colitis with severe colonic hemorrhage in a patient on rofecoxib." Am J Gastroenterol 97 (2002): 3209-10
9. Bombardier C, Laine L, Reicin A, et al. "Comparison of upper gastrointestinal toxicity of refecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group." N Engl J Med 343 (2000): 1520-8
10. Laine L, Bombardier C, Hawkey CJ, et al. "Stratifying the risk of NSAID-related upper gastrointestinal clinical events: Results of a double-blind outcomes study in patients with rheumatoid arthritis." Gastroenterology 123 (2002): 1006-12
11. Cannon GW, Caldwell JR, Holt P, McLean B, Seidenberg B, Bolognese J, Ehrich E, Mukhopadhyay S, Daniels B "Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium - Results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip." Arthritis Rheum 43 (2000): 978-87
12. Bombardier C "An evidence-based evaluation of the gastrointestinal safety of coxibs." Am J Cardiol 89(6 Suppl 1) (2002): 3-9
13. Langman MJ, Jensen DM, Watson DJ, et al. "Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs." JAMA 282 (1999): 1929-33
14. Hawkey CJ, Langman MJ "Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors." Gut 52 (2003): 600-8
15. Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, Stern S, Quan H, Bolognese J "A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis." Gastroenterology 117 (1999): 776-83
16. Juni P, Dieppe P, Egger M "Risk of myocardial infarction associated with selective COX-2 inhibitors: questions remain." Arch Intern Med 162 (2002): 2639-40; author reply 2640-2
17. Levesque LE, Brophy JM, Zhang B "The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults." Ann Intern Med 142 (2005): 481-9
18. Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q "Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with Rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (Ibuprofen, Diclofenac, and Nabumetone)." Am J Cardiol 89 (2002): 204-9
19. Whelton A, White WB, Bello AE, Puma JA, Fort JG "Effects of celecoxib and rofecoxib on blood pressure and edema in patients >/=65 years of age with systemic hypertension and osteoarthritis." Am J Cardiol 90 (2002): 959-63
20. Mukherjee D, Nissen SE, Topol EJ "Risk of cardiovascular events associated with selective COX-2 inhibitors." JAMA 286 (2001): 954-9
21. Mamdani M, Juurlink DN, Lee DS, et al. "Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study." Lancet 363 (2004): 1751-6
22. "Summaries for patients. Risk for heart attacks with different NSAIDs." Ann Intern Med 142 (2005): I45
23. Ray WA, Michael Stein C, Hall K, Daugherty JR, Griffin MR "Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study." Lancet 359 (2002): 118-23
24. Bannwarth B, Dougados M "Cardiovascular thrombotic events and COX-2 inhibitors: results in patients with osteoarthritis receiving rofecoxib." J Rheumatol 30 (2003): 421-2
25. Whelton A "COX-2-specific inhibitors and the kidney: effect on hypertension and oedema." J Hypertens 20 Suppl 6 (2002): S31-5
26. Graham DJ, Campen D, Hui R, et al. "Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study." Lancet 365 (2005): 475-81
27. Aw TJ, Haas SJ, Liew D, Krum H "Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure." Arch Intern Med 165 (2005): 490-6
28. Gibofsky A "Clinical profiles of celecoxib and rofecoxib in the rheumatic diseases." J Hypertens 20 Suppl 6 (2002): S25-30
29. Wolfe F, Zhao S, Pettitt D "Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal antiinflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care." J Rheumatol 31 (2004): 1143-51
30. Ofran Y, Bursztyn M, Ackerman Z "Rofecoxib-induced renal dysfunction in a patient with compensated cirrhosis and heart failure." Am J Gastroenterol 96 (2001): 1941
31. Alim N, Peterson L, Zimmerman SW, Updike S "Rofecoxib-induced acute interstitial nephritis." Am J Kidney Dis 41 (2003): 720-1
32. Swan SK, Rudy DW, Lasseter KC, et al. "Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet." Ann Intern Med 133 (2000): 1-9
33. Perazella MA, Eras J "Are selective COX-2 inhibitors nephrotoxic?." Am J Kidney Dis 35 (2000): 937-40
34. Reinhold SW, Fischereder M, Riegger GA, Kramer BK "Acute renal failure after administration of a single dose of a highly selective COX-2 inhibitor." Clin Nephrol 60 (2003): 295-6
35. Smith KJ, Skelton H "Acute onset of neutrophilic dermatosis in patients after therapy with a COX-2-specific inhibitor." Int J Dermatol 42 (2003): 389-93
36. Markus R, Reddick ME, Rubenstein MC "Rofecoxib-induced pseudoporphyria." J Am Acad Dermatol 50 (2004): 647-8
37. Clark DW, Coulter DM "Psoriasis associated with rofecoxib." Arch Dermatol 139 (2003): 1223
38. Palop-Larrea V, Melchor-Penella MA, Ortega-Monzo C, Martinez-Mir I "Leukocytoclastic vasculitis related to rofecoxib." Ann Pharmacother 37 (2003): 1731-2
39. Daugherty KK, Gora-Harper ML "Idiopathic paresthesia reaction associated with rofecoxib." Ann Pharmacother 36 (2002): 264-6
40. Ashwath ML, Katner HP "Recurrent aseptic meningitis due to different non-steroidal anti-inflammatory drugs including rofecoxib." Postgrad Med J 79 (2003): 295-6
41. Bonnel RA, Villalba ML, Karwoski CB, Beitz J "Aseptic meningitis associated with rofecoxib." Arch Intern Med 162 (2002): 713-5
42. Crofford LJ "COX-2: Where are we in 2003? - Specific cyclooxygenase-2 inhibitors and aspirin-exacerbated respiratory disease." Arthritis Res Ther 5 (2003): 25-7
43. Meyer C, Gahler R "Central retinal vein occlusion in a patient with rheumatoid arthritis taking rofecoxib." Lancet 360 (2002): 1100
Some side effects may not be reported. You may report them to the FDA.