WARNINGS
GASTROINTESTINAL (GI) EFFECTS - RISK OF GI ULCERATION, BLEEDING, AND PERFORATION
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. 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. These trends continue thus, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
Although the risk of GI toxicity is not completely eliminated with VIOXX, the results of the VIOXX GI outcomes research (VIGOR) study demonstrate that in patients treated with VIOXX, the risk of GI toxicity with VIOXX 50 mg once daily is significantly less than with naproxen 500 mg twice daily. (See CLINICAL STUDIES, Special Studies, VIGOR.)
NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Previous studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.
ANAPHYLACTOID REACTIONS
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to VIOXX. In post-marketing experience, rare cases of anaphylactic/anaphylactoid reactions and angioedema have been reported in patients receiving VIOXX. VIOXX should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
ADVANCED RENAL DISEASE
Treatment with VIOXX is not recommended in patients with advanced renal disease. If VIOXX therapy must be initiated, close monitoring of the patient's kidney function is advisable (see PRECAUTIONS, Renal Effects).
PREGNANCY
In late pregnancy VIOXX should be avoided because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
GENERAL
VIOXX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of VIOXX in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.
CARDIOVASCULAR EFFECTS
The information below should be taken into consideration and caution should be exercised when VIOXX is used in patients with a medical history of ischemic heart disease.
In VIGOR, a study in 8076 patients (mean age 58; VIOXX n=4047, naproxen n=4029) with a median duration of exposure of 9 months, the risk of developing a serious cardiovascular thrombotic event was significantly higher in patients treated with VIOXX 50 mg once daily (n=45) as compared to patients treated with naproxen 500 mg twice daily (n=19). In VIGOR, mortality due to cardiovascular thrombotic events (7 vs 6, VIOXX vs naproxen, respectively) was similar between the treatment groups. (See CLINICAL STUDIES, Special Studies, VIGOR, Other Safety Findings: Cardiovascular Safety.) In a placebo-controlled database derived from 2 studies with a total of 2142 elderly patients (mean age 75; VIOXX n=1067, placebo n=1075) with a median duration of exposure of approximately 14 months, the number of patients with serious cardiovascular thrombotic events was 21 vs 35 for patients treated with VIOXX 25 mg once daily versus placebo, respectively. In these same 2 placebo-controlled studies, mortality due to cardiovascular thrombotic events was 8 vs 3 for VIOXX versus placebo, respectively. The significance of the cardiovascular findings from these 3 studies (VIGOR and 2 placebo-controlled studies) is unknown. Prospective studies specifically designed to compare the incidence of serious CV events in patients taking VIOXX versus NSAID comparators or placebo have not been performed. Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, in patients taking VIOXX, antiplatelet therapies should not be discontinued and should be considered in patients with an indication for cardiovascular prophylaxis. (See CLINICAL STUDIES, Special Studies, Platelets ; PRECAUTIONS, Drug Interactions, Aspirin.) Prospective, long-term studies on concomitant administration of VIOXX and aspirin evaluating cardiovascular outcomes have not been conducted.
FLUID RETENTION, EDEMA, AND HYPERTENSION
Fluid retention, edema, and hypertension have been reported in some patients taking VIOXX. In clinical trials of VIOXX at daily doses of 25 mg in patients with rheumatoid arthritis the incidence of hypertension was twice as high in patients treated with VIOXX as compared to patients treated with naproxen 1000 mg daily. Clinical trials with VIOXX at daily doses of 12.5 and 25 mg in patients with osteoarthritis have shown effects on hypertension and edema similar to those observed with comparator NSAIDs; these occurred with an increased frequency with chronic use of VIOXX at daily doses of 50 mg. (See ADVERSE REACTIONS.) VIOXX should be used with caution, and should be introduced at the lowest recommended dose in patients with fluid retention, hypertension, or heart failure.
RENAL EFFECTS
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Caution should be used when initiating treatment with VIOXX in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with VIOXX. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS, Advanced Renal Disease).
HEPATIC EFFECTS
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 (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs, including VIOXX. In controlled clinical trials of VIOXX, the incidence of borderline elevations of liver tests at doses of 12.5 and 25 mg daily 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 (12.5 or 25 mg QD) and 0.1% of patients taking placebo had notable elevations of ALT or AST.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with VIOXX. The maximum recommended chronic daily dose in patients with moderate hepatic insufficiency is 12.5 mg daily. Use of VIOXX is not recommended in patients with severe hepatic insufficiency (see CLINICAL PHARMACOLOGY, Special Populations and DOSAGE AND ADMINISTRATION, Hepatic Insufficiency). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), VIOXX should be discontinued.
HEMATOLOGICAL EFFECTS
Anemia is sometimes seen in patients receiving VIOXX. In placebo-controlled trials, there were no significant differences observed between VIOXX and placebo in clinical reports of anemia. Patients on long-term treatment with VIOXX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. VIOXX does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages (see CLINICAL STUDIES, Special Studies, Platelets).
PREEXISTING ASTHMA
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, VIOXX should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
INFORMATION FOR PATIENTS
Physicians should instruct their patients to read the patient package insert before starting therapy with VIOXX and to reread it each time the prescription is renewed in case any information has changed.
VIOXX can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up. For additional gastrointestinal safety information see CLINICAL STUDIES, Special Studies, VIGOR and WARNINGS, Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding and Perforation. Patients should be informed that VIOXX is not a substitute for aspirin for cardiovascular prophylaxis because of its lack of effect on platelets. For additional cardiovascular safety information see CLINICAL STUDIES, Special Studies, VIGOR and PRECAUTIONS, Cardiovascular Effects.
Patients should promptly report signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, unexplained weight gain, edema or chest pain to their physicians.
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS).
In late pregnancy VIOXX should be avoided because it may cause premature closure of the ductus arteriosus.
LABORATORY TESTS
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.
DRUG INTERACTIONS
ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors. In patients with mild to moderate hypertension, administration of 25 mg daily of VIOXX with the ACE inhibitor benazepril, 10 to 40 mg for 4 weeks, was associated with an average increase in mean arterial pressure of about 3 mm Hg compared to ACE inhibitor alone. This interaction should be given consideration in patients taking VIOXX concomitantly with ACE inhibitors. Aspirin: Concomitant administration of low-dose aspirin with VIOXX may result in an increased rate of GI ulceration or other complications, compared to use of VIOXX alone. In a 12-week endoscopy study conducted in OA patients there was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking low-dose (81 mg) enteric coated aspirin plus VIOXX 25 mg daily, as compared to those taking ibuprofen 2400 mg daily alone. Patients taking low-dose aspirin plus ibuprofen were not studied. (See CLINICAL STUDIES, Special Studies, Upper Endoscopy in Patients with Osteoarthritis and Rheumatoid Arthritis.)
At steady state, VIOXX 50 mg once daily had no effect on the anti-platelet activity of low-dose (81 mg once daily) aspirin, as assessed by ex vivo platelet aggregation and serum TXB2 generation in clotting blood. Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, in patients taking VIOXX, antiplatelet therapies should not be discontinued and should be considered in patients with an indication for cardiovascular prophylaxis. (See CLINICAL STUDIES, Special Studies, Platelets and PRECAUTIONS, Cardiovascular Effects.) Prospective, long-term studies on concomitant administration of VIOXX and aspirin have not been conducted. Cimetidine: Co-administration with high doses of cimetidine [800 mg twice daily] increased the Cmax of rofecoxib by 21%, the AUC0-120hr by 23% and the t1/2 by 15%. These small changes are not clinically significant and no dose adjustment is necessary. Digoxin: Rofecoxib 75 mg once daily for 11 days does not alter the plasma concentration profile or renal elimination of digoxin after a single 0.5 mg oral dose.
Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
Ketoconazole: Ketoconazole 400 mg daily did not have any clinically important effect on the pharmacokinetics of rofecoxib. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In post-marketing experience there have been reports of increases in plasma lithium levels. Thus, when VIOXX and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate: VIOXX 12.5, 25, and 50 mg, each dose administered once daily for 7 days, had no effect on the plasma concentration of methotrexate as measured by AUC0-24hr in patients receiving single weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. At higher than recommended doses, VIOXX 75 mg administered once daily for 10 days increased plasma concentrations by 23% as measured by AUC0-24hr in patients receiving methotrexate 7.5 to 15 mg/week for rheumatoid arthritis. At 24 hours postdose, a similar proportion of patients treated with methotrexate alone (94%) and subsequently treated with methotrexate co-administered with 75 mg of rofecoxib (88%) had methotrexate plasma concentrations below the measurable limit (5 ng/mL). Standard monitoring of methotrexate-related toxicity should be continued if VIOXX and methotrexate are administered concomitantly. Oral Contraceptives: Rofecoxib did not have any clinically important effect on the pharmacokinetics of ethinyl estradiol and norethindrone.
Prednisone/prednisolone: Rofecoxib did not have any clinically important effect on the pharmacokinetics of prednisolone or prednisone.
Rifampin: Co-administration of VIOXX with rifampin 600 mg daily, a potent inducer of hepatic metabolism, produced an approximate 50% decrease in rofecoxib plasma concentrations. Therefore, a starting daily dose of 25 mg of VIOXX should be considered for the treatment of osteoarthritis when VIOXX is co-administered with potent inducers of hepatic metabolism.
Theophylline: VIOXX 12.5, 25, and 50 mg administered once daily for 7 days increased plasma theophylline concentrations (AUC(0-(infinity)) ) by 38 to 60% in healthy subjects administered a single 300-mg dose of theophylline. Adequate monitoring of theophylline plasma concentrations should be considered when therapy with VIOXX is initiated or changed in patients receiving theophylline.
These data suggest that rofecoxib may produce a modest inhibition of cytochrome P450 (CYP) 1A2. Therefore, there is a potential for an interaction with other drugs that are metabolized by CYP 1A2 (e.g., amitriptyline, tacrine, and zileuton). Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing VIOXX therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. In single and multiple dose studies in healthy subjects receiving both warfarin and rofecoxib, prothrombin time (measured as INR) was increased by approximately 8% to 11%. In post-marketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving VIOXX concurrently with warfarin.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Rofecoxib was not carcinogenic in mice given oral doses up to 30 mg/kg (male) and 60 mg/kg (female) (approximately 5- and 2-fold the human exposure at 25 and 50 mg daily based on AUC0-24) and in male and female rats given oral doses up to 8 mg/kg (approximately 6- and 2-fold the human exposure at 25 and 50 mg daily based on AUC0-24) for two years.
Rofecoxib was not mutagenic in an Ames test or in a V-79 mammalian cell mutagenesis assay, nor clastogenic in a chromosome aberration assay in Chinese hamster ovary (CHO) cells, in an in vitro and an in vivo alkaline elution assay, or in an in vivo chromosomal aberration test in mouse bone marrow.
Rofecoxib did not impair male fertility in rats at oral doses up to 100 mg/kg (approximately 20- and 7-fold human exposure at 25 and 50 mg daily based on the AUC0-24) and rofecoxib had no effect on fertility in female rats at doses up to 30 mg/kg (approximately 19- and 7-fold human exposure at 25 and 50 mg daily based on AUC0-24).
PREGNANCY
TERATOGENIC EFFECTS: PREGNANCY CATEGORY C.
Rofecoxib was not teratogenic in rats at doses up to 50 mg/kg/day (approximately 28- and 10-fold human exposure at 25 and 50 mg daily based on AUC0-24). There was a slight, non-statistically significant increase in the overall incidence of vertebral malformations only in the rabbit at doses of 50 mg/kg/day (approximately 1- or <1-fold human exposure at 25 and 50 mg daily based on AUC0-24). There are no studies in pregnant women. VIOXX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NONTERATOGENIC EFFECTS
Rofecoxib produced peri-implantation and post-implantation losses and reduced embryo/fetal survival in rats and rabbits at oral doses >/=10 and >/=75 mg/kg/day, respectively (approximately 9- and 3-fold [rats] and 2- and <1-fold [rabbits] human exposure based on the AUC0-24 at 25 and 50 mg daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function. There was an increase in the incidence of postnatal pup mortality in rats at >/=5 mg/kg/day (approximately 5- and 2-fold human exposure at 25 and 50 mg daily based on AUC0-24). In studies in pregnant rats administered single doses of rofecoxib, there was a treatment-related decrease in the diameter of the ductus arteriosus at all doses used (3-300 mg/kg: 3 mg/kg is approximately 2- and <1-fold human exposure at 25 or 50 mg daily based on AUC0-24). As with other drugs known to inhibit prostaglandin synthesis, use of VIOXX during the third trimester of pregnancy should be avoided.
LABOR AND DELIVERY
Rofecoxib produced no evidence of significantly delayed labor or parturition in females at doses 15 mg/kg in rats (approximately 10- and 3-fold human exposure as measured by the AUC0-24 at 25 and 50 mg). The effects of VIOXX on labor and delivery in pregnant women are unknown.
Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to VIOXX while pregnant. Healthcare providers are encouraged to report any prenatal exposure to VIOXX by calling the Pregnancy Registry at (800) 986-8999.
NURSING MOTHERS
Rofecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. There was an increase in pup mortality and a decrease in pup body weight following exposure of pups to milk from dams administered VIOXX during lactation. The dose tested represents an approximate 18- and 6-fold human exposure at 25 and 50 mg based on AUC0-24. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VIOXX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
PEDIATRIC USE
Safety and effectiveness in pediatric patients below the age of 18 years have not been evaluated.
GERIATRIC USE
Of the patients who received VIOXX in osteoarthritis clinical trials, 1455 were 65 years of age or older. This included 460 patients who were 75 years or older, and in one of these studies, 174 patients who were 80 years or older. No substantial differences in safety and effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. As with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients. Dosage adjustment in the elderly is not necessary; however, therapy with VIOXX should be initiated at the lowest recommended dose.
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