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Volume 3 September 13, 2006 Number 6

An Exclusive Continuing Education Publication of Acadiana Consultant Pharmacy Service
Author, Publisher, Editor-in Chief, Typesetter & Printer, Charles S. Feucht,PD,FASCP PharmD candidate

Medication News & Update

September 12, 2006
New findings over Vioxx risks published in JAMA
by Alison Fischer

In a meta-analysis of studies involving COX-2 inhibitors, researchers found that Merck & Co.'s Vioxx (rofecoxib) was associated with an increased risk of renal problems and heart arrhythmia. In a separate analysis of previously published COX-2 inhibitor data, researchers suggest that the data showed that Vioxx increases the risk of cardiovascular events during the first 30 days of treatment.

In the first meta-analysis, Harvard researchers examined results from 114 trials of COX-2 inhibitors, involving a total of 116 094 patients, in an effort to identify risks of kidney-related problems and arrhythmia. According to the researchers, the results suggested that patients taking Vioxx had an increased risk of experiencing renal problems and heart arrhythmia compared to control groups.

Furthermore, the researchers concluded that there was no "class effect" because other COX-2 inhibitors examined in the analysis were "not significantly associated" with an increased risk of these problems. "Vioxx seems to increase renal and arrhythmia (risks) more than any of the other drugs," noted researcher Eric Ding, as reported in Morningstar.

In a separate study, researchers at the University of Newcastle in Australia reviewed data from controlled observational studies to compare the risks of serious cardiovascular events in patients who received COX-2 inhibitors or other NSAIDs. The researchers indicated that their findings confirm those from randomised trials regarding the cardiovascular risks associated with Vioxx, including an increased risk within one month of starting treatment.

JAMA published both study results online ahead of its scheduled publication date, due to the "public health implications" of the findings.

Rofecoxib
Vioxx®

Classification:
• Analgesics
    • Nonsteroidal Antiinflammatory Drugs (NSAIDs)
        • COX-2 inhibitors
• Musculoskeletal Agents
    • Antiinflammatory Agents
        • Nonsteroidal antiinflammatory drugs (NSAIDs)

Description, Mechanism of Action, Pharmacokinetics


NOTE: This drug is discontinued in the US.

Description: Rofecoxib is a selective cyclooxygenase-2 (COX-2), nonsteroidal anti-inflammatory drug (NSAID). Compared to celecoxib, another COX-2 selective NSAID, rofecoxib lacks a sulfonamide chain and is not primarily dependent on cytochrome P-450 enzymes for metabolism. Rofecoxib demonstrates comparable efficacy to non-selective NSAIDs (e.g. ibuprofen and diclofenac) in patients with osteoarthritis or acute pain. In addition, rofecoxib provides similar efficacy compared with other NSAIDs for pauciarticular or polyarticular course juvenile rheumatoid arthritis (JRA). Rofecoxib exhibits anti-inflammatory, analgesic, and antipyretic activities but does not inhibit platelet aggregation. Although the risk of GI toxicity is not completely eliminated with rofecoxib, the results of the VIOXX GI Outcomes Research (VIGOR) study demonstrate that in patients treated with rofecoxib 50 mg/day, the risk of GI toxicity is significantly less than with naproxen 1000 mg/day. However, the VIGOR study demonstrated an increased risk of cardiovascular thrombotic events with rofecoxib as compared to naproxen; the significance of these cardiovascular findings was unknown and more data were to be collected. It has been hypothesized that COX-1 cyclooxygenase antagonism may contribute to the renal adverse effects of NSAIDs; however, clinical trials have shown similar adverse renal effects with rofecoxib and non-selective NSAIDs. Rofecoxib was initially FDA-approved on May 21, 1999.

NOTE: On September 27, 2004, Merck announced removal of rofecoxib from the worldwide market, including the U.S. market, based on new data from a trial called the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial. The APPROVe trial was to see if rofecoxib 25 mg PO once daily was effective in preventing the recurrence of colon polyps compared to placebo. This trial was discontinued early because of an observed increased risk for serious cardiovascular events, such as heart attacks and strokes, after 18 months of continuous treatment with rofecoxib as compared with placebo. The results seen with rofecoxib in relation to cardiovascular risks may not apply to other drugs in the COX-2 class; more data regarding the risk of cardiovascular events with other COX-2 inhibitors will need to be obtained. Rofecoxib will no longer be available at pharmacies.

NOTE: The FDA issued a public health advisory on December 23, 2004 in response to recent data from controlled clinical trials showing that the COX-2 inhibitors may be associated with an increased risk of serious cardiovascular events (heart attack and stroke), especially when used chronically or in very high risk settings (e.g., post open heart surgery) (see Contraindications and Adverse Reactions discussions). The FDA also noted in December 2004 that preliminary results from a long-term clinical trial (up to three years) suggest that long-term use of a non-selective NSAID, naproxen, may be associated with an increased cardiovascular (CV) risk compared to placebo. The FDA is collecting and will be analyzing the clinical data (recent and historic) for rofecoxib (Vioxx), celecoxib (Celebrex), valdecoxib (Bextra), and also for naproxen (Aleve and many other brands) and other nonselective NSAIDs to determine the need for additional regulatory action. A FDA advisory committee meeting is planned for February 2005. The FDA is making the following interim recommendations until further analysis is made:
-Prescribers should consider this emerging information when weighing the benefits of COX-2 inhibitor use against risks for individual patients. Patients who are at a high risk of gastrointestinal (GI) bleeding, have a history of intolerance to non-selective NSAIDs, or are not doing well on non-selective NSAIDs may be appropriate candidates for COX-2 selective agents. Assess the individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs. See the most recent package labeling changes of these drugs for additional details.
-Patients are advised that all over-the-counter (OTC) pain medications, including NSAIDs, should be used in strict accordance with the label directions. If use of an OTC NSAID is needed for longer than 10 days, a patient should consult their health care provider.


Mechanism of Action: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase (COX). There are 2 isoenzymes of COX, COX-1 and COX-2. The isoenzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step in the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. The isoenzyme COX-1 produces thromboxane A2 whereas the isoenzyme COX-2 produces prostaglandin I2 (PGI2). Selective inhibition of the COX-2 enzyme results in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. Due to its selective COX-2 inhibitory activity, rofecoxib does not inhibit platelet aggregation as seen with aspirin or other non-selective NSAIDs (see Cardiovascular Effects). COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
•Anti-inflammatory Activity: The anti-inflammatory mechanism of rofecoxib is due to decreased prostaglandin synthesis via inhibition of COX-2. Although anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoe, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Rofecoxib is considered to be a selective COX-2 inhibitor. The in vitro selectivity of COX-2 inhibition (COX-1:COX-2 IC50) as determined by whole blood assay for rofecoxib is 35 as compared to diclofenac 3.0, etodolac 2.4, and meloxicam 2.0 (NOTE: A higher number indicates greater COX-2 selectivity).[4086]
•Analgesic Activity: Rofecoxib is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, rofecoxib has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
•Chemoprevention Activity: Many neoplasms overexpress COX-2 messenger RNA and COX-2 protein suggesting a contributory role for COX-2 in carcinogenesis. Mechanisms of COX-2 in tumorigenesis include conversion of procarcinogens to active carcinogens, stimulation of cancer cell proliferation, inhibition of apoptosis, increased invasiveness, and enhancement of angiogenesis. Expression of COX-2 by colorectal cancers has been associated with a poor prognosis, decreased survival, and advanced Dukes tumor stage.[2639]
•Gastrointestinal Effects: Although COX-2 selective inhibitors were developed in hopes of avoiding the GI toxicity associated with non-selective NSAIDs, GI adverse reactions do occur with these agents, albeit at a lower rate. The role of COX-2 in tissue repair processes, in H. pylori infections and other ulcers where its expression is increased, in tolerance of dietary antigens, and in colitis has yet to be determined.
•Renal Effects: In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. Activity of COX-2 in the renal cortex appears to be inhibited by angiotensin II and stimulated by intravascular volume depletion and low sodium intake. The COX-2 isoenzyme is constitutively expressed in the kidney. In response to decreased intravascular volume, COX-2 activation leads to prostaglandin production. Maintenance of an adequate intravascular volume is achieved by prostaglandin synthesis and subsequent renin release through angiotensin II and aldosterone generation. If prostaglandin production is inhibited by a NSAID regardless of COX 2 selectivity, renal blood flow is reduced. Consequently, antidiuretic hormone (ADH) production and sodium reabsorption are increased, which leads to a reduction in glomerular filtration rate, reduced urinary sodium excretion, and the potential for increased blood pressure. Glomerular filtration rate reduction of elderly or salt-depleted patients after administration of a COX 2 inhibitor has been demonstrated in several trials.[4732] [4733] [4734] In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen in increased blood pressure, which can be significant in selected individuals.
•Cardiovascular Effects: Selective inhibition of COX-2 will inhibit the production of PGI2 but not of thromboxane A2, which is produced by COX-1. Thromboxane A2 causes platelet aggregation, vasoconstriction, and vascular proliferation whereas PGI2 inhibits platelet aggregation, vascular smooth muscle contraction and proliferation, leukocyte endothelial cell interactions, and cholesteryl ester hydrolysis. As PGI2 inhibits platelet aggregation, prevention of its production in the presence of an inducer of platelet aggregation (thromboxane A2) may create an imbalance favoring a pro-thrombotic state (see Adverse Effects). Also, inhibition of PGI2 could lead to sodium and water retention, which may increase blood pressure, or worsen heart failure or other cardiovascular morbidity (see Renal Effects). The presence of the thromboxane metabolite, 2,3-dinor thromboxane B2, in urine reflects platelet activation, and platelet activation facilitates atherogenesis.[7455] The amount of thromboxane metabolite excretion was higher in male as compared with female mice deficient in LDL receptors. Interestingly, excretion of the thromboxane metabolite by female mice deficient in both LDL and PGI2 receptors exceeded the amount excreted by male mice deficient in both receptors. Thus, in female mice, PGI2 decreases platelet activation. Furthermore, PGI2 appears to reduce oxidative stress only in female mice by serving as an antioxidant. In female mice deficient in both LDL and PGI2 receptors, lipid peroxidation was increased as compared with female mice deficient only in LDL receptors. Male mice deficient in both receptors did not have further lipid peroxidation as compared with male mice deficient only in LDL receptors. In vitro, estrogen has been shown to increase the expression of COX-2 in vascular tissues and to augment PGI2 production. Despite the differences between men and women in regard to age-dependent increases in cardiovascular disease, the mechanisms of atheroprotection in women before the menopause are largely unknown. In mice, estrogen, by acting on estrogen receptor subtype alpha, upregulates prostacyclin (PGI2) production by COX-2 activation.[7455]

Pharmacokinetics: Rofecoxib is administered orally. Rofecoxib is well absorbed, with peak plasma levels of rofecoxib occurring approximately 2—3 hours after an oral dose. The bioavailability is approximately 93%. Vioxx® tablets and oral suspension are bioequivalent. Both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional across the clinical dose range of 12.5—50 mg. At higher doses, there is a less than proportional increase in Cmax and AUC which is thought to be due to the low aqueous solubility of the drug. When Vioxx® tablets are taken with a high fat meal, peak plasma levels are delayed for about one to two hours with no significant effect on the peak plasma concentration (Cmax) or extent of absorption (AUC). Vioxx® tablets can be administered without regard to the timing of meals. The food effect on the oral suspension formulation has not been studied. Rofecoxib is highly bound to plasma proteins (about 87%). The apparent steady-state volume of distribution is 91 or 86 L following a 12.5 or 25 mg dose, respectively. Rofecoxib does cross the blood-brain barrier.

Rofecoxib metabolism is primarily mediated via reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-dihydro derivatives of rofecoxib, which account for nearly 56 percent of recovered radioactivity in the urine. An additional 8.8 percent of the dose was recovered as the glucuronide of the hydroxy derivative, a product of oxidative metabolism. The biotransformation of rofecoxib and this metabolite is reversible in humans to a limited extent (less than 5 percent). These metabolites are inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 plays a minor role in metabolism of rofecoxib. Inhibition of CYP 3A activity by administration of ketoconazole does not affect rofecoxib disposition. However, induction of general hepatic metabolic activity by administration of the non-specific inducer rifampin significantly decreases rofecoxib plasma concentrations (See Drug Interactions). Rofecoxib is eliminated predominantly by hepatic metabolism with little (<1%) unchanged drug recovered in the urine and 14% unchanged drug recovered in the feces. The metabolites are primarily eliminated by the renal route; 72% of the total dose is recovered in the urine as metabolites. The apparent plasma clearance is about 140 and 120 mL/min after doses of 12.5 and 25 mg, respectively. Higher plasma clearance rates are observed at doses below the therapeutic range, suggesting non-linear metabolism. The mean effective half-life is 17 hours.

•Special Populations: Renal insufficiency, race, and gender have minimal influence on the pharmacokinetics of rofecoxib. The systemic exposure was 9% lower and the maximum serum concentration was 18% lower in 6 patients that underwent dialysis 4 hours after rofecoxib administration. Receipt of dialysis 48 hours after rofecoxib did not affect the elimination of the drug. Children at least 2 years of age and adolescents with pauciarticular or polyarticular juvenile rheumatoid arthritis have a slightly increased systemic drug exposure compared to healthy adults due to a lower rofecoxib clearance, especially in children 2—11 years of age. The apparent oral clearance of rofecoxib increases with body weight and body surface area. Impaired hepatic function and advanced age may affect the pharmacokinetics of rofecoxib. A pharmacokinetic study in mild (Child-Pugh score less than or equal to 6) hepatic insufficiency patients indicated that rofecoxib AUC was similar between these patients and healthy subjects. Limited data in patients with moderate (Child-Pugh score 7-9) hepatic insufficiency suggest a trend towards higher AUC (about 69 percent) of rofecoxib in these patients; more data are needed. Patients with severe hepatic insufficiency have not been studied. Elderly subjects (over 65 years old) have a 34% increase in rofecoxib AUC compared to younger subjects.

Description, Mechanism of Action, Pharmacokinetics last revised 1/14/2005 12:43:00 PM


Indications

• bone pain

• migraine prophylaxis†

• dental pain

• mild pain

• dysmenorrhea

• moderate pain

• headache

• osteoarthritis

• juvenile rheumatoid arthritis (JRA)

• rheumatoid arthritis

• migraine

   

† non-FDA-approved indication

Dosage


For the relief of the signs and symptoms of osteoarthritis:
Oral dosage:
Adults: NOTE: This drug is discontinued in the US. Initially, 12.5 mg PO once daily. The lowest effective dose of rofecoxib should be sought for each patient. Some patients may benefit by increasing the dose to 25 mg PO once daily. The maximum recommended daily dose for chronic therapy is 25 mg.
Elderly: NOTE: This drug is discontinued in the US. Initiate therapy at the lowest recommended adult dose. Dose adjustment in the elderly is not generally necessary.
Adolescents and Children: Safe and effective use has not been established.

For the treatment of acute mild pain or moderate pain including bone pain, dental pain, headache, and orthopedic surgical pain:
Oral dosage:
Adults: NOTE: This drug is discontinued in the US. The recommended initial dose of rofecoxib is 50 mg PO one time, then 50 mg PO once daily as needed for <= 5 days. Use of rofecoxib for more than 5 days in management of pain has not been studied.
Elderly: NOTE: This drug is discontinued in the US. Initiate therapy at the lowest recommended adult dose. Dose adjustment in the elderly is not generally necessary.
Adolescents and Children: Safe and effective use has not been established.

For the relief of the signs and symptoms of pauciarticular or polyarticular juvenile rheumatoid arthritis (JRA):
NOTE: Use of the 12.5 mg/5 ml (2.5 mg/ml) suspension rather than the tablets is recommended to improve dosing accuracy in low weight children.
Oral dosage:
Adolescents and Children > 11 years: NOTE: This drug is discontinued in the US. 25 mg PO once daily.
Children 2—11 years and >= 10 kg (22 pounds): NOTE: This drug is discontinued in the US. 0.6 mg/kg (up to 25 mg total dose) PO once daily.
Children < 2 years: Safe and effective use has not been established.

For the treatment of primary dysmenorrhea:
Oral dosage:
Adults: NOTE: This drug is discontinued in the US. The recommended initial dose of rofecoxib is 50 mg PO one time, then 50 mg PO once daily as needed for <= 5 days. Use of rofecoxib for more than 5 days in management of pain has not been studied
Adolescents and Children: Safe and effective use has not been established.

For the treatment of rheumatoid arthritis (RA):
Oral dosage:
Adults: NOTE: This drug is discontinued in the US. 25 mg PO once daily. The maximum recommended daily dose for chronic therapy is 25 mg. In a limited 8 week trial, patients in the rofecoxib 25 mg and 50 mg groups (171 and 161 patients, respectively) showed significant improvement in key efficacy endpoints, including patient global assessment of pain, patient and investigator global assessment of disease activity, and Stanford Health Assessment Questionnaire Disability Index.[2854] No additional efficacy was seen with the 50 mg/day dose versus the 25 mg/day dose. Rofecoxib 25 mg/day and naproxen 500 mg twice daily showed generally similar effects in the treatment of RA.
Elderly: NOTE: This drug is discontinued in the US. Initiate therapy at the lowest recommended adult dose. Dose adjustment in the elderly is not generally necessary.
Adolescents and Children: Safe and effective use has not been established.

For the treatment of migraine headache:
•for the acute treatment of migraine with or without aura:
Oral dosage:
Adults: NOTE: This drug is discontinued in the US. 25—50 mg PO once daily helps reduce pain and sensitivity to light, sound, and nausea. The safety of treating more than 5 attacks per month has not been established. Chronic daily use for the acute treatment of migraine is not recommended.
•for perimenstrual migraine prophylaxis†:
Oral dosage:
Adults: NOTE: This drug is discontinued in the US. In a small pilot study of 14 women with consistent history of at least 1 migraine during the perimenstrual period of each month, rofecoxib 25 mg or 50 mg PO once daily resulted in a mean of 2.6 +/- 2.8 migraines/month as compared with a mean of 5.6 +/- 2.9 migraines in the month before the study. The women began rofecoxib 5 days before their expected menses for a total of 10 days for 2 consecutive menstrual cycles.[4806]

Maximum Dosage Limits:
NOTE: This drug is discontinued in the US.
•Adults: 25 mg/day PO for chronic therapy; 50 mg/day PO for acute therapy not to exceed 5 days.
•Elderly: 25 mg/day PO for chronic therapy; 50 mg/day PO for acute therapy not to exceed 5 days.
•Adolescents: 25 mg/day PO.
•Children > 11 years: 25 mg/day PO.
•Children 2—11 years and >= 10 kg: 0.6 mg/kg/day PO or 25 mg/day PO; whichever is less.
Children < 2 years: Safe and effective use has not been established.

Patients with hepatic impairment:
Do not exceed 12.5 mg PO daily on a chronic basis for patients with moderate hepatic impairment (Child-Pugh score: 7—9). Rofecoxib is not recommended in patients with severe hepatic insufficiency.

Patients with renal impairment:
No dosage adjustment needed; however, rofecoxib has not been studied in patients with severe renal insufficiency. The use of rofecoxib is not recommended in patients with advanced renal disease.

†non-FDA approved indication


Indications...Dosage last revised 9/30/2004 2:15:00 PM



Administration Guidelines


NOTE: This drug is discontinued in the US.

Oral Administration
•Rofecoxib is administered orally as tablets or suspension.
•Rofecoxib tablets can be administered with or without food. The effect of food on the oral suspension formulation is unknown.
•Rofecoxib oral suspension 12.5 mg/5 mL or 25 mg/5 mL may be substituted for rofecoxib tablets 12.5 or 25 mg, respectively. Shake before using. Use of the 12.5 mg/5 ml (2.5 mg/ml) suspension rather than the tablets is recommended to improve dosing accuracy in low weight children.

Administration last revised 9/30/2004 2:15:00 PM


Contraindications/Precautions

• infants

• GI perforation

• NSAID hypersensitivity

• heart failure

• salicylate hypersensitivity

• hepatic disease

• acute bronchospasm

• hypertension

• acute myocardial infarction

• hypovolemia

• alcoholism

• immunosuppression

• anemia

• jaundice

• angina

• myocardial infarction

• anticoagulant therapy

• nasal polyps

• asthma

• neutropenia

• bone marrow suppression

• peptic ulcer disease

• breast-feeding

• peripheral edema

• cardiac disease

• pregnancy

• chemotherapy

• renal disease

• children

• renal failure

• coronary artery disease

• renal impairment

• corticosteroid therapy

• rheumatoid arthritis

• dehydration

• stroke

• diabetes mellitus

• systemic lupus erythematosus (SLE)

• edema

• tobacco smoking

• elderly

• ulcerative colitis

• GI bleeding

• urticaria

• GI disease

   

• Absolute contraindications are in italics.


NOTE: This drug is discontinued in the US.

Rofecoxib is contraindicated in patients with known salicylate hypersensitivity or NSAID hypersensitivity who have experienced asthma, urticaria, or other allergic reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactoid reactions to rofecoxib have been reported in such patients. A study of patients with history of a cutaneous reaction to NSAIDs demonstrated that the safety profile of more selective COX-2 inhibitors varies by drug. Of the NSAID-sensitive patients treated with rofecoxib, 3% had a reaction.[3602] Rofecoxib should not be used in asthma patients with aspirin-sensitive asthma or the aspirin triad because of the approximate 5% cross-sensitivity that occurs between aspirin and NSAIDs. The triad typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who experience severe, potentially fatal, acute bronchospasm after taking aspirin or other NSAIDs. In one report, 60 patients with aspirin-sensitive asthma who were treated with rofecoxib did not experience any cross-reactions.[3604]

Most spontaneous reports of fatal GI events with NSAID therapy are in elderly or debilitated patients and therefore special care should be taken in treating this population. Although the safety profile of rofecoxib was similar in elderly versus younger patients in a short-term study; experience with chronic NSAID therapy in elderly and debilitated patients suggest greater potential for serious GI adverse events. In addition, elderly patients are at-risk for renal toxicity associated with long-term NSAID use.

Because serious GI tract ulceration and bleeding can occur without warning or symptoms in patients receiving NSAIDs, patients receiving rofecoxib should be monitored for the signs and symptoms of GI bleeding. A few cases of serious GI bleeding and obstruction have been reported in patients receiving rofecoxib in clinical trials. NSAIDs should be prescribed with extreme caution in patients with a prior history of GI bleeding, GI perforation or ulcerative GI disease (e.g., ulcerative colitis). 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. Studies have shown that patients with a prior history of peptic ulcer disease and/or GI bleeding, have a greater than 10-fold higher risk for developing a GI bleed during NSAID therapy than patients with neither of these risk factors. Pharmacoepidemiological studies have identified several other factors that may increase the risk for GI bleeding such as: corticosteroid therapy, anticoagulant therapy, myelosuppressive chemotherapy, longer duration of NSAID therapy, tobacco smoking, alcoholism, older age, and poor general health status. Although the risk of GI toxicity is not completely eliminated with rofecoxib, the results of the VIOXX GI Outcomes Research (VIGOR) study demonstrate that in patients treated with rofecoxib 50 mg/day, the risk of GI toxicity is significantly less than with naproxen 1000 mg/day.[4031]

Administer rofecoxib to patients with pre-existing renal disease, fluid retention, hypertension or edema cautiously; fluid retention and peripheral edema have occurred. Conditions such as congestive heart failure or hypertension can be exacerbated. No information is available regarding the use of rofecoxib in patients with advanced kidney disease. Therefore, treatment with rofecoxib is not recommended in these patients; however, if rofecoxib therapy must be initiated, close monitoring of renal function is advisable. Clinical trials with rofecoxib have shown renal effects (e.g., sodium, potassium, and fluid retention and decreases in renal function) and mild increases in blood pressure and peripheral edema similar to those observed with comparator NSAIDs. The risk of hypertension and peripheral edema increases with chronic use of rofecoxib at doses greater than the 12.5—25 mg range indicated for osteoarthritis. 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 NSAID 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 renal impairment, renal failure, heart failure, liver dysfunction, diabetes mellitus, systemic lupus erythematosus (SLE), rheumatoid arthritis, hypovolemia (dehydration), sodium depletion, those taking diuretics or ACE inhibitors, or older patients. Discontinuation of NSAID therapy is usually followed by recovery. Patients should be rehydrated before starting therapy with rofecoxib.

Hepatic disease may decrease the metabolism of rofecoxib (See Pharmacokinetics). Studies of rofecoxib in hepatic disease are limited, therefore the use of rofecoxib is not recommended for patients with severe hepatic insufficiency. Chronic daily doses should not exceed 12.5 mg for patients with moderate hepatic impairment (Child-Pugh score: 7—9). Patients with hepatic impairment are prone to fluid retention and hemodynamic compromise. Since the efficacy of 12.5 mg rofecoxib PO daily for rheumatoid arthritis (RA) has not been evaluated, another drug may be more appropriate for patients with RA and moderate hepatic impairment. In patients taking NSAIDs, elevations of liver tests can occur and in rare cases, progress to severe hepatic reactions. A patient with symptoms and/or signs suggesting liver dysfunction (e.g., jaundice), 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 rofecoxib.

Anemia is sometimes seen in patients receiving rofecoxib, and rofecoxib therapy could potentially worsen pre-existing anemia. Patients on long-term treatment with rofecoxib should have their hemoglobin or hematocrit assessed if they exhibit any signs or symptoms of anemia or blood loss.

NOTE: Rofecoxib was discontinued from the US market in September 2004 due to observed increased risks in cardiovascular adverse events, such as acute myocardial infarction and stroke. Merck announced removal of rofecoxib from the worldwide market, including the U.S. market, based on new data from a trial called the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial. The APPROVe trial was to see if rofecoxib 25 mg PO once daily was effective in preventing the recurrence of colon polyps compared to placebo. This trial was discontinued early because of an observed increased risk for serious cardiovascular events, such as heart attacks and strokes, after 18 months of continuous treatment with rofecoxib as compared with placebo. Prior to market removal, caution was recommended when rofecoxib was used in patients with ischemic cardiac disease (i.e., angina, myocardial infarction or other coronary artery disease). The VIOXX GI Outcomes Research (VIGOR) study (n=8076, mean age=58), the risk of developing a serious cardiovascular thrombotic event was significantly in patients treated with rofecoxib 50 mg/day (1.1%) as compared to patients treated with naproxen 1000 mg/day (0.47%).[4031] This finding was largely due to a difference in the incidence of myocardial infarction between the 2 groups (rofecoxib 0.57%; naproxen 0.2%). In the VIGOR study, mortality due to cardiovascular thrombotic events was similar between the treatment groups. However, the VIGOR study was not designed to look at cardiovascular risk, which introduces the possibility of bias, the study was conducted in patients with rheumatoid arthritis, who are associated with a significant increased risk of cardiovascular events, and used doses higher than what is currently recommended for long-term use. In addition, it has been suggested that naproxen may provide a cardioprotective effect that could have contributed to the difference in cardiovascular thrombotic events. However, in a retrospective, cohort study using administrative data, no difference in the short-term rate of acute myocardial infarction was noted in subjects >= 65 years treated with rofecoxib (n=12,156) as compared to celecoxib (n=15,271), naproxen (n=5669), non-naproxen non-selective NSAIDs (n=33,868), or controls not exposed to NSAIDs (n=100,000).[4032] Rofecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages. Because of its lack of platelet effects, rofecoxib is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, in patients taking rofecoxib, antiplatelet regimens should not be discontinued and should be considered in patients with an indication for cardiovascular prophylaxis.

The pharmacological activity of rofecoxib in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting unsuspected infection that may accompany coexisting painful conditions. NSAIDs should be used with caution in patients with immunosuppression or neutropenia. NSAIDs may mask the signs of infection such as fever or pain in patients with bone marrow suppression.

Rofecoxib is only approved for use in children at least 2 years of age with pauciarticular or polyarticular course juvenile rheumatoid arthritis (JRA). Rofecoxib has not been studied in children with systemic type JRA. Safety and effectiveness of rofecoxib in infants or children below the age of 2 years have not been evaluated. In addition, rofecoxib should not be used in children that weigh less than 10 kg (22 pounds). The apparent oral clearance of rofecoxib increases with body weight. (see Pharmacokinetics).

Rofecoxib is classified as a FDA pregnancy risk category C drug. There are no studies in pregnant women. Rofecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus; its use should especially be avoided during the third trimester to avoid premature closure of the ductus arteriosus. No studies have been conducted to evaluate the effect of rofecoxib on the closure of the ductus arteriosus in humans [consider pregnancy category D (3rd trimester)]. The manufacturer maintains a registry to monitor the pregnancy outcomes of women exposed to rofecoxib while pregnant. Health care providers are encouraged to report any prenatal exposure to rofecoxib by calling the US Pregnancy Registry at (800) 986—8999.

Rofecoxib is excreted in animal milk; however, it is not known whether it 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 rofecoxib, a decision should be made whether to continue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.


Contraindications last revised 9/30/2004 2:15:00 PM


Drug Interactions

• Alendronate

• Leflunomide

 

 Aminoglycosides

• Lithium

• Amitriptyline

• Methotrexate

• Amphotericin B

 

 Nonsteroidal antiinflammatory drugs (NSAIDs)

 

 Anticoagulants

• Pamidronate

 

 Antihypertensive Agents

• Pemetrexed

 

 Antineoplastic Agents

• Pentamidine

• Antithymocyte Globulin

 

 Photosensitizing Agents

• Cidofovir

 

 Platelet Inhibitors

 

 Corticosteroids

 

 Radiopaque Contrast Agents

• Cyclosporine

• Rifampin

• Donepezil

• Risedronate

• Drospirenone; Ethinyl Estradiol

• Rivastigmine

• Entecavir

 

 Salicylates

• Ethanol

• Strontium-89 Chloride

• Feverfew, Tanacetum parthenium

• Sulfinpyrazone

• Foscarnet

• Tacrine

• Galantamine

• Theophylline, Aminophylline

• Ganciclovir

 

 Thrombolytic Agents

• Garlic, Allium sativum

• Tizanidine

• Ginger, Zingiber officinale

• Vancomycin

• Ginkgo, Ginkgo biloba

• Zileuton

 

 Immunosuppressives

• Zoledronic Acid



NOTE: Rofecoxib is a substrate of the hepatic cytochrome isoenzyme CYP2C9. Some evidence suggests that rofecoxib may produce a modest inhibition of cytochrome P450 (CYP) 1A2. Therefore, there is a potential for an interaction with other drugs metabolized via CYP1A2.[4718]

Because rofecoxib exerts similar pharmacologic characteristics to other systemic nonsteroidal antiinflammatory drugs (NSAIDs), including other COX-2 inhibitors, additive pharmacodynamic effects, including a potential increase for additive adverse gastrointestinal (GI) effects, may be seen if rofecoxib is used with other NSAIDs.[6144] The drugs may represent duplicative therapies and generally concurrent use should be avoided.

Cytochrome 3A4 plays a minor role in metabolism of rofecoxib. In human studies, the potential for rofecoxib to inhibit or induce CYP 3A4 activity was investigated in studies using the intravenous erythromycin breath test and the oral midazolam test. No significant difference in erythromycin demethylation was observed with rofecoxib (75 mg daily) compared to placebo, indicating no induction of hepatic CYP 3A4. A 30% reduction of the AUC of midazolam was observed with rofecoxib (25 mg daily). This reduction is most likely due to increased first pass metabolism through induction of intestinal CYP 3A4 by rofecoxib.[6144] The effects of rofecoxib on the pharmacokinetics and/or pharmacodynamics of ketoconazole, oral contraceptives, and digoxin have been studied in vivo and clinically important interactions have not been found.[6144] Ketoconazole 400 mg daily did not have any clinically important effect on the pharmacokinetics of rofecoxib. Rofecoxib did not have any clinically important effect on the pharmacokinetics of ethinyl estradiol and norethindrone. 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.

Rofecoxib lacks platelet inhibitory effects and has minimal gastric ulceration or hemorrhagic potential. However, additive effects may be seen in patients receiving other NSAIDs, corticosteroids, salicylates, platelet inhibitors, anticoagulants, or thrombolytic agents.[6144] Aspirin, ASA, in low doses, can be used with rofecoxib.[6144] However, concomitant administration of aspirin with rofecoxib may result in an increased rate of GI ulceration or other complications, compared to use of rofecoxib alone. For example, similar numbers of patients had a gastroduodenal ulceration defined as a mucosal break of at least 3 mm long with unequivocal depth after 12 weeks of either enteric-coated aspirin 81 mg and rofecoxib 25 mg daily (58 of 377) or ibuprofen 800 mg three times daily (62 of 374). In contrast, significantly fewer patients randomized to either placebo or enteric-coated aspirin 81 mg daily met the endpoint (21 of 381 and 27 of 387, respectively). All patients had osteoarthritis, did not have gastrointestinal ulcers or erosive esophagitis at baseline, were at least 50 years old, and were not taking aspirin for cardiovascular prophylaxis.[6836] Because of its lack of platelet effects, rofecoxib is not a substitute for aspirin for cardiovascular prophylaxis.[6144] Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. In single and multiple dose studies, rofecoxib increased the mean INR by 8—11% in healthy subjects receiving stabilized warfarin doses.[6144] Post-marketing reports of increases in INR, sometimes associated with bleeding events, in predominantly elderly patients have been reported during concurrent administration of rofecoxib and warfarin. In an observational study,[7493] patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs.[7493] Anticoagulant activity and signs and symptoms of GI bleeding should be monitored, particularly in the first few days, after initiating or changing rofecoxib therapy in patients receiving warfarin or similar agents.[6144]

Ethanol can be irritating to the gastric mucosa and additive GI effects may be seen in patients who ingest ethanol along with NSAIDs, including rofecoxib. It is advisable to limit intake of alcoholic beverages during rofecoxib therapy. Prolonged concomitant administration should be avoided.[6144]

NSAIDs interfere with lithium excretion and may lead to elevated lithium serum concentrations.[5385] Clinically significant interactions rarely occur, but lithium toxicity has been reported. It is thought that prostaglandins are involved in the renal clearance of lithium and that NSAIDs interfere with this process. Increased lithium levels develop over 5—10 days after adding a NSAID and return to pretreatment levels within 7 days of stopping the NSAID. If NSAID therapy is started or stopped in a patient stabilized on lithium, monitor for evidence of lithium toxicity or decreased clinical effects, respectively.[5385] [6144] [6347]

The concomitant administration of cidofovir and NSAIDs is contraindicated due to the potential for increased nephrotoxicity. NSAIDs should be discontinued 7 days prior to beginning cidofovir.[5118]

In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate.[5067] Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. Rofecoxib 12.5, 25, and 50 mg/day for 7 days had no effect on the plasma concentrations of methotrexate in patients receiving single weekly methotrexate doses of 7.5—20 mg/week for rheumatoid arthritis.[6144] Rofecoxib 75 mg/day reduced the renal clearance of methotrexate resulting in a 23% increase in AUC when given for ten days to rheumatoid arthritis patients receiving methotrexate 7.5 to 15 mg per week.[6144] It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; these higher doses may lead to unexpected toxicity in combination with NSAIDs.[5067] Concurrent use of NSAIDs may lead to an increased risk of GI bleeding in patients with methotrexate-induced thrombocytopenia or mask fever, pain, swelling and other signs and symptoms of an infection.[6144]

Clinical status and serum creatinine and potassium levels should be closely monitored when cyclosporine is given with salicylates or other nonsteroidal antiinflammatory drugs (NSAIDs). Pharmacodynamic interactions have been reported between cyclosporine and NSAIDs, consisting of additive decreases in renal function with concomitant use.[5134] [5936] NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.[6144]

Co-administration of rofecoxib with rifampin 600 mg daily, a potent, non-specific inducer of hepatic metabolism, produced a 50% decrease in rofecoxib plasma concentrations.[6144] When rofecoxib is coadministered with rifampin, the patient should be monitored for potential loss of rofecoxib efficacy and need for a higher dosage requirement. The manufacturer recommends a higher initial daily dosage of 25 mg of rofecoxib for the treatment of osteoarthritis when rofecoxib is co-administered with rifampin or other potent inducers of hepatic metabolism (unspecified).[6144]

Garlic, Allium sativum;[2233] ginger, Zingiber officinale;[5200] and ginkgo, Ginkgo biloba [5200] also have clinically significant effects on platelet aggregation leading to a potential increased risk of bleeding when used with NSAIDs. An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia due to decreases in platelet aggregation. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin [6303], and strontium-89 chloride [4694]. However, rofecoxib may be associated with less risk than other NSAIDs due to its lack of platelet inhibitory effects and minimal gastric ulceration or hemorrhagic potential.[4031] [6144]

In a retrospective study, those women taking an NSAID concomitantly with alendronate had a 70% increased risk of developing a GI adverse event, such as gastric ulceration.[5375] The use of rofecoxib may be an alternative to a traditional NSAID in these patients, but the incidence of GI effects has not been evaluated with the combination of rofecoxib and alendronate.

Since the use of NSAIDs and aspirin, ASA, is associated with GI irritation, exercise caution when administering these agents with risedronate due to the potential for additive GI toxicity. During clinical trials for osteoporosis, the majority of patients took either NSAIDs or aspirin and the incidence of adverse upper GI reactions was similar between risedronate-treated (24.5%) and placebo-treated patients (24.8%).[6090]

Preclinical data suggest agents that inhibit prostaglandin synthesis such as NSAIDs could decrease the efficacy of photosensitizing agents used in photodynamic therapy.[6383] [6625]

NSAIDs, to varying degrees, have been associated with an elevation in blood pressure (approximately 5 mm Hg) when given over a period of weeks. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs, including selective COX-2 inhibitors such as rofecoxib, may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways. NSAIDs have been shown to attenuate the effects of diuretics, beta-blockers, angiotensin-converting enzyme inhibitors (ACE-Is), vasodilators, central alpha-2 agonists, peripheral alpha-1 blockers, and angiotensin II blockers. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs.[4087] Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.[3154]

It is possible that additive nephrotoxicity may occur in patients who receive NSAIDs concurrently with other nephrotoxic agents.[6144] These include aminoglycosides, amphotericin B [5062], cisplatin [5123], foscarnet [5106], ganciclovir [5173], pamidronate [7799], pentamidine [5612], and vancomycin [5198], and zoledronic acid [6318].

In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs.[4709] Leflunomide has inhibited the metabolism of diclofenac in vitro. Leflunomide also altered protein binding, increasing the free fraction of both ibuprofen and diclofenac by 13—50%. The clinical significance of these interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.

Nonsteroidal antiinflammatory drugs (NSAIDs) may cause additive pharmacodynamic GI effects with Alzheimer's disease (AD) agents that inhibit cholinesterase (e.g., donepezil [6382], galantamine [5234], rivastigmine [6380], or tacrine [6381]), leading to GI intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of AD [4040], there are no clinical data at this time to suggest that NSAIDs alone [6384] [6386] or as combined therapy with AD agents result in synergistic effects in AD.

Feverfew appears to inhibit prostaglandin synthesis, reportedly at a different step in the prostaglandin pathway than the NSAIDs, which inhibit cyclooxygenase.[2911] [2912] Theoretically, the NSAIDs might decrease the effectiveness of feverfew, Tanacetum parthenium. However, clinical interactions have not been reported.[5314]

Drug interaction studies do not support the potential for clinically important interactions between antacids or cimetidine with rofecoxib.[6144] The manufacturer reported that coadministration of rofecoxib with either a calcium carbonate antacid or an aluminum/magnesium antacid to elderly subjects decreased rofecoxib AUC by 13% or 8%, respectively. Either antacid decreased the peak plasma concentrations of rofecoxib by about 20%. Co-administration with high doses of cimetidine (800 mg twice daily) increased the Cmax of rofecoxib by 21%, the AUC by 23% and the half-life by 15%.[6144]

Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Drugs that may have additive effects on serum potassium with drospirenone; ethinyl estradiol (Yasmin®) include chronic treatment with NSAIDs, and monitoring of serum potassium in the 1st month of concurrent therapy is recommended.[4716]

Rofecoxib 12.5, 25, and 50 mg/day given for 7 days increased the AUC and half-life of theophylline, while decreasing the oral clearance of theophylline, in healthy subjects following a single 300 mg oral theophylline dose on day 6 of rofecoxib administration. Adequate monitoring of theophylline levels should be considered when therapy with rofecoxib is initiated or changed in patients receiving theophylline. These data suggest that rofecoxib may produce a modest inhibition of cytochrome P450 (CYP) 1A2.[4797] Therefore, there is a potential for an interaction with other drugs metabolized via CYP1A2 such as amitriptyline, tacrine, or zileuton.[4718] NOTE: This list may not be inclusive of all agents that are metabolized by CYP1A2.[4718]

Sulfinpyrazone is an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, including rofecoxib (CYP2C9 substrate).[4718] Sulfinpyrazone and its metabolites inhibit platelet cyclooxygenase leading to decreased platelet aggregation.[6482] Co-administration of sulfinpyrazone with NSAIDs may increase the risk of GI ulceration and/or bleeding.

Use of pemetrexed with rofecoxib, a nonsteroidal anti-inflammatory drug (NSAID), may increase the systemic exposure to pemetrexed.[5105] The clearance of pemetrexed is reduced about 20% in patients with normal renal function that also take ibuprofen 400 mg four times daily. Patients with a creatinine clearance between 45 and 79 ml/minute should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days after pemetrexed administration. Due to an absence of data, NSAIDs with longer half-lives should not be taken by anyone (regardless of renal function status) for a period of 5 days before, the day of, and 2 days after pemetrexed administration. If use of a NSAID is unavoidable, monitor patients for myelosuppression, renal, and gastrointestinal adverse effects from pemetrexed.[5105]

Because the use of other nephrotoxic drugs including nonsteroidal anti-inflammatory drugs (NSAIDs) is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, NSAID therapy should be withheld, when possible, during radiopaque contrast agent administration.[5423]

Rofecoxib may potentiate the adverse effects of tizanidine.[6899] Eight cases of this interaction have been reported in post-marketing safety reports. Most adverse reactions reported involved the nervous system (e.g., hallucinations, psychosis, somnolence, hypotonia, etc.) and the cardiovascular system (e.g., hypotension, tachycardia, bradycardia). In all cases, discontinuation of tizanidine, rofecoxib, or both resolved adverse effects. Rechallenges with both drugs were not performed. The mechanism of this interaction is unclear.

Because entecavir is primarily eliminated by the kidneys and nonsteroidal anti-inflammatory agents (NSAIDs) can affect renal function, concurrent administration with NSAIDs may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.[8007]

The combined use of selective serotonin reuptake inhibitors (SSRIs) and either aspirin, ASA or nonsteroidal antiinflammatory drugs (NSAIDs) may elevate the risk for an upper GI bleed. In a large cohort, the observed/expected risk ratio for GI bleeding when an SSRI was combined with a NSAID was 12.2 (CI 7.1—19.5) vs. 3.6 (CI 2.7—4.7) when a SSRI was used alone. [5738] [4115] [8028] SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin or NSAIDs. Aspirin and NSAIDs also also impair the gastric mucosa defenses by inhibiting prostaglandin formation. In the cohort study evaluating SSRIs and NSAIDs, COX-2 inhibitor use was not evaluated separately; the absolute risk of GI bleed when an SSRI is combined with a COX-2 selective agent is not known. In patients at risk for GI bleed, the combined use of COX-2 inhibitors and SSRIs should be approached cautiously.


Interactions last revised 6/1/2005 11:01:00 AM


Adverse Reactions

• abdominal pain

• headache

• anaphylactoid reactions

• heart failure

• anemia

• hemorrhoids

• angina

• hepatic failure

• aseptic meningitis

• hepatic necrosis

• asthenia

• hepatitis

• atrial fibrillation

• hyperbilirubinemia

• back pain

• hypertension

• bleeding

• jaundice

• cholecystitis

• melena

• constipation

• myocardial infarction

• diarrhea

• nausea/vomiting

• dizziness

• odynophagia

• dysgeusia

• oral ulceration

• dyspepsia

• palpitations

• dysphagia

• pancreatitis

• edema

• peptic ulcer

• elevated hepatic enzymes

• peripheral edema

• esophageal stricture

• premature ventricular contractions (PVCs)

• esophageal ulceration

• pyrosis (heartburn)

• esophagitis

• rash (unspecified)

• fatigue

• renal failure (unspecified)

• fever

• sinusitis

• flatulence

• stomatitis

• gastritis

• stroke

• gastroesophageal reflux

• urticaria

• GI bleeding

• weakness

• GI obstruction

• weight gain

• GI perforation

• xerostomia


NOTE: This drug is discontinued in the US.

The most common gastrointestinal adverse reactions (> 2%) to rofecoxib were mild to moderate complaints including diarrhea (6.5%), nausea/vomiting (5.2%), pyrosis (heartburn) (4.2%), dyspepsia (3.5%), and abdominal pain (3.4%). The 50 mg daily dose of rofecoxib is associated with a higher incidence of GI adverse effects (e.g., abdominal pain, epigastric pain, pyrosis, nausea, and vomiting) as compared to 12.5 or 25 mg/day. Serious GI bleeding and GI obstruction have been reported in patients receiving rofecoxib. Pre-marketing clinical trials in patients with osteoarthritis demonstrated that the incidence of endoscopically observed GI ulceration is lower with rofecoxib 25 or 50 mg/day than that observed for ibuprofen 2400 mg/day. The incidence of endoscopic ulceration ranged from 4.1—5.3% for rofecoxib 25 mg daily, 7.3—8.8% for rofecoxib 50 mg daily, 27.7—29.2% for ibuprofen 2400 mg daily, and 5.1—9.9% for placebo. The correlation between endoscopic findings and adverse GI adverse events has not been fully established. The VIGOR study evaluated the comparative GI and general safety of rofecoxib 50 mg/day and naproxen 500 mg/day in 8076 patients with rheumatoid arthritis. The incidence of peptic ulcer bleeding (i.e., symptomatic peptic ulcers, upper GI perforation, GI obstruction or minor upper GI bleeding) was 1.38% (56 of 4047patients) for rofecoxib and 3% (121 of 4029 patients) for naproxen, and the incidence of complicated bleeding events (a subset of all bleeding events, i.e., upper GI perforation, GI obstruction, or major upper GI bleeding) was 0.4% (16 of 4047 patients) and 0.9% (37 of 4029 patients), respectively. The risk reduction for peptic ulcer and complicated peptic ulcer events of rofecoxib as compared to naproxen was 46% and 43%, respectively.[4031] Less common GI effects (> 0.1—1.9% incidence) that occurred with rofecoxib regardless of causality included: anorexia, cholecystitis, constipation, dysgeusia, flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease (GERD), hematochezia, hemorrhoids, melena, pancreatitis, peptic ulcer, oral ulceration, stomatitis, vomiting, and xerostomia. Patients receiving rofecoxib and their health care providers should monitor for the signs and symptoms of GI perforation, ulceration and bleeding, even in the absence of previous GI tract symptoms. Experience with chronic NSAID therapy in elderly and debilitated patients suggest greater potential for serious GI adverse events.

Epigastric discomfort (3.8%) has been reported in patients receiving rofecoxib. Rare cases of esophagitis (> 0.1—1.9%) have been reported in patients receiving rofecoxib. 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.

Slightly elevated hepatic enzymes (borderline values) 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/hyperbilirubinemia and fatal fulminant hepatitis, hepatic necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of rofecoxib, 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/day) 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 rofecoxib. Use of rofecoxib is not recommended in patients with moderate or severe hepatic insufficiency (see Pharmacokinetics). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), rofecoxib should be discontinued.

Anemia is sometimes seen in patients receiving rofecoxib. Patients on long-term treatment with rofecoxib should have their hemoglobin or hematocrit assessed if they exhibit any signs or symptoms of anemia or blood loss. Rofecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages.

Anaphylactoid reactions (e.g., shaking, facial flushing, and hypotension) to rofecoxib have been reported. In one case, the patient had a history of a previous reaction to a NSAID. Urticaria, rash (unspecified), and dermatitis were reported rarely (0.1—1.9%) in patients receiving rofecoxib. Allergic reactions to rofecoxib were reported in 3% of patients tested who had previous cutaneous reactions to other NSAIDs.[3602] Patients who develop urticaria, bronchospasm, or other signs and symptoms of an anaphylactoid reaction should be advised to seek emergency care immediately.

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 due to rofecoxib has been reported in several patients. All cases presented with 2 or more symptoms of aseptic meningitis within 1—12 days of starting rofecoxib. All patients improved upon discontinuation of rofecoxib.[3605] 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.[4420] 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.

Adverse effects occurring >= 2% of patients treated with rofecoxib and with an incidence greater than placebo (regardless of causation) included: dizziness (3%), sinusitis (2.7%), back pain (2.5%), fatigue/asthenia (weakness) (2.2%), and bronchitis (2%). Headache was reported during clinical trials with rofecoxib; however, the incidence of headache was less in patients receiving rofecoxib as compared to those given placebo. Overuse of rofecoxib 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 rofecoxib has been defined as taking 3 or more doses per day more often than 5 days per week.[4043] 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.[4043]

Lower extremity edema (3.7%) and hypertension (3.5%) occurred relatively frequently in patients receiving 12.5—25 mg daily of rofecoxib in pre-marketing trials. In rheumatoid arthritis patients receiving rofecoxib 25 mg/day for at least 3 months, the incidence of hypertension was 10% as compared to 4.7% in patients receiving naproxen 1000 mg/day. In adults (76% White, 14% Black) with stable hypertension (systolic < 150 mmHg) and normal renal function, the mean change from baseline in average 24-hour systolic pressure was 4.2 +/-1.1 mmHg and diastolic pressure was 1.5 +/- 0.6 mmHg after 6 weeks of rofecoxib 25 mg daily. 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). Clinic blood pressure results taken between 7 and 11 in the morning were similar for systolic readings but were higher for diastolic (mean change from baseline of 2.4 +/- 0.9 mmHg). Of the 108 patients, an increase in the systolic blood pressure of 0—10 mmHg occurred in 40%, an increase in 10—20 mmHg occurred in 18%, and a greater than 20 mmHg increase occurred in 6%. Furthermore, of 73 patients who had a baseline ambulatory systolic blood pressure less than 135 mmHg, 22 had a reading of 135 mmHg or higher at week 6.[7519 The incidence of renal adverse effects (hypertension and peripheral edema) increases with chronic daily dosage above 12.5—25 mg (the dosage range indicated for osteoarthritis). The 50 mg daily dose of rofecoxib evaluated during osteoarthritis pre-marketing trials was associated with a higher incidence of lower extremity edema (6.3%) and hypertension (8.2%). Fluid retention (0.1—1.9%), weight gain (0.1—1.9%), and congestive heart failure (< 0.1%) have also occurred in patients taking rofecoxib. Cardiovascular adverse reactions have been reported in > 0.1—1.9% of patients treated with rofecoxib for osteoarthritis. Reported side effects include angina, atrial fibrillation, bradycardia, irregular heartbeat, palpitations, premature ventricular contractions (PVCs), tachycardia, and venous insufficiency. Merck announced removal of rofecoxib from the worldwide market, including the U.S. market, in September 2004 based on new data from a trial called the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial. The APPROVe trial was to see if rofecoxib 25 mg PO once daily was effective in preventing the recurrence of colon polyps compared to placebo. This trial was discontinued early because of an observed increased risk for serious cardiovascular events, such as myocardial infarction and stroke, after 18 months of continuous treatment with rofecoxib as compared with placebo. The VIGOR study demonstrated a higher incidence of cardiovascular thrombotic events in rheumatoid arthritis patients treated with rofecoxib 50 mg/day vs. naproxen 1000 mg/day. This finding was primarily due to an increased incidence of myocardial infarction in the rofecoxib group.[4031] Various mechanisms for the increased incidence of vascular events associated with rofecoxib in the VIGOR trial have been proposed; all may play a role. First, naproxen in doses of 500 mg twice daily inhibits > 90% of platelet thromboxane A2 production during the dosing interval. However, naproxen produces less consistent inhibition of thromboxane A2 than low-dose aspirin and in clinical trials the cardioprotective effects of naproxen have been inconsistent. A second theory is that selective COX-2 inhibitors promote thrombosis due to an alteration of the ratio of endothelial prostacyclin to platelet-derived thromboxane or an increase in blood pressure. Meta-analyses, however, do not support the hypothesis that rofecoxib is prothrombotic.[4051] Another possible mechanism is decreased cardioprotection due to COX-2 inhibition, which can inhibit ischemic preconditioning.

Serious or life-threatening renal failure (unspecified) has been reported in patients with normal or impaired renal function after short-term therapy with rofecoxib. Renal function should be closely monitored for any signs of potential nephrotoxicity after initiating therapy with rofecoxib, especially in high-risk patients (see Contraindications/Precautions).

The adverse experience profile in the analgesia studies was generally similar to those reported in the osteoarthritis studies. An additional adverse experience with rofecoxib in the post-dental pain surgery studies included post-dental extraction alveolitis (dry socket) (>= 2%). In 110 patients treated with rofecoxib for post-orthopedic surgery pain, the most commonly reported adverse experiences (regardless of causation) in this study were constipation, fever, and nausea.


Adverse Reactions last revised 1/31/2005 5:22:00 PM


Monitoring Parameters

Monitoring Parameters
•CBC
•LFTs
•serum creatinine/BUN
•stool guaiac

 

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