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Vioxx

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Vioxx

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Vioxx

CLINICAL PHARMACOLOGY

Mechanism of Action

VIOXX (rofecoxib) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of VIOXX (rofecoxib) is believed to be due to inhibition of prostaglandin synthesis, via inhibition of cyclooxygenase-2 (COX-2). At therapeutic concentrations in humans, VIOXX (rofecoxib) does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. Studies to elucidate the mechanism of action of VIOXX (rofecoxib) in the acute treatment of migraine have not been conducted.

Pharmacokinetics

Absorption

The mean oral bioavailability of VIOXX (rofecoxib) at therapeutically recommended doses of 12.5, 25, and 50 mg is approximately 93%. The area under the curve (AUC) and peak plasma level (Cmax) following a single 25-mg dose were 3286 (±843) nghr/mL and 207 (±111) ng/mL, respectively. Both Cmax and AUC are roughly dose proportional across the clinical dose range. At doses greater than 50 mg, there is a less than proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. The plasma concentration-time profile exhibited multiple peaks. The median time to maximal concentration (Tmax), as assessed in nine pharmacokinetic studies, is 2 to 3 hours. Individual Tmax values in these studies ranged between 2 to 9 hours. This may not reflect rate of absorption as Tmax may occur as a secondary peak in some individuals. With multiple dosing, steady-state conditions are reached by Day 4. The AUC0-24hr and Cmax at steady state after multiple doses of 25 mg rofecoxib was 4018 (±1140) nghr/mL and 321 (±104) ng/mL, respectively, in healthy adults. The accumulation factor based on geometric means was 1.67. The AUC0-24hr and Cmax at steady state after multiple doses of 25 mg rofecoxib was 6934 (±2158) nghr/mL and 519 (±163) ng/mL, respectively, in adult RA patients (N=12, mean body weight 62 kg).

VIOXX (rofecoxib) Tablets 12.5 mg and 25 mg are bioequivalent to VIOXX (rofecoxib) Oral Suspension 12.5 mg/5 mL and 25 mg/5 mL, respectively.

Food and Antacid Effects

Food had no significant effect on either the peak plasma concentration (Cmax) or extent of absorption (AUC) of rofecoxib when VIOXX (rofecoxib) Tablets were taken with a high fat meal. The time to peak plasma concentration (Tmax), however, was delayed by 1 to 2 hours. The food effect on the suspension formulation has not been studied. VIOXX (rofecoxib) tablets can be administered without regard to timing of meals.

There was a 13% and 8% decrease in AUC when VIOXX (rofecoxib) was administered with calcium carbonate antacid and magnesium/aluminum antacid to elderly subjects, respectively. There was an approximate 20% decrease in Cmax of rofecoxib with either antacid.

Distribution

Rofecoxib is approximately 87% bound to human plasma protein over the range of concentrations of 0.05 to 25 mcg/mL. The apparent volume of distribution at steady state (Vdss) is approximately 91 L following a 12.5-mg dose and 86 L following a 25-mg dose.

Rofecoxib has been shown to cross the placenta in rats and rabbits, and the blood-brain barrier in rats.

Metabolism

Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-dihydro derivatives of rofecoxib, which account for nearly 56% of recovered radioactivity in the urine. An additional 8.8% 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 (<5%). 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 400 mg daily does not affect rofecoxib disposition. However, induction of general hepatic metabolic activity by administration of the non-specific inducer rifampin 600 mg daily produces a 50% decrease in rofecoxib plasma concentrations. (Also see Drug Interactions.)

Excretion

Rofecoxib is eliminated predominantly by hepatic metabolism with little (<1%) unchanged drug recovered in the urine. Following a single radiolabeled dose of 125 mg, approximately 72% of the dose was excreted into the urine as metabolites and 14% in the feces as unchanged drug.

The plasma clearance after 12.5- and 25-mg doses was approximately 141 and 120 mL/min, respectively. Higher plasma clearance was observed at doses below the therapeutic range, suggesting the presence of a saturable route of metabolism (i.e., non-linear elimination). The effective half-life (based on steady-state levels) was approximately 17 hours.

Special Populations

Gender

The pharmacokinetics of rofecoxib are comparable in men and women.

Geriatric

After a single dose of 25 mg VIOXX (rofecoxib) in elderly subjects (over 65 years old) a 34% increase in AUC was observed as compared to the young subjects. Dosage adjustment in the elderly is not necessary; however, therapy with VIOXX (rofecoxib) should be initiated at the lowest recommended dose.

Pediatric

The steady state pharmacokinetics of rofecoxib was evaluated in patients ≥ 2 years to ≤ 17 years of age who weigh more than 10 kg with pauciarticular and polyarticular course Juvenile Rheumatoid Arthritis (JRA). The apparent clearance after oral administration of rofecoxib in patients ≥ 12 years to ≤ 17 years of age was similar to that of healthy adults and higher than that of adult RA patients. The apparent clearance after oral administration of rofecoxib in patients ≥ 2 years to ≤ 11 years of age was less than that of adults and increased with age. The apparent oral clearance of rofecoxib increases with body weight (and body surface area). (See Table 1.)

Table 1 Rofecoxib Apparent Oral Clearance (CL/F, mean ± SD) in JRA Patients* and Adults.

JRA patients

Adults

Group 2- to 5-year- old (N=21)

6- to 11-year-old (N=13)

12- to 17- year-old (N=11)

Healthy Age range: 20-48 (N=26)
RA Patients Age range: 31-64 (N=12)

Body Weight (kg) (mean ± SD)

17 ± 2

29 ± 6

57 ± 13

77 ± 13

62 ± 11

CL/F (mL/min)

37 ± 15

52 ± 13

87 ± 21

96 ± 30

65 ± 20

* Pauciarticular and Polyarticular Course JRA

A dose of 0.6 mg/kg to a maximum of 25 mg once daily in patients > 2 years to < 11 years of age and body weight 10 kg or above and a dose of 25 mg once daily in patients ≥ 12 years to ≤ 17 years of age would yield an AUC slightly higher than that of the 25-mg tablet once daily in healthy adults (AUC Geometric Mean Ratio, 1.12) and slightly lower than that in adult RA patients (AUC GMR, 0.77).

Race

Meta-analysis of pharmacokinetic studies has suggested a slightly (10-15%) higher AUC of rofecoxib in Blacks and Hispanics as compared to Caucasians. No dosage adjustment is necessary on the basis of race.

Hepatic Insufficiency

A single-dose pharmacokinetic study in mild (Child-Pugh score ≤6) hepatic insufficiency patients indicated that rofecoxib AUC was similar between these patients and healthy subjects. A pharmacokinetic study in patients with moderate (Child-Pugh score 7-9) hepatic insufficiency indicated that mean rofecoxib plasma concentrations were higher (mean AUC: 55%; mean Cmax: 53%) relative to healthy subjects. Since patients with hepatic insufficiency are prone to fluid retention and hemodynamic compromise, the maximum recommended chronic dose of VIOXX (rofecoxib) for patients with moderate hepatic insufficiency is 12.5 mg daily. (See PRECAUTIONS, Hepatic Effects and DOSAGE AND ADMINISTRATION, Hepatic Insufficiency.) Patients with severe hepatic insufficiency have not been studied.

Renal Insufficiency

In a study (N=6) of patients with end stage renal disease undergoing dialysis, peak rofecoxib plasma levels and AUC declined 18% and 9%, respectively, when dialysis occurred four hours after dosing. When dialysis occurred 48 hours after dosing, the elimination profile of rofecoxib was unchanged. While renal insufficiency does not influence the pharmacokinetics of rofecoxib, use of VIOXX (rofecoxib) in advanced renal disease is not recommended. (See WARNINGS, Advanced Renal Disease.)

DRUG INTERACTIONS

(Also see PRECAUTIONS, Drug Interactions.)

General

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. In vitro studies in rat hepatocytes also suggest that rofecoxib might be a mild inducer for CYP 3A4.

Drug interaction studies with the recommended doses of rofecoxib have identified potentially significant interactions with rifampin, theophylline, and warfarin. Patients receiving these agents with VIOXX (rofecoxib) should be appropriately monitored. Drug interaction studies do not support the potential for clinically important interactions between antacids or cimetidine with rofecoxib. Similar to experience with other nonsteroidal anti-inflammatory drugs (NSAIDs), studies with rofecoxib suggest the potential for interaction with ACE inhibitors. The effects of rofecoxib on the pharmacokinetics and/or pharmacodynamics of ketoconazole, prednisone/prednisolone, oral contraceptives, and digoxin have been studied in vivo and clinically important interactions have not been found.

CLINICAL STUDIES

Adults

Osteoarthritis (OA)

VIOXX (rofecoxib) has demonstrated significant reduction in joint pain compared to placebo. VIOXX (rofecoxib) was evaluated for the treatment of the signs and symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of 6 to 86 weeks duration that enrolled approximately 3900 patients. In patients with OA, treatment with VIOXX (rofecoxib) 12.5 mg and 25 mg once daily resulted in improvement in patient and physician global assessments and in the WOMAC (Western Ontario and McMaster Universities) osteoarthritis questionnaire, including pain, stiffness, and functional measures of OA. In six studies of pain accompanying OA flare, VIOXX (rofecoxib) provided a significant reduction in pain at the first determination (after one week in one study, after two weeks in the remaining five studies); this continued for the duration of the studies. In all OA clinical studies, once daily treatment in the morning with VIOXX (rofecoxib) 12.5 and 25 mg was associated with a significant reduction in joint stiffness upon first awakening in the morning. At doses of 12.5 and 25 mg, the effectiveness of VIOXX (rofecoxib) was shown to be comparable to ibuprofen 800 mg TID and diclofenac 50 mg TID for treatment of the signs and symptoms of OA. The ibuprofen studies were 6-week studies; the diclofenac studies were 12-month studies in which patients could receive additional arthritis medication during the last 6 months.

Rheumatoid Arthritis (RA)

VIOXX (rofecoxib) has demonstrated significant reduction of joint tenderness/pain and joint swelling compared to placebo. VIOXX (rofecoxib) was evaluated for the treatment of the signs and symptoms of RA in two 12-week placebo- and active-controlled clinical trials that enrolled a total of approximately 2,000 patients. VIOXX (rofecoxib) was shown to be superior to placebo on all primary endpoints (number of tender joints, number of swollen joints, patient and physician global assessments of disease activity). In addition, VIOXX (rofecoxib) was shown to be superior to placebo using the American College of Rheumatology 20% (ACR20) Responder Index, a composite of clinical, laboratory, and functional measures of RA. VIOXX (rofecoxib) 25 mg once daily and naproxen 500 mg twice daily showed generally similar effects in the treatment of RA. A 50-mg dose once daily of VIOXX (rofecoxib) was also studied; however, no additional efficacy was seen compared to the 25-mg dose.

Analgesia, including Dysmenorrhea

In acute analgesic models of post-operative dental pain, post-orthopedic surgical pain, and primary dysmenorrhea, VIOXX (rofecoxib) relieved pain that was rated by patients as moderate to severe. The analgesic effect (including onset of action) of a single 50-mg dose of VIOXX (rofecoxib) was generally similar to 550 mg of naproxen sodium or 400 mg of ibuprofen. In single-dose post-operative dental pain studies, the onset of analgesia with a single 50-mg dose of VIOXX (rofecoxib) occurred within 45 minutes. In a multiple-dose study of post-orthopedic surgical pain in which patients received VIOXX (rofecoxib) or placebo for up to 5 days, 50 mg of VIOXX (rofecoxib) once daily was effective in reducing pain. In this study, patients on VIOXX (rofecoxib) consumed a significantly smaller amount of additional analgesic medication than patients treated with placebo (1.5 versus 2.5 doses per day of additional analgesic medication for VIOXX (rofecoxib) and placebo, respectively).

Migraine with or without aura

The efficacy of VIOXX (rofecoxib) in the acute treatment of migraine headaches was demonstrated in two double-blind, placebo-controlled, outpatient trials. Doses of 25 and 50 mg were compared to placebo in the treatment of one migraine attack. A second dose of VIOXX (rofecoxib) was not allowed in either trial. In these controlled short-term studies, patients were predominantly female (88%) and Caucasian (84%), with a mean age of 40 years (range 18 to 78). Patients were instructed to treat a moderate to severe headache. Headache relief, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of relief was assessed for up to 24 hours postdose. Other medication, with the exception of NSAIDs (including COX-2 inhibitors) or combination medications that contained NSAIDs, was permitted from 2 hours after the dose of study medication. The frequency and time to use of additional medications were also recorded.

In both placebo-controlled trials, the percentage of patients achieving headache relief 2 hours after treatment was significantly greater among patients receiving VIOXX (rofecoxib) at all doses compared to those who received placebo (Table 2). There were no statistically significant differences between the 25- and the 50-mg dose groups in either trial.

Table 2 Percentage of Patients with Headache Relief (Mild or No Headache) 2 hours Following Treatment

Trial

VIOXX (rofecoxib) 25 mg

VIOXX (rofecoxib) 50 mg

Placebo

1

54%* (n=176)

57%* (n=187)

34% (n=175)

2

60%* (n=187)

62%* (n=188)

30% (n=187)

*p<0.0001 vs. placebo

Note that, in general, comparisons of results obtained in different clinical studies conducted under different conditions by different investigators with different samples of patients are ordinarily unreliable for purposes of quantitative comparison.

The estimated probability of achieving initial headache relief within 2 hours following treatment is depicted in Figure 1.

Figure 1 : Estimated Probability of Achieving Initial Headache Relief within 2 Hours

Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache relief (no or mild pain) following treatment with VIOXX (rofecoxib) or placebo. The plot is based on pooled data from the 2 placebo-controlled, outpatient trials in adults providing evidence of efficacy. Patients taking additional medication or not achieving headache relief prior to 2 hours were censored at 2 hours.

There was a decreased incidence of migraine-associated nausea, photophobia and phonophobia in VIOXX (rofecoxib) treated patients compared to placebo. The estimated probability of taking other medication for migraine over the 24 hours following initial dose of study treatment is summarized in Figure 2.

Figure 2 : Estimated Probability of Patients Taking Additional Medication for Migraines over the 24 Hours Following the Initial Dose of Study Treatment

This Kaplan-Meier plot is based on pooled data obtained in 2 placebo-controlled outpatient trials. Patients not using additional medications were censored at 24 hours. The plot includes both patients who had headache relief at 2 hours and those who had no response to the initial dose. Additional medication was not allowed within 2 hours postdose.

VIOXX (rofecoxib) was effective regardless of presence of aura, gender, race, age, presence of menses or dysmenorrhea. Similarly, the concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral contraceptives did not affect efficacy. VIOXX (rofecoxib) was also effective whether or not there was a history of prior response to NSAIDs.

Special Studies

The following special studies were conducted to evaluate the comparative safety of VIOXX (rofecoxib) .

VIOXX (rofecoxib) GI Clinical Outcomes Research (VIGOR Study)

Study Design

The VIGOR study was designed to evaluate the comparative GI safety of VIOXX (rofecoxib) 50 mg once daily (twice the highest dose recommended for chronic use in OA and RA) versus naproxen 500 mg twice daily (common therapeutic dose). The general safety and tolerability of VIOXX (rofecoxib) 50 mg once daily versus naproxen 500 mg twice daily was also studied. VIGOR was a randomized, double-blind study (median duration of 9 months) in 8076 patients with rheumatoid arthritis (RA) requiring chronic NSAID therapy (mean age 58 years). Patients were not permitted to use concomitant aspirin or other antiplatelet drugs. Patients with a recent history of myocardial infarction or stroke and patients deemed to require low-dose aspirin for cardiovascular prophylaxis were to be excluded from the study. Fifty-six percent of patients used concomitant oral corticosteroids. The GI safety endpoints (confirmed by a blinded adjudication committee) included:

PUBs-symptomatic ulcers, upper GI perforation, obstruction, major or minor upper GI bleeding.

Complicated PUBs (a subset of PUBs)-upper GI perforation, obstruction or major upper GI bleeding.

Study Results

Gastrointestinal Safety in VIGOR

The VIGOR study showed a significant reduction in the risk of development of PUBs, including complicated PUBs in patients taking VIOXX (rofecoxib) compared to naproxen (see Table 3).

Table 3 VIGOR-Summary of Patients with Gastrointestinal Safety Events1 COMPARISON TO NAPROXEN

GI Safety Endpoints

VIOXX (rofecoxib) 50 mg daily (N=4047)2 n3 (Cumulative Rate4)

Naproxen 1000 mg daily (N=4029)2 n3 (Cumulative Rate4)

Relative Risk of VIOXX (rofecoxib) compared to naproxen5

95% CI5

PUBs

56 (1.80)

121 (3.87)

0.46*

(0.33, 0.64)

Complicated PUBs

16 (0.52)

37 (1.22)

0.43*

(0.24, 0.78)

1As confirmed by an independent committee blinded to treatment, 2N=Patients randomized, 3n=Patients with events, 4Kaplan-Meier cumulative rate at end of study when at least 500 patients remained (approx. 10 1/2 months), 5Based on Cox proportional hazard model

*p-value ≤ 0.005 for relative risk compared to naproxen

The risk reduction for PUBs and complicated PUBs for VIOXX (rofecoxib) compared to naproxen (approximately 50%) was maintained in patients with or without the following risk factors for developing a PUB (Kaplan-Meier cumulative rate of PUBs at approximately 10 1/2 months, VIOXX (rofecoxib) versus naproxen, respectively): with a prior PUB (5.12, 11.47); without a prior PUB (1.54, 3.27); age 65 or older (2.83, 6.49); or younger than 65 years of age (1.48, 3.01). A similar risk reduction for PUBs and complicated PUBs (approximately 50%) was also maintained in patients with or without Helicobacter pylori infection or concomitant corticosteroid use.

Other Safety Findings

Cardiovascular Safety

The VIGOR study showed a higher incidence of adjudicated serious cardiovascular thrombotic events in patients treated with VIOXX (rofecoxib) 50 mg once daily as compared to patients treated with naproxen 500 mg twice daily (see Table 4). This finding was largely due to a difference in the incidence of myocardial infarction between the groups. (See Table 5.) (See PRECAUTIONS, Cardiovascular Effects.) Adjudicated serious cardiovascular events (confirmed by a blinded adjudication committee) included: sudden death, myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack and peripheral venous and arterial thromboses.

Table 4 VIGOR-Summary of Patients with Serious Cardiovascular Thrombotic Adverse Events1 Over Time COMPARISON TO NAPROXEN

Treatment Group

Patients Randomized

 

4 Months2

8 Months3

10 ½ months4

VIOXX 50 mg

4047

Total number of events Cumulative Rate

17

29

45

0.46%

0.82%

1.81%*

Naproxen1000 mg

4029

Total number of events Cumulative Rate

9

15

19

0.23%

0.43%

0.60%

1Confirmed by blinded adjudication committee, 2Number of patients remaining after 4 months were 3405 and 3395 for VIOXX and naproxen respectively, 3Number of patients remaining after 8 months were 2806 and 2798 for VIOXX and naproxen respectively, 4Number of patients remaining were 531 and 514 for VIOXX and naproxen respectively.

† Kaplan-Meier cumulative rate.

* p-value <0.002 for the overall relative risk compared to naproxen by Cox proportional hazard model

Table 5 VIGOR- Serious Cardiovascular 1 Thrombotic Adverse Events

VIOXX 50 mg N2=4047 n3

Naproxen 1000 mg N2=4029 n3

Any CV thrombotic event

45 *

19

Cardiac events

28**

10

Fatal MI/Sudden death

5

4

Non-fatal MI

18**

4

Unstable angina

5

2

Cerebrovascular

11

8

Ischemic stroke

9

8

TIA

2

0

Peripheral

6

1

1Confirmed by blinded adjudication committee, 2N=Patients randomized, 3n=Patients with events

* p-value <0.002 and ** p-value ≤0.006 for relative risk compared to naproxen by Cox proportional hazard model

For cardiovascular data from 2 long-term placebo-controlled studies, see PRECAUTIONS, Cardiovascular Effects.

Upper Endoscopy in Patients with Osteoarthritis and Rheumatoid Arthritis

The VIGOR study described above compared clinically relevant outcomes. Several studies summarized below have utilized scheduled endoscopic evaluations to assess the occurrence of asymptomatic ulcers in individual patients taking VIOXX (rofecoxib) or a comparative agent. The results of outcomes studies, such as VIGOR, are more clinically relevant than the results of endoscopy studies (see CLINICAL STUDIES, Special Studies, VIGOR).

Two identical (U.S. and Multinational) endoscopy studies in a total of 1516 patients were conducted to compare the percentage of patients who developed endoscopically detectable gastroduodenal ulcers with VIOXX (rofecoxib) 25 mg daily or 50 mg daily, ibuprofen 2400 mg daily, or placebo. Entry criteria for these studies permitted enrollment of patients with active Helicobacter pylori infection, baseline gastroduodenal erosions, prior history of an upper gastrointestinal perforation, ulcer, or bleed (PUB), and/or age ≥65 years. However, patients receiving aspirin (including low-dose aspirin for cardiovascular prophylaxis) were not enrolled in these studies. Patients who were 50 years of age and older with osteoarthritis and who had no ulcers at baseline were evaluated by endoscopy after weeks 6, 12, and 24 of treatment. The placebo-treatment group was discontinued at week 16 by design.

Treatment with VIOXX (rofecoxib) 25 mg daily or 50 mg daily was associated with a significantly lower percentage of patients with endoscopic gastroduodenal ulcers than treatment with ibuprofen 2400 mg daily. See Figures 3 and 4 for the results of these studies.

Figure 3 : COMPARISON TO IBUPROFEN

Life-Table Cumulative Incidence Rate of Gastroduodenal Ulcers 3 mm** (Intention-to-Treat)

p < 0.001 versus ibuprofen 2400 mg

** Results of analyses using a ≥ 5mm gastroduodenal ulcer endpoint were consistent.

*** The primary endpoint was the cumulative incidence of gastroduodenal ulcer at 12 weeks.

Figure 4 : COMPARISON TO IBUPROFEN

Life-Table Cumulative Incidence Rate of Gastroduodenal Ulcers 3 mm** (Intention-to-Treat)

† p < 0.001 versus ibuprofen 2400 mg

** Results of analyses using a ≥ 5mm gastroduodenal ulcer endpoint were consistent.

*** The primary endpoint was the cumulative incidence of gastroduodenal ulcer at 12 weeks.

In a similarly designed 12-week endoscopy study in RA patients treated with VIOXX (rofecoxib) 50 mg once daily (twice the highest dose recommended for chronic use in OA and RA) or naproxen 1000 mg daily (common therapeutic dose), treatment with VIOXX (rofecoxib) was associated with a significantly lower percentage of patients with endoscopic gastroduodenal ulcers than treatment with naproxen.

A similarly designed 12-week endoscopy study was conducted in OA patients treated with low-dose enteric coated aspirin 81 mg daily, low-dose enteric coated aspirin 81 mg plus VIOXX (rofecoxib) 25 mg daily, ibuprofen 2400 mg daily, or placebo. There was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking low-dose aspirin plus VIOXX (rofecoxib) 25 mg as compared to those taking ibuprofen 2400 mg daily alone. Patients taking low-dose aspirin plus ibuprofen were not studied. (See PRECAUTIONS, Drug Interactions, Aspirin.)

Serious clinically significant upper GI bleeding has been observed in patients receiving VIOXX (rofecoxib) in controlled trials, albeit infrequently (see WARNINGS, Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation).

Assessment of Fecal Occult Blood Loss in Healthy Subjects

Occult fecal blood loss associated with VIOXX (rofecoxib) 25 mg daily, VIOXX (rofecoxib) 50 mg daily, ibuprofen 2400 mg per day, and placebo was evaluated in a study utilizing 51Cr-tagged red blood cells in 67 healthy males. After 4 weeks of treatment with VIOXX (rofecoxib) 25 mg daily or VIOXX (rofecoxib) 50 mg daily, the increase in the amount of fecal blood loss was not statistically significant compared with placebo-treated subjects. In contrast, ibuprofen 2400 mg per day produced a statistically significant increase in fecal blood loss as compared with placebo-treated subjects and VIOXX (rofecoxib) -treated subjects. The clinical relevance of this finding is unknown.

Platelets

Multiple doses of VIOXX (rofecoxib) 12.5, 25, and up to 375 mg administered daily up to 12 days had no effect on bleeding time relative to placebo. There was no inhibition of ex vivo arachidonic acid- or collagen-induced platelet aggregation with 12.5, 25, and 50 mg of VIOXX (rofecoxib) .

Because of its lack of platelet effects, VIOXX (rofecoxib) is not a substitute for aspirin for cardiovascular prophylaxis. (See PRECAUTIONS, Cardiovascular Effects.)

Pediatric Patients

Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis (JRA)

In a 12-week, double-blind active-controlled, non-inferiority study, 310 patients, 2 years to 17 years of age with pauciarticular or polyarticular course JRA, received the following treatments: lower-dose VIOXX (rofecoxib) 0.3 mg/kg (to a maximum of 12.5 mg) once daily in patients ≥ 2 years to ≤ 11 years of age or VIOXX (rofecoxib) 12.5 mg once daily in patients ≥ 12 years to ≤ 17 years of age; higher-dose VIOXX (rofecoxib) 0.6 mg/kg (to a maximum of 25 mg) once daily in patients ≥ 2 years to ≤ 11 years of age or VIOXX (rofecoxib) 25 mg once daily in patients ≥ 12 years to ≤ 17 years of age; NSAID comparator targeted to an effective dose in patients

≥ 2 years to ≤ 17 years of age. The response rates were based upon the JRA Definition of Improvement ≥ 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates were 55% in both the VIOXX (rofecoxib) 0.6 mg/kg (to a maximum of 25 mg) and NSAID comparator treatment groups achieving the non-inferiority criterion. A single non-inferiority trial is not sufficient to support a conclusion of equivalence.

In a 52-week open-label extension to the 12-week study, 160 patients received VIOXX (rofecoxib) 0.6 mg/kg to a maximum of 25 mg once daily (patients ≥ 2 years to ≤ 11 years of age) or 25 mg once daily (patients ≥ 12 years to ≤ 17 years of age) and 67 patients ≥ 2 years to ≤ 17 years of age received NSAID comparator targeted to an effective dose. There were no unexpected safety findings.

Last reviewed on RxList: 12/28/2004
This monograph has been modified to include the generic and brand name in many instances.

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