Pharmacokinetics
Absorption
The mean oral bioavailability of VIOXX at
therapeutically recommended doses of 12.5, 25, and 50 mg is
approximately 93%. The area under the curve (AUC) and peak plasma
level (C max ) following a single 25-mg dose were 3286 (±843) ng•hr/mL
and 207 (±111) ng/mL, respectively. Both C max 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 C max 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 (T max ),
as assessed in nine pharmacokinetic studies, is 2 to 3 hours.
Individual T max values in these studies ranged between 2 to 9
hours. This may not reflect rate of absorption as T max may occur as
a secondary peak in some individuals. With multiple dosing,
steady-state conditions are reached by Day 4. The AUC 0-24hr and C
max at steady state after multiple doses of 25 mg rofecoxib was 4018
(±1140) ng•hr/mL and 321 (±104) ng/mL, respectively. The
accumulation factor based on geometric means was 1.67. VIOXX
(rofecoxib tablets and oral suspension) VIOXX Tablets 12.5 mg and 25
mg are bioequivalent to VIOXX 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 (C max ) or extent of absorption (AUC) of rofecoxib
when VIOXX Tablets were taken with a high fat meal. The time to peak
plasma concentration (T max ), however, was delayed by 1 to 2 hours.
The food effect on the suspension formulation has not been studied.
VIOXX tablets can be administered without regard to timing of meals.
There was a 13% and 8% decrease in AUC when VIOXX was administered
with calcium carbonate antacid and magnesium/aluminum antacid to
elderly subjects, respectively. There was an approximate 20%
decrease in C max 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 (V dss ) 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 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 should be initiated at the lowest
recommended dose.
Pediatric VIOXX has not been investigated in patients below 18 years
of age.
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 C max : 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 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 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 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
Osteoarthritis (OA)
VIOXX has demonstrated significant reduction in joint pain compared
to placebo. VIOXX 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 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 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 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 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 has demonstrated significant reduction of joint
tenderness/pain and joint swelling compared to placebo. VIOXX 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 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 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 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 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
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 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 occurred
within 45 minutes. In a multiple-dose study of post-orthopedic
surgical pain in which patients received VIOXX or placebo for up to
5 days, 50 mg of VIOXX once daily was effective in reducing pain. In
this study, patients on VIOXX 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 and placebo, respectively).
Migraine with or without aura
The efficacy of VIOXX 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 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 at all doses compared to
those who received placebo (Table 1). There were no statistically
significant differences between the 25- and the 50-mg dose groups in
either trial.
There was a decreased incidence of migraine-associated phonophobia
VIOXX 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.
VIOXX 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 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. VIOXX GI Clinical Outcomes Research
(VIGOR Study)
Study Design
The VIGOR study was designed to evaluate the comparative GI safety
of VIOXX 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 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 compared to naproxen (see Table 2).
The risk reduction for PUBs and complicated PUBs for VIOXX 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 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 50
mg once daily as compared to patients treated with naproxen 500 mg
twice daily (see Table 3). This finding was largely due to a
difference in the incidence of myocardial infarction between the
groups. (See Table 4.) (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.
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 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 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 ³65
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 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.
In a similarly designed 12-week endoscopy study in RA patients
treated with VIOXX 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 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 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 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 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 25 mg daily, VIOXX 50
mg daily, ibuprofen 2400 mg per day, and placebo was evaluated in a
study utilizing 51 Cr-tagged red blood cells in 67 healthy males.
After 4 weeks of treatment with VIOXX 25 mg daily or VIOXX 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-treated subjects. The clinical
relevance of this finding is unknown.
Platelets Multiple doses of VIOXX 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.
Because of its lack of platelet effects, VIOXX
is not a substitute for aspirin for cardiovascular
prophylaxis. (See PRECAUTIONS, Cardiovascular Effects.)
INDICATIONS AND USAGE
VIOXX is indicated:
-
For relief of the signs and symptoms of
osteoarthritis.
-
For relief of the signs and symptoms of
rheumatoid arthritis in adults.
-
For the management of acute pain in adults.
-
For the treatment of primary dysmenorrhea.
-
For the acute treatment of migraine attacks
with or without aura in adults.
-
The safety and effectiveness of VIOXX have not
been established for cluster headache, which is present in an
older, predominantly male, population.
CONTRAINDICATIONS
VIOXX is contraindicated in patients with known
hypersensitivity to rofecoxib or any other component of VIOXX.
VIOXX should not be given to patients who have experienced
asthma, urticaria, or allergic-type reactions after taking
aspirin or other NSAIDs. Severe, rarely fatal,
anaphylactic-like reactions to NSAIDs have been reported in
such patients (see WARNINGS, Anaphylactoid Reactions and
PRECAUTIONS, Preexisting Asthma).
WARNINGS
Gastrointestinal (GI) Effects - Risk of GI Ulceration,
Bleeding, and Perforation
Serious gastrointestinal toxicity such as bleeding,
ulceration, and perforation of the stomach, small intestine or
large intestine, can occur at any time, with or without
warning symptoms, in patients treated with nonsteroidal
anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal
problems, such as dyspepsia, are common and may also occur at
any time during NSAID therapy. Therefore, physicians and
patients should remain alert for ulceration and bleeding, even
in the absence of previous GI tract symptoms. Patients should
be informed about the signs and/or symptoms of serious GI
toxicity and the steps to take if they occur.
The utility of periodic laboratory monitoring
has not been demonstrated, nor has it been adequately
assessed. Only one in five patients who develop a serious
upper GI adverse event on NSAID therapy is symptomatic. It has
been demonstrated that upper GI ulcers, gross bleeding or
perforation, caused by NSAIDs, appear to occur in
approximately 1% of patients treated for 3-6 months, and in
about 2-4% of patients treated for one year. These trends
continue thus, increasing the likelihood of developing a
serious GI event at some time during the course of therapy.
However, even short-term therapy is not without risk.
Although the risk of GI toxicity is not completely eliminated
with VIOXX, the results of the VIOXX GI outcomes research
(VIGOR) study demonstrate that in patients treated with VIOXX,
the risk of GI toxicity with VIOXX 50 mg once daily is
significantly less than with naproxen 500 mg twice daily. (See
CLINICAL STUDIES, Special Studies, VIGOR.)
NSAIDs should be prescribed with extreme caution in patients
with a prior history of ulcer disease or gastrointestinal
bleeding. Most spontaneous reports of fatal GI events are in
elderly or debilitated patients and therefore special care
should be taken in treating this population. To minimize the
potential risk for an adverse GI event, the lowest effective
dose should be used for the shortest possible duration.
For high risk patients, alternate therapies that do not
involve NSAIDs should be considered. Previous studies have
shown that patients with a prior history of peptic ulcer
disease and/or gastrointestinal bleeding and who use NSAIDs,
have a greater than 10-fold higher risk for developing a GI
bleed than patients with neither of these risk factors. In
addition to a past history of ulcer disease,
pharmacoepidemiological studies have identified several other
co-therapies or co-morbid conditions that may increase the
risk for GI bleeding such as: treatment with oral
corticosteroids, treatment with anticoagulants, longer
duration of NSAID therapy, smoking, alcoholism, older age, and
poor general health status.
Anaphylactoid Reactions
As with NSAIDs in general, anaphylactoid reactions have
occurred in patients without known prior exposure to VIOXX. In
post-marketing experience, rare cases of anaphylactic/anaphylactoid
reactions and angioedema have been reported in patients
receiving VIOXX. VIOXX should not be given to patients with
the aspirin triad. This symptom complex typically occurs in
asthmatic patients who experience rhinitis with or without
nasal polyps, or who exhibit severe, potentially fatal
bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma).
Emergency help should be sought in cases where an
anaphylactoid reaction occurs.
Advanced Renal Disease
Treatment with VIOXX is not recommended in patients with
advanced renal disease. If VIOXX therapy must be initiated,
close monitoring of the patient's kidney function is advisable
(see PRECAUTIONS, Renal Effects).
Pregnancy
In late pregnancy VIOXX should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
VIOXX cannot be expected to substitute for corticosteroids or
to treat corticosteroid insufficiency. Abrupt discontinuation
of corticosteroids may lead to exacerbation of
corticosteroid-responsive illness. Patients on prolonged
corticosteroid therapy should have their therapy tapered
slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of VIOXX in reducing
inflammation, and possibly fever, may diminish the utility of
these diagnostic signs in detecting infectious complications
of presumed noninfectious, painful conditions.
Cardiovascular Effects
The information below should be taken into consideration and
caution should be exercised when VIOXX is used in patients
with a medical history of ischemic heart disease.
In VIGOR, a study in 8076 patients (mean age
58; VIOXX n=4047, naproxen n=4029) with a median duration of
exposure of 9 months, the risk of developing a serious
cardiovascular thrombotic event was significantly higher in
patients treated with VIOXX 50 mg once daily (n=45) as
compared to patients treated with naproxen 500 mg twice daily
(n=19). In VIGOR, mortality due to cardiovascular thrombotic
events (7 vs 6, VIOXX vs naproxen, respectively) was similar
between the treatment groups. (See CLINICAL STUDIES, Special
Studies, VIGOR, Other Safety Findings: Cardiovascular Safety.)
In a placebo-controlled database derived from 2 studies with a
total of 2142 elderly patients (mean age 75; VIOXX n=1067,
placebo n=1075) with a median duration of exposure of
approximately 14 months, the number of patients with serious
cardiovascular thrombotic events was 21 vs 35 for patients
treated with VIOXX 25 mg once daily versus placebo,
respectively. In these same 2 placebo-controlled studies,
mortality due to cardiovascular thrombotic events was 8 vs 3
for VIOXX versus placebo, respectively. The significance of
the cardiovascular findings from these 3 studies (VIGOR and 2
placebo-controlled studies) is unknown.
Prospective studies specifically designed to
compare the incidence of serious CV events in patients taking
VIOXX versus NSAID comparators or placebo have not been
performed. Because of its lack of platelet effects, VIOXX is
not a substitute for aspirin for cardiovascular prophylaxis.
Therefore, in patients taking VIOXX, antiplatelet therapies
should not be discontinued and should be considered in
patients with an indication for cardiovascular prophylaxis.
(See CLINICAL STUDIES, Special Studies, Platelets;
PRECAUTIONS, Drug Interactions, Aspirin.) Prospective,
long-term studies on concomitant administration of VIOXX and
aspirin evaluating cardiovascular outcomes have not been
conducted.
Fluid Retention, Edema, and Hypertension
Fluid retention, edema, and hypertension have been reported in
some patients taking VIOXX. In clinical trials of VIOXX at
daily doses of 25 mg in patients with rheumatoid arthritis the
incidence of hypertension was twice as high in patients
treated with VIOXX as compared to patients treated with
naproxen 1000 mg daily. Clinical trials with VIOXX at daily
doses of 12.5 and 25 mg in patients with osteoarthritis have
shown effects on hypertension and edema similar to those
observed with comparator NSAIDs; these occurred with an
increased frequency with chronic use of VIOXX at daily doses
of 50 mg. (See ADVERSE REACTIONS.) VIOXX should be used with
caution, and should be introduced at the lowest recommended
dose in patients with fluid retention, hypertension, or heart
failure.
Renal Effects
Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury. Renal toxicity has
also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In
these patients, administration of a nonsteroidal
anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow,
which may precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal
function, heart failure, liver dysfunction, those taking
diuretics and ACE inhibitors, and the
elderly. Discontinuation of NSAID therapy is usually followed
by recovery to the pretreatment state.
Caution should be used when initiating treatment with VIOXX in
patients with considerable dehydration. It is advisable to
rehydrate patients first and then start therapy with VIOXX.
Caution is also recommended in patients with pre-existing
kidney disease (see WARNINGS, Advanced Renal Disease).
Hepatic Effects
Borderline elevations of one or more liver tests may occur in
up to 15% of patients taking NSAIDs, and notable elevations of
ALT or AST (approximately three or more times the upper limit
of normal) have been reported in approximately 1% of patients
in clinical trials with NSAIDs. These laboratory abnormalities
may progress, may remain unchanged, or may be transient with
continuing therapy.
Rare cases of severe hepatic reactions,
including jaundice and fatal fulminant hepatitis, liver
necrosis and hepatic failure (some with fatal outcome) have
been reported with NSAIDs, including VIOXX. In controlled
clinical trials of VIOXX, the incidence of borderline
elevations of liver tests at doses of 12.5 and 25 mg daily was
comparable to the incidence observed with ibuprofen and lower
than that observed with diclofenac. In placebo-controlled
trials, approximately 0.5% of patients taking rofecoxib (12.5
or 25 mg QD) and 0.1% of patients taking placebo had notable
elevations of ALT or AST.
A patient with symptoms and/or signs suggesting liver
dysfunction, or in whom an abnormal liver test has occurred,
should be monitored carefully for evidence of the development
of a more severe hepatic reaction while on therapy with VIOXX.
The maximum recommended chronic daily dose in patients with
moderate hepatic insufficiency is 12.5 mg daily. Use of VIOXX
is not recommended in patients with severe hepatic
insufficiency (see CLINICAL PHARMACOLOGY, Special Populations
and DOSAGE AND ADMINISTRATION, Hepatic Insufficiency). If
clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g.,
eosinophilia, rash, etc.), VIOXX should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving VIOXX. In
placebo-controlled trials, there were no significant
differences observed between VIOXX and placebo in clinical
reports of anemia. Patients on long-term treatment with VIOXX
should have their hemoglobin or hematocrit checked if they
exhibit any signs or symptoms of anemia or blood loss. VIOXX
does not generally affect platelet counts, prothrombin time
(PT), or partial thromboplastin time (PTT), and does not
inhibit platelet aggregation at indicated dosages (see
CLINICAL STUDIES, Special Studies, Platelets).
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The
use of aspirin in patients with aspirin-sensitive asthma has
been associated with severe bronchospasm which can be fatal.
Since cross reactivity, including bronchospasm, between
aspirin and other nonsteroidal anti-inflammatory drugs has
been reported in such aspirin-sensitive patients, VIOXX should
not be administered to patients with this form of aspirin
sensitivity and should be used with caution in patients with
preexisting asthma.
Information for Patients
Physicians should instruct their patients to read the patient
package insert before starting therapy with VIOXX and to
reread it each time the prescription is renewed in case any
information has changed. VIOXX can cause discomfort and,
rarely, more serious side effects, such as gastrointestinal
bleeding, which may result in hospitalization and even fatal
outcomes. Although serious GI tract ulcerations and bleeding
can occur without warning symptoms, patients should be alert
for the signs and symptoms of ulcerations and bleeding, and
should ask for medical advice when observing any indicative
signs or symptoms. Patients should be apprised of the
importance of this follow-up.
For additional gastrointestinal safety
information see CLINICAL STUDIES, Special Studies, VIGOR and
WARNINGS, Gastrointestinal (GI) Effects - Risk of GI
Ulceration, Bleeding and Perforation. Patients should be
informed that VIOXX is not a substitute for aspirin for
cardiovascular prophylaxis because of its lack of effect on
platelets. For additional cardiovascular safety information
see CLINICAL STUDIES, Special Studies, VIGOR and PRECAUTIONS,
Cardiovascular Effects.
Patients should promptly report signs or
symptoms of gastrointestinal ulceration or bleeding, skin
rash, unexplained weight gain, edema or chest pain to their
physicians. Patients should be informed of the warning signs
and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, pruritus, jaundice, right upper quadrant tenderness,
and "flu-like" symptoms). If these occur, patients should be
instructed to stop therapy and seek immediate medical therapy.
Patients should also be instructed to seek immediate emergency
help in the case of an anaphylactoid reaction (see WARNINGS).
In late pregnancy VIOXX should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur
without warning symptoms, physicians should monitor for signs
or symptoms of GI bleeding.
Drug Interactions
ACE inhibitors: Reports suggest that NSAIDs may diminish the
antihypertensive effect of Angiotensin Converting Enzyme (ACE)
inhibitors. In patients with mild to moderate hypertension,
administration of 25 mg daily of VIOXX with the ACE inhibitor
benazepril, 10 to 40 mg for 4 weeks, was associated with an
average increase in mean arterial pressure of about 3 mm Hg
compared to ACE inhibitor alone. This interaction should be
given consideration in patients taking VIOXX concomitantly
with ACE inhibitors.
Aspirin: Concomitant administration of low-dose aspirin
with VIOXX may result in an increased rate of GI ulceration or
other complications, compared to use of VIOXX alone. In a
12-week endoscopy study conducted in OA patients there was no
difference in the cumulative incidence of endoscopic
gastroduodenal ulcers in patients taking low-dose (81 mg)
enteric coated aspirin plus VIOXX 25 mg daily, as compared to
those taking ibuprofen 2400 mg daily alone. Patients taking
low-dose aspirin plus ibuprofen were not studied. (See
CLINICAL STUDIES, Special Studies, Upper Endoscopy in Patients
with Osteoarthritis and Rheumatoid Arthritis.)
At steady state, VIOXX 50 mg once daily had no effect on the
anti-platelet activity of low-dose (81 mg once daily) aspirin,
as assessed by ex vivo platelet aggregation and serum TXB2
generation in clotting blood. Because of its lack of platelet
effects, VIOXX is not a substitute for aspirin for
cardiovascular prophylaxis. Therefore, in patients taking
VIOXX, antiplatelet therapies should not be discontinued and
should be considered in patients with an indication for
cardiovascular prophylaxis. (See CLINICAL STUDIES, Special
Studies, Platelets and PRECAUTIONS, Cardiovascular Effects.)
Prospective, long-term studies on concomitant administration
of VIOXX and aspirin have not been conducted.
Cimetidine: Co-administration with high doses of
cimetidine [800 mg twice daily] increased the C max of
rofecoxib by 21%, the AUC 0-120hr by 23% and the t 1/2 by 15%.
These small changes are not clinically significant and no dose
adjustment is necessary.
Digoxin: Rofecoxib 75 mg once daily for 11 days does
not alter the plasma concentration profile or renal
elimination of digoxin after a single 0.5 mg oral dose.
Furosemide: Clinical studies, as well as post-marketing
observations, have shown that NSAIDs can reduce the
natriuretic effect of furosemide and thiazides in some
patients. This response has been attributed to inhibition of
renal prostaglandin synthesis.
Ketoconazole: Ketoconazole 400 mg daily did not have
any clinically important effect on the pharmacokinetics of
rofecoxib.
Lithium: NSAIDs have produced an elevation of plasma
lithium levels and a reduction in renal lithium clearance. In
post-marketing experience there have been reports of increases
in plasma lithium levels. Thus, when VIOXX and lithium are
administered concurrently, subjects should be observed
carefully for signs of lithium toxicity.
Methotrexate: VIOXX 12.5, 25, and 50 mg, each dose
administered once daily for 7 days, had no effect on the
plasma concentration of methotrexate as measured by AUC 0-24hr
in patients receiving single weekly methotrexate doses of 7.5
to 20 mg for rheumatoid arthritis. At higher than recommended
doses, VIOXX 75 mg administered once daily for 10 days
increased plasma concentrations by 23% as measured by AUC
0-24hr in patients receiving methotrexate 7.5 to 15 mg/week
for rheumatoid arthritis. At 24 hours postdose, a similar
proportion of patients treated with methotrexate alone (94%)
and subsequently treated with methotrexate co-administered
with 75 mg of rofecoxib (88%) had methotrexate plasma
concentrations below the measurable limit (5 ng/mL). Standard
monitoring of methotrexate-related toxicity should be
continued if VIOXX and methotrexate are administered
concomitantly.
Oral Contraceptives: Rofecoxib did not
have any clinically important effect on the pharmacokinetics
of ethinyl estradiol and norethindrone.
Prednisone/prednisolone: Rofecoxib did not have any
clinically important effect on the pharmacokinetics of
prednisolone or prednisone.
Rifampin: Co-administration of VIOXX with rifampin 600
mg daily, a potent inducer of hepatic metabolism, produced an
approximate 50% decrease in rofecoxib plasma concentrations.
Therefore, a starting daily dose of 25 mg of VIOXX should be
considered for the treatment of osteoarthritis when VIOXX is
co-administered with potent inducers of hepatic metabolism.
Theophylline: VIOXX 12.5, 25, and 50 mg administered
once daily for 7 days increased plasma theophylline
concentrations (AUC (0-¥) ) by 38 to 60% in healthy subjects
administered a single 300-mg dose of theophylline. Adequate
monitoring of theophylline plasma concentrations should be
considered when therapy with VIOXX is initiated or changed in
patients receiving theophylline. These data suggest that
rofecoxib may produce a modest inhibition of cytochrome P450 (CYP)
1A2. Therefore, there is a potential for an interaction with
other drugs that are metabolized by CYP 1A2 (e.g.,
amitriptyline, tacrine, and zileuton).
Warfarin: Anticoagulant activity should be monitored,
particularly in the first few days after initiating or
changing VIOXX therapy in patients receiving warfarin or
similar agents, since these patients are at an increased risk
of bleeding complications. In single and multiple dose studies
in healthy subjects receiving both warfarin and rofecoxib,
prothrombin time (measured as INR) was increased by
approximately 8% to 11%. In post-marketing experience,
bleeding events have been reported, predominantly in the
elderly, in association with increases in prothrombin time in
patients receiving VIOXX concurrently with warfarin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Rofecoxib was not carcinogenic in mice given oral doses up to
30 mg/kg (male) and 60 mg/kg (female) (approximately 5- and
2-fold the human exposure at 25 and 50 mg daily based on AUC
0-24 ) and in male and female rats given oral doses up to 8
mg/kg (approximately 6- and 2-fold the human exposure at 25
and 50 mg daily based on AUC 0-24 ) for two years.
Rofecoxib
was not mutagenic in an Ames test or in a V-79 mammalian cell
mutagenesis assay, nor clastogenic in a chromosome aberration
assay in Chinese hamster ovary (CHO) cells, in an in vitro and
an in vivo alkaline elution assay, or in an in vivo
chromosomal aberration test in mouse bone marrow.
Rofecoxib
did not impair male fertility in rats at oral doses up to 100
mg/kg (approximately 20- and 7-fold human exposure at 25 and
50 mg daily based on the AUC 0-24 ) and rofecoxib had no
effect on fertility in female rats at doses up to 30 mg/kg
(approximately 19- and 7-fold human exposure at 25 and 50 mg
daily based on AUC 0-24 ).
Pregnancy
Teratogenic effects: Pregnancy Category C. Rofecoxib
was not teratogenic in rats at doses up to 50 mg/kg/day
(approximately 28- and 10-fold human exposure at 25 and 50 mg
daily based on AUC 0-24 ). There was a slight,
non-statistically significant increase in the overall
incidence of vertebral malformations only in the rabbit at
doses of 50 mg/kg/day (approximately 1- or <1-fold human
exposure at 25 and 50 mg daily based on AUC 0-24 ). There are
no studies in pregnant women. VIOXX should be used during
pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Nonteratogenic effects: Rofecoxib produced peri-implantation
and post-implantation losses and reduced embryo/fetal survival
in rats and rabbits at oral doses ³10 and ³75 mg/kg/day,
respectively (approximately 9- and 3-fold [rats] and 2- and
<1-fold [rabbits] human exposure based on the AUC 0-24 at 25
and 50 mg daily). These changes are expected with inhibition
of prostaglandin synthesis and are not the result of permanent
alteration of female reproductive function. There was an
increase in the incidence of postnatal pup mortality in rats
at ³5 mg/kg/day (approximately 5- and 2-fold human exposure at
25 and 50 mg daily based on AUC 0-24 ).
In studies in pregnant rats administered single
doses of rofecoxib, there was a treatment-related decrease in
the diameter of the ductus arteriosus at all doses used (3-300
mg/kg: 3 mg/kg is approximately 2- and <1-fold human exposure
at 25 or 50 mg daily based on AUC 0-24 ). As with other drugs
known to inhibit prostaglandin synthesis, use of VIOXX during
the third trimester of pregnancy should be avoided.
Labor and delivery
Rofecoxib produced no evidence of significantly delayed labor
or parturition in females at doses 15 mg/kg in rats
(approximately 10- and 3-fold human exposure as measured by
the AUC 0-24 at 25 and 50 mg). The effects of VIOXX on labor
and delivery in pregnant women are unknown. Merck & Co., Inc.
maintains a registry to monitor the pregnancy outcomes of
women exposed to VIOXX while pregnant. Healthcare providers
are encouraged to report any prenatal exposure to VIOXX by
calling the Pregnancy Registry at (800) 986-8999.
Nursing mothers
Rofecoxib is excreted in the milk of lactating rats at
concentrations similar to those in plasma. There was an
increase in pup mortality and a decrease in pup body weight
following exposure of pups to milk from dams administered
VIOXX during lactation. The dose tested represents an
approximate 18- and 6-fold human exposure at 25 and 50 mg
based on AUC 0-24 . It is not known whether this drug is
excreted in human milk. Because many drugs are excreted in
human milk and because of the potential for serious adverse
reactions in nursing infants from VIOXX, a decision should be
made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the
mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age
of 18 years have not been evaluated.
Geriatric Use
Of the patients who received VIOXX in osteoarthritis clinical
trials, 1455 were 65 years of age or older. This included 460
patients who were 75 years or older, and in one of these
studies, 174 patients who were 80 years or older. No
substantial differences in safety and effectiveness were
observed between these subjects and younger subjects. Greater
sensitivity of some older individuals cannot be ruled out. As
with other NSAIDs, including those that selectively inhibit
COX-2, there have been more spontaneous post-marketing reports
of fatal GI events and acute renal failure in the elderly than
in younger patients. Dosage adjustment in the elderly is not
necessary; however, therapy with VIOXX should be initiated at
the lowest
recommended dose.
ADVERSE REACTIONS
Osteoarthritis: Approximately 3600
patients with osteoarthritis were treated with VIOXX;
approximately 1400 patients received VIOXX for 6months or
longer and approximately 800 patients for one year or longer.
The following table of adverse experiences lists all adverse
events, regardless of causality, occurring in at least 2% of
patients receiving VIOXX in nine controlled studies of 6-week
to 6-month duration conducted in patients with OA at the
therapeutically recommended doses (12.5 and 25 mg), which
included a placebo and/or positive control group.
In the OA studies, the following spontaneous
adverse events occurred in >0.1% to 1.9% of patients treated
with VIOXX regardless of causality.
Body as a Whole: abdominal distension, abdominal
tenderness, abscess, chest pain, chills, contusion, cyst,
diaphragmatic hernia, fever, fluid retention, flushing, fungal
infection, infection, laceration, pain, pelvic pain,
peripheral edema, postoperative pain, syncope, trauma, upper
extremity edema, viral syndrome.
Cardiovascular System: angina pectoris, atrial
fibrillation, bradycardia, hematoma, irregular heartbeat,
palpitation, premature ventricular contraction, tachycardia,
venous insufficiency.
Digestive System: acid reflux, aphthous stomatitis,
constipation, dental caries, dental pain, digestive gas
symptoms, dry mouth, duodenal disorder, dysgeusia, esophagitis,
flatulence, gastric disorder, gastritis, gastroenteritis,
hematochezia, hemorrhoids, infectious gastroenteritis, oral
infection, oral lesion, oral ulcer,
vomiting.
Eyes, Ears, Nose, and Throat: allergic rhinitis,
blurred vision, cerumen impaction, conjunctivitis, dry throat,
epistaxis, laryngitis, nasal congestion, nasal secretion,
ophthalmic injection, otic pain, otitis, otitis media,
pharyngitis, tinnitus, tonsillitis.
Immune System: allergy, hypersensitivity, insect bite
reaction.
Metabolism and Nutrition: appetite change,
hypercholesterolemia, weight gain.
Musculoskeletal System: ankle sprain, arm pain,
arthralgia, back strain, bursitis, cartilage trauma, joint
swelling, muscular cramp, muscular disorder, muscular
weakness, musculoskeletal pain, musculoskeletal stiffness,
myalgia, osteoarthritis, tendinitis, traumatic arthropathy,
wrist fracture.
Nervous System: hypesthesia, insomnia, median nerve
neuropathy, migraine, muscular spasm,
paresthesia, sciatica, somnolence, vertigo. Psychiatric:
anxiety, depression, mental acuity decreased.
Respiratory System: asthma, cough, dyspnea, pneumonia,
pulmonary congestion, respiratory infection.
Skin and Skin Appendages: abrasion, alopecia, atopic
dermatitis, basal cell carcinoma, blister, cellulitis, contact
dermatitis, herpes simplex, herpes zoster, nail unit disorder,
perspiration, pruritus, rash, skin erythema, urticaria,
xerosis.
Urogenital System: breast mass, cystitis, dysuria,
menopausal symptoms, menstrual disorder, nocturia, urinary
retention, vaginitis. The following serious adverse events
have been reported rarely (estimated <0.1%) in patients taking
VIOXX, regardless of causality. Cases reported only in the
post-marketing experience are indicated in italics.
Cardiovascular: cerebrovascular accident, congestive
heart failure, deep venous thrombosis, hypertensive crisis,
myocardial infarction, pulmonary edema, pulmonary embolism,
transient ischemic attack, unstable angina.
Gastrointestinal: cholecystitis, colitis, colonic
malignant neoplasm, duodenal perforation, duodenal ulcer,
esophageal ulcer, gastric perforation, gastric ulcer,
gastrointestinal bleeding, hepatic failure, hepatitis,
intestinal obstruction, jaundice, pancreatitis.
Hemic and lymphatic: agranulocytosis, aplastic anemia,
leukopenia, lymphoma, pancytopenia, thrombocytopenia.
Immune System: anaphylactic/anaphylactoid reaction,
angioedema, bronchospasm, hypersensitivity vasculitis.
Metabolism and nutrition: hyponatremia.
Nervous System: aseptic meningitis,
epilepsy aggravated.
Psychiatric: confusion, hallucinations.
Skin and Skin Appendages: severe skin reactions,
including Stevens-Johnson syndrome and toxic epidermal
necrolysis.
Urogenital System: acute renal failure, breast
malignant neoplasm, hyperkalemia, interstitial nephritis,
prostatic malignant neoplasm, urolithiasis, worsening chronic
renal failure. In 1-year controlled clinical trials and in
extension studies for up to 86 weeks (approximately 800
patients treated with VIOXX for one year or longer), the
adverse experience profile was qualitatively similar to that
observed in studies of shorter duration.
Rheumatoid Arthritis: Approximately 1,100 patients were treated with
VIOXX in the Phase III rheumatoid arthritis efficacy studies.
These studies included extensions of up to 1 year. The adverse
experience profile was generally similar to that reported in
the osteoarthritis studies. In studies of at least three
months, the incidence of hypertension in RA patients receiving
the 25 mg once daily dose of VIOXX was 10.0% and the incidence
of hypertension in patients receiving naproxen 500 mg twice
daily was 4.7%.
Analgesia, including primary dysmenorrhea:
Approximately one thousand patients were treated with VIOXX in
analgesia studies. All patients in post-dental surgery pain
studies received only a single dose of study medication.
Patients in primary dysmenorrhea studies may have taken up to
3 daily doses of VIOXX, and those in the post-orthopedic
surgery pain study were prescribed 5 daily doses of VIOXX.
The adverse experience profile in the analgesia studies was
generally similar to those reported in the osteoarthritis
studies. The following additional adverse experience, which
occurred at an incidence of at least 2% of patients treated
with VIOXX, was observed in the post-dental pain surgery
studies: post-dental extraction alveolitis (dry socket).
Migraine with or without aura: Approximately 750 patients were treated with a
single dose of VIOXX 25 mg or 50 mg in two single-attack
migraine studies. Approximately 460 patients in the 3-month
extension phase of one study treated up to 8 (average 3)
migraine attacks per month. In single attack studies, the
following adverse events were more frequent in the VIOXX
treatment groups (25 mg and 50 mg) compared to the placebo
group, and occurred at an incidence of at least 2% of patients
treated: dizziness, nausea, somnolence and dyspepsia.
In the 3-month extension phase of one study, the following
adverse events occurred at an incidence of at least 2% of
patients treated in the VIOXX treatment groups (25 mg and 50
mg): dizziness, dry mouth, nausea, and vomiting.
Clinical Studies in OA and RA with VIOXX 50 mg (Twice the
highest dose recommended for chronic use) In OA and RA
clinical trials which contained VIOXX 12.5 or 25 mg as well as
VIOXX 50 mg, VIOXX 50 mg QD was associated with a higher
incidence of gastrointestinal symptoms (abdominal pain,
epigastric pain, heartburn, nausea and vomiting), lower
extremity edema, hypertension, serious* adverse experiences
and discontinuation due to clinical adverse experiences
compared to the recommended chronic doses of 12.5 and 25 mg
(see DOSAGE AND ADMINISTRATION).
OVERDOSAGE
No overdoses of VIOXX were reported during clinical trials.
Administration of single doses of VIOXX 1000 mg to 6 healthy
volunteers and multiple doses of 250 mg/day for 14 days to 75
healthy volunteers did not result in serious toxicity.
In the event of overdose, it is reasonable to employ the usual
supportive measures, e.g., remove unabsorbed material from the
gastrointestinal tract, employ clinical monitoring, and
institute supportive therapy, if required.
Rofecoxib is not removed by hemodialysis; it is not known
whether rofecoxib is removed by peritoneal dialysis.
DOSAGE AND ADMINISTRATION
VIOXX is administered orally. The lowest dose of VIOXX should
be sought for each patient.
Osteoarthritis
The recommended starting dose of VIOXX is 12.5
mg once daily. Some patients may receive additional benefit by
increasing the dose to 25 mg once daily. The maximum
recommended daily dose is 25 mg.
Rheumatoid Arthritis
The recommended dose is 25 mg once daily. The maximum
recommended daily dose is 25 mg.
Management of Acute Pain and Treatment of Primary Dysmenorrhea
The recommended dose of VIOXX is 50 mg once daily. The maximum
recommended daily dose is 50 mg. Use of VIOXX for more than 5
days in management of pain has not been studied. Chronic use
of VIOXX 50 mg daily is not recommended. (See ADVERSE
REACTIONS, Clinical Studies in OA and RA with VIOXX 50 mg).
Acute Treatment of Migraine Attacks with or without aura
The recommended starting dose of VIOXX is 25 mg once daily.
Some patients may receive additional benefit with 50 mg as
compared to 25 mg. The maximum recommended daily dose is 50
mg. The safety of treating more than 5 migraine attacks in any
given month has not been established. Chronic daily use of
VIOXX for the acute treatment of migraine is not recommended.
Hepatic Insufficiency
Because of significant increases in both AUC and C max in
patients with moderate hepatic impairment (Child-Pugh score:
7-9), the maximum recommended chronic daily dose is 12.5 mg.
(See CLINICAL PHARMACOLOGY, Special Populations). The efficacy
of 12.5 mg in rheumatoid arthritis patients with moderate
hepatic insufficiency has not been studied.
VIOXX Tablets may be taken with or without food.
Oral Suspension
VIOXX Oral Suspension 12.5 mg/5 mL or 25 mg/5 mL may be
substituted for VIOXX Tablets 12.5 or 25 mg, respectively, in
any of the above indications. Shake before using.
HOW SUPPLIED
Tablets VIOXX, 12.5 mg, are cream/off-white, round, shallow
cup tablets engraved MRK 74 on one side and VIOXX on the
other.
Tablets VIOXX, 25 mg, are yellow, round tablets engraved MRK
110 on one side and VIOXX on the other.
Tablets VIOXX, 50 mg, are orange, round tablets engraved MRK
114 on one side and VIOXX on the other.
Oral Suspension VIOXX, 12.5 mg/5 mL, is an opaque, white to
faint yellow suspension with a strawberry flavor that is
easily resuspended upon shaking.
Oral Suspension VIOXX, 25 mg/5 mL, is an opaque, white to
faint yellow suspension with a strawberry flavor that is
easily resuspended upon shaking.
Storage
VIOXX Tablets: Store at 25°C (77°F), excursions permitted to
15-30°C (59-86°F).
VIOXX Oral Suspension: Store at 25°C (77°F), excursions
permitted to 15-30°C (59-86°F).
