VIOXX
Vioxx is a non-steroidal anti-inflammatory drug (NSAID) that is used in the treatment of generalized pain, As well as the treatment of inflammation and stiffness of arthritis. It can be used to treat menstrual cramps, too.
There’s So Much More to Life Than Osteoarthritis
Pain
If osteoarthritis pain keeps you from the activities you enjoy most, there are
things you can do about it. This site is designed to help you learn about
managing your pain—and to tell you about VIOXX, a prescription medicine that can
provide relief for osteoarthritis, the most common type of arthritis.
Spend a few minutes looking through the information provided, then discuss it
with your doctor. Information about your osteoarthritis, combined with a
medicine like VIOXX, can help make it easier to do the things you want to do.
VIOXX Can Provide 24-Hour Relief of Osteoarthritis Pain to Help You Enjoy
Everyday Things Again
Managing pain isn’t about being able to climb Mount Everest or run a marathon.
It’s about controlling the pain that keeps you from doing simple things, like
taking a walk or bending down to build sand castles with your child.
VIOXX can help you do the things you enjoy, with all-day, all-night relief. One
little tablet, taken just once a day, can provide 24-hour relief from
osteoarthritis pain. And VIOXX can be taken with or without food, so you don’t
have to worry about scheduling it around meals.
In rare cases, serious stomach problems, such as bleeding, can occur without
warning. People with allergic reactions, such as asthma, to aspirin or other
arthritis medicines should not take VIOXX.
One Pill for 24-Hour Relief
In clinical studies lasting up to 21 months, osteoarthritis patients taking 1
small tablet of VIOXX reported a significant reduction in arthritis pain.
Once-daily VIOXX continued to provide relief from pain for the length of the
studies.
So VIOXX can help make it easier for you to do the things you want to do—like
sitting down on the grass to watch your kid’s soccer game—with all-day and
all-night relief.
Why let pain force you to put the things you enjoy most on hold? One tablet of
VIOXX, once a day, can provide 24-hour relief of osteoarthritis symptoms to help
you do the things you enjoy.
IMPORTANT INFORMATION ABOUT VIOXX
Tell your doctor if you have liver or kidney disease, or a history of angina,
heart attack, or a blocked artery in your heart. VIOXX cannot take the place of
aspirin for prevention of heart attack or stroke. VIOXX should not be used by
women in late pregnancy.
Brand Name(s): Vioxx
Generic Name Rofecoxib
Phonetic: roe fa cox' ib
Who is this for?
Rofecoxib is used to relieve the pain and inflammation caused by osteoarthritis.
It is also used to relieve minor pain, headache, and menstrual pain and
discomfort.
When should I be careful taking it?
Before taking rofecoxib,
tell your doctor and pharmacist if you are allergic to rofecoxib, aspirin or
other medications for pain or arthritis, or any other drugs.
tell your doctor and pharmacist what prescription and nonprescription
medications you are taking, especially anticoagulants (''blood thinners'') such
as warfarin (Coumadin), aspirin, benazepril (Lotensin), captopril (Capoten),
cimetidine (Tagamet), diuretics (''water pills''), enalapril (Vasotec),
fosinopril (Monopril), lisinopril (Zestril, Prinivil), lithium (Eskalith,
Lithobid), methotrexate, moexipril (Univasc), quinapril (Accupril), ramipril (Altace),
rifampin (Rifadin, Rimactane), trandolapril (Mavik), any medications for high
blood pressure, and vitamins.
tell your doctor if you have or have ever had liver, heart, or kidney disease;
high blood pressure; asthma; or an ulcer or any stomach problems or diseases.
tell your doctor if you are pregnant, plan to become pregnant, or are
breast-feeding. If you become pregnant while taking rofecoxib, call your doctor.
if you are having surgery, including dental surgery, tell the doctor or dentist
that you are taking rofecoxib.
What side effects should I watch for?
Although side effects from rofecoxib are not common, they can occur. Tell your
doctor if any of these symptoms are severe or do not go away:
upset stomach
dizziness
heartburn
vomiting
constipation
If you experience any of the following symptoms, call your doctor immediately:
bloody vomit
bloody diarrhea or black, tarry stools
swelling of the face, hands, feet, ankles, or lower legs
unexplained weight gain
fatigue, unusual tiredness
yellowing of the skin or eyes
right upper abdominal pain
flu-like symptoms
skin rash
itching
How should I take it?
Rofecoxib comes as a tablet and liquid to take by mouth. It is usually taken
once a day. Follow the directions on the prescription label carefully, and ask
your doctor or pharmacist to explain any part you do not understand. Take
rofecoxib exactly as directed. Do not take more or less of it or take it more
often than prescribed by your doctor.
What happens if I miss a dose?
Take the missed dose as soon as you remember it. However, if it is almost time
for the next dose, skip the missed dose and continue your regular dosing
schedule. Do not take a double dose to make up for a missed one.
Where should I keep it?
Keep this medication in the container it came in, tightly closed, and out of
reach of children. Store it at room temperature and away from excess heat and
moisture (not in the bathroom). Throw away any medication that is outdated or no
longer needed. Talk to your pharmacist about the proper disposal of your
medication.
Vioxx
Patient Monograph
CATEGORIES: Arthritis, osteoarthritis; Arthritis, rheumatoid;
Dysmenorrhea; Pain, moderate to severe; FDA Approved 1999 May; Pregnancy
Category C
Drug Classes: Analgesics, non-narcotic; COX-2 inhibitors; Nonsteroidal
anti-inflammatory drugs
BRAND NAMES: Vioxx
FOREIGN BRAND AVAILABILITY:
Dolib (India)
Flanax (Colombia)
Rofetab (India)
Sivoz (Colombia)
COST OF THERAPY:
$75.75 (Osteoarthritis; Vioxx; 12.5 mg; 1 tablet/day; 30 day supply)
DESCRIPTION
Note: The trade name has been used throughout this monograph for clarity.
Vioxx (rofecoxib) is described chemically as
4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
Rofecoxib is a white to off-white to light yellow powder. It is sparingly
soluble in acetone, slightly soluble in methanol and isopropyl acetate, very
slightly soluble in ethanol, practically insoluble in octanol, and insoluble in
water. The empirical formula for rofecoxib is C17H14O4S, and the molecular
weight is 314.36.
Each tablet of Vioxx for oral administration contains either 12.5, 25, or 50 mg
of rofecoxib and the following inactive ingredients: croscarmellose sodium,
hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline
cellulose, and yellow ferric oxide. The 50 mg tablets also contain red ferric
oxide.
Each 5 ml of the oral suspension contains either 12.5 or 25 mg of rofecoxib and
the following inactive ingredients: citric acid (monohydrate), sodium citrate (dihydrate),
sorbitol solution, strawberry flavor, xanthan gum, and purified water. Added as
preservatives are sodium methylparaben 0.13% and sodium propylparaben 0.02%.
CLINICAL PHARMACOLOGY
Mechanism of Action
Vioxx is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits
anti-inflammatory, analgesic, and antipyretic activities in animal models. The
mechanism of action of Vioxx is believed to be due to inhibition of
prostaglandin synthesis, via inhibition of cyclooxygenase-2 (COX-2). At
therapeutic concentrations in humans, Vioxx does not inhibit the
cyclooxygenase-1 (COX-1) isoenzyme.
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 (Cmax) following a single 25 mg dose were 3286 (±843) ng·h/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 2-3 hours.
Individual Tmax values in these studies ranged between 2-9 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 AUC(0-24h) and Cmax at steady state after multiple doses of 25 mg rofecoxib
was 4018 (±1140) ng·h/ml and 321 (±104) ng/ml, respectively. The accumulation
factor based on geometric means was 1.67.
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 (Cmax) or
extent of absorption (AUC) of rofecoxib when Vioxx tablets were taken with a
high fat meal. The time to peak plasma concentration (Tmax), however, was
delayed by 1-2 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 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 µg/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 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 Cmax: 53%) relative to
healthy subjects. 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 4 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 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 6-86 weeks
duration that enrolled approximately 3900 patients. In patients with OA,
treatment with Vioxx 12.5 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
1 week in one study, after 2 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 2000 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 vs 2.5 doses per day of additional analgesic
medication for Vioxx and placebo, respectively).
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 (56%) 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 1).
TABLE 1 VIGOR-Summary of Patients With Gastrointestinal Safety Events† —
Comparison to Naproxen
GI Safety Endpoints
PUBs Complicated PUBs
Vioxx, 50 mg daily (n=4047) 56 (1.80‡) 16 (0.52)
Naproxen 1000 mg daily (n=4029) 121 (3.87) 37 (1.22)
Relative risk of Vioxx compared to naproxen§ 0.46* 0.43*
95% CI§ (0.33, 0.64) (0.24, 0.78)
* p-value £0.005 for relative risk compared to naproxen.
† As confirmed by an independent committee blinded to treatment.
‡ Kaplan-Meier cumulative rate at end of study when at least 500 patients
remained (approx. 10½ months).
§ Based on Cox proportional hazard model.
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 10½ 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 2). This finding
was largely due to a difference in the incidence of myocardial infarction
between the groups. (See TABLE 3.) (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 2 VIGOR-Summary of Patients With Serious Cardiovascular Thrombotic Adverse
Events* Over Time — Comparison to Naproxen
Vioxx 50 mg Naproxen 1000 mg
(n=4047) (n=4029)
4 Months† 17 (0.46%)¤ 9 (0.23%)
8 Months‡ 29 (0.82%) 15 (0.43%)
10½ Months§ 45 (1.81%¶) 19 (0.60%)
* Confirmed by blinded adjudication committee.
† Number of patients remaining after 4 months were 3405 and 3395 for Vioxx and
naproxen respectively.
‡ Number of patients remaining after 8 months were 2806 and 2798 for Vioxx and
naproxen respectively.
§ Number 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 3 VIGOR-Serious Cardiovascular Thrombotic Adverse Events*
Vioxx 50 mg Naproxen 1000 mg
(n=4047) (n=4029)
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
* Confirmed by blinded adjudication committee.
† p-value <0.002.
‡ 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
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 (US 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 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 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.
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/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 25 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/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.
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 1 in 5 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 1 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; 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 3 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.
Use of Vioxx is not recommended in patients with severe hepatic insufficiency
(see CLINICAL PHARMACOLOGY, Special Populations). 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 the Patient
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.
Carcinogenesis, Mutagenesis, and 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(0-24h)] 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(0-24h)] for 2 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(0-24h)] 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(0-24h)].
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(0-24h)]. 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(0-24h)]. 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(0-24h) 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(0-24h)]. 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(0-24h)]. 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(0-24h) 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(0-24h). 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 postmarketing 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.
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, 10-40 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. At steady state, Vioxx 50 mg once daily had no effect on the
anti-platelet activity of low-dose (81 mg once daily) aspirin, as assessed by ex
vivo platelet aggregation and serum TXB2 generation in clotting blood. Because
of its lack of platelet effects, Vioxx is not a substitute for aspirin for
cardiovascular prophylaxis. Therefore, in patients taking Vioxx, antiplatelet
therapies should not be discontinued and should be considered in patients with
an indication for cardiovascular prophylaxis. (See CLINICAL STUDIES, Special
Studies, Platelets and PRECAUTIONS, Cardiovascular Effects.) Prospective,
long-term studies on concomitant administration of Vioxx and aspirin have not
been conducted.
Cimetidine: Co-administration with high doses of cimetidine [800 mg twice daily]
increased the Cmax of rofecoxib by 21%, the AUC(0-120h) by 23% and the T½ 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(0-24h) 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(0-24h) 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 38-60% 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 CYP1A2 (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.
ADVERSE REACTIONS
Osteoarthritis
Approximately 3600 patients with osteoarthritis were treated with Vioxx;
approximately 1400 patients received Vioxx for 6 months or longer and
approximately 800 patients for 1 year or longer. TABLE 4 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.
TABLE 4 Clinical Adverse Experiences Occurring in ³2.0% of Patients Treated With
Rofecoxib in OA Clinical Trials
Rofecoxib Ibuprofen Diclofenac
Placebo 12.5 or 25 mg daily 2400 mg daily 150 mg daily
(n=783) (n=2829) (n=847) (n=498)
Body as a Whole/Site Unspecified
Abdominal pain 4.1% 3.4% 4.6% 5.8%
Asthenia/fatigue 1.0% 2.2% 2.0% 2.6%
Dizziness 2.2% 3.0% 2.7% 3.4%
Influenza-like disease 3.1% 2.9% 1.5% 3.2%
Lower extremity edema 1.1% 3.7% 3.8% 3.4%
Upper respiratory infection 7.8% 8.5% 5.8% 8.2%
Cardiovascular System
Hypertension 1.3% 3.5% 3.0% 1.6%
Digestive System
Diarrhea 6.8% 6.5% 7.1% 10.6%
Dyspepsia 2.7% 3.5% 4.7% 4.0%
Epigastric discomfort 2.8% 3.8% 9.2% 5.4%
Heartburn 3.6% 4.2% 5.2% 4.6%
Nausea 2.9% 5.2% 7.1% 7.4%
Eyes, Ears, Nose, and Throat
Sinusitis 2.0% 2.7% 1.8% 2.4%
Musculoskeletal System
Back pain 1.9% 2.5% 1.4% 2.8%
Nervous System
Headache 7.5% 4.7% 6.1% 8.0%
Respiratory System
Bronchitis 0.8% 2.0% 1.4% 3.2%
Urogenital System
Urinary tract infection 2.7% 2.8% 2.5% 3.6%
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, 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, leukopenia, lymphoma, thrombocytopenia.
Immune System: Anaphylactic/anaphylactoid reaction, angioedema, bronchospasm,
hypersensitivity vasculitis.
Metabolism and Nutrition: Hyponatremia.
Nervous System: Aseptic meningitis.
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 1 year or longer), the
adverse experience profile was qualitatively similar to that observed in studies
of shorter duration.
Rheumatoid Arthritis
Approximately 1100 patients were treated with Vioxx in the Phase 3 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 3 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 1000 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).
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).
*Adverse experience that resulted in death, permanent or substantial disability,
hospitalization, congenital anomaly, or cancer, was immediately life
threatening, was due to an overdose, or was thought by the investigator to
require intervention to prevent one of the above outcomes.
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.)
Hepatic Insufficiency
Because of significant increases in both AUC and Cmax, patients with moderate
hepatic impairment (Child-Pugh score: 7-9) should be treated with the lowest
possible dose (see CLINICAL PHARMACOLOGY, Special Populations).
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
Vioxx Tablets
Vioxx tablets are available in:
12.5 mg: Cream/off-white, round, shallow cup tablets engraved "MRK 74" on one
side and "VIOXX" on the other.
25 mg: Yellow, round tablets engraved "MRK 110" on one side and "VIOXX" on the
other.
50 mg: Orange, round tablets engraved "MRK 114" on one side and "VIOXX" on the
other.
Storage: Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F).
Vioxx Oral Suspension
Vioxx oral suspension is available in:
12.5 mg/5 ml as an opaque, white to faint yellow suspension with a strawberry
flavor that is easily resuspended upon shaking.
25 mg/5 ml as an opaque, white to faint yellow suspension with a strawberry
flavor that is easily resuspended upon shaking.
Storage: Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F).