### VIOXX®(rofecoxib tablets and oral suspension)

**DESCRIPTION**

VIOXX[^1] (rofecoxib) is described chemically as
4-\[4-(methylsulfonyl)phenyl\]-3-phenyl-2(5*H)-*furanone. It has the
following chemical structure:

![](media/image1.wmf){width="1.6458333333333333in"
height="1.4423611111111112in"}

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
C~17~H~14~O~4~S, and the molecular weight is 314.36.

Each tablet of VIOXX for oral administration contains either 12.5 or
25 mg of rofecoxib and the following inactive ingredients:
croscarmellose sodium, hydroxypropyl cellulose, lactose, magnesium
stearate, microcrystalline cellulose, and yellow 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 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 (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) nghr/mL and 321 (104)
ng/mL, respectively. The accumulation factor based on geometric means
was 1.67.

VIOXX Tablets and VIOXX Oral Suspension are bioequivalent.

## 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 g/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 CYP3A 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 pharmacokinetic study in mild (Child-Pugh score [\<]{.underline}6)
hepatic insufficiency patients indicated that rofecoxib AUC was similar
between these patients and healthy subjects. Limited data in patients
with moderate (Child-Pugh score 7-9) hepatic insufficiency suggest a
trend towards higher AUC (about 69%) of rofecoxib in these patients, but
more data are needed to evaluate pharmacokinetics in these patients.
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 at present because no safety information is
available regarding the use of VIOXX in these patients.

# 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 rofecoxib have identified potentially
significant interactions with rifampin, methotrexate 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
antiinflammatory 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.

# 

# 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).

# 

# Special Studies

## Upper Endoscopy in Patients with Osteoarthritis:

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
*Heliobacter pylori* infection, baseline gastroduodenal erosions, prior
history of an upper gastrointestinal perforation, ulcer, or bleed (PUB),
and/or age [\>]{.underline} 65 years. However, patients receiving
aspirin (including low-dose aspirin for cardiovascular prophylaxis) were
not enrolled in these studies. Patients who were 50 years of age and
older with osteoarthritis and who had no ulcers at baseline were
evaluated by endoscopy after weeks 6, 12, and 24 of treatment. The
placebo-treatment group was discontinued at week 16 by design.

Treatment with VIOXX 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.
However, the studies cannot rule out at least some increase in the rate
of endoscopic gastroduodenal ulcers when comparing VIOXX to placebo. See
Figures 1 and 2 and accompanying Tables for the results of these
studies.

+--------------------------------------+----------------+-------------+
|                                      |                |             |
+--------------------------------------+----------------+-------------+
| **Figure 1**                         |                |             |
|                                      |                |             |
| **Comparison to Ibuprofen**          |                |             |
|                                      |                |             |
| **Life-Table Cumulative Incidence    |                |             |
| Rate of Gastroduodenal**             |                |             |
|                                      |                |             |
| **Ulcers 3mm\*\*                     |                |             |
| (Intention-to-Treat)**               |                |             |
|                                      |                |             |
| ![](media/imag                       |                |             |
| e2.png){width="2.9923611111111112in" |                |             |
| height="2.467361111111111in"}        |                |             |
|                                      |                |             |
| > † p \< 0.001 versus ibuprofen 2400 |                |             |
| > mg                                 |                |             |
| >                                    |                |             |
| > \*\* Results of analyses using a   |                |             |
| > 5mm gastroduodenal ulcer endpoint  |                |             |
| > were consistent.                   |                |             |
| >                                    |                |             |
| > \*\*\* The primary endpoint was    |                |             |
| > the cumulative incidence of        |                |             |
| > gastroduodenal ulcer at 12 weeks.  |                |             |
+--------------------------------------+----------------+-------------+

> **[TABLE 1]{.underline}**
>
> **[Endoscopic Gastroduodenal Ulcers at 12 weeks]{.underline}**
>
> **[U.S. Study]{.underline}**

+-----------+-----------------+-----------+-------+-------------------+
| **        | **Number of     | **C       | **    | **95% CI**        |
| Treatment | Patients with   | umulative | Ratio |                   |
| [Gr       | Ulcer/Total     | Incidence | of    | **on**            |
| oup]{.und | [Number of      | [Rate]{.u | Ra    |                   |
| erline}** | Patients        | nderline} | tes** | **[Ratio of       |
|           | ]{.underline}** | **[\*]{.u |       | Rat               |
|           |                 | nderline} | **vs. | es]{.underline}** |
|           |                 |           | [Pl   |                   |
|           |                 |           | acebo |                   |
|           |                 |           | ]{.un |                   |
|           |                 |           | derli |                   |
|           |                 |           | ne}** |                   |
+-----------+-----------------+-----------+-------+-------------------+
| Placebo   | 11/158          | 9.9%      |       |                   |
+-----------+-----------------+-----------+-------+-------------------+
| VIOXX     | 7/186           | 4.1%      | 0.41  | (0.16, 1.05)      |
| 25 mg     |                 |           |       |                   |
+-----------+-----------------+-----------+-------+-------------------+
| VIOXX     | 12/178          | 7.3%      | 0.74  | (0.33, 1.64)      |
| 50 mg     |                 |           |       |                   |
+-----------+-----------------+-----------+-------+-------------------+
| Ibuprofen | 42/167          | 27.7%     | 2.79  | (1.47, 5.30)      |
+-----------+-----------------+-----------+-------+-------------------+

> \*by life table analysis

+-----------------------------------------------------------------------+
| **Figure 2**                                                          |
|                                                                       |
| **Comparison to Ibuprofen**                                           |
|                                                                       |
| **Life-Table Cumulative Incidence Rate of Gastroduodenal**            |
|                                                                       |
| **Ulcers 3mm\*\* (Intention-to-Treat)**                               |
|                                                                       |
| ![](media/image3.png){width="3.609722222222222in"                     |
| height="2.9763888888888888in"}                                        |
|                                                                       |
| > † p \< 0.001 versus ibuprofen 2400 mg                               |
| >                                                                     |
| > \*\* Results of analyses using a 5mm gastroduodenal ulcer endpoint  |
| > were consistent.                                                    |
| >                                                                     |
| > \*\*\* The primary endpoint was the cumulative incidence of         |
| > gastroduodenal ulcer at 12 weeks.                                   |
+-----------------------------------------------------------------------+

> **[TABLE 2]{.underline}**
>
> **[Endoscopic Gastroduodenal Ulcers at 12 weeks]{.underline}**
>
> **[Multinational Study]{.underline}**

+-----------+------------------+-----------+----------+---------------+
| **        | **Number of      | **C       | **Ratio  | **95% CI**    |
| Treatment | Patients with    | umulative | of       |               |
| [Gr       | Ulcer/Total      | Incidence | Rates**  | **on**        |
| oup]{.und | [Number of       | [Rate]{.u |          |               |
| erline}** | Patient          | nderline} | **vs.    | **[Ratio of   |
|           | s]{.underline}** | **[\*]{.u | [Placeb  | Rates]{       |
|           |                  | nderline} | o]{.unde | .underline}** |
|           |                  |           | rline}** |               |
+-----------+------------------+-----------+----------+---------------+
| Placebo   | 5/182            | 5.1%      |          |               |
+-----------+------------------+-----------+----------+---------------+
| VIOXX     | 9/187            | 5.3%      | 1.04     | (0.36, 3.01)  |
| 25 mg     |                  |           |          |               |
+-----------+------------------+-----------+----------+---------------+
| VIOXX     | 15/182           | 8.8%      | 1.73     | (0.65, 4.61)  |
| 50 mg     |                  |           |          |               |
+-----------+------------------+-----------+----------+---------------+
| Ibuprofen | 49/187           | 29.2%     | 5.72     | (2.36, 13.89) |
+-----------+------------------+-----------+----------+---------------+

> \*by life table analysis

The correlation between findings of endoscopic studies, and the relative
incidence of clinically serious upper GI events that may be observed
with different products, has not been fully established. Serious
clinically significant upper GI bleeding has been observed in patients
receiving VIOXX in controlled trials, albeit infrequently (see WARNINGS
-- Gastrointestinal \[GI\] Effects). Prospective, long-term studies
required to compare the incidence of serious, clinically significant
upper GI adverse events in patients taking VIOXX versus comparator NSAID
products have not been performed.

# *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.
Similarly, bleeding time was not altered in a single dose study with 500
or 1000 mg of VIOXX. There was no inhibition of *ex vivo* arachidonic
acid- or collagen-induced platelet aggregation with 12.5, 25, and 50 mg
of VIOXX.

# INDICATIONS AND USAGE

VIOXX is indicated:

For relief of the signs and symptoms of osteoarthritis.

For the management of acute pain in adults (see CLINICAL STUDIES).

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 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.

It is unclear, at the present time, how the above rates apply to VIOXX
(see CLINICAL STUDIES, Special Studies, *Upper Endoscopy in Patients
with Osteoarthritis*). Among 3357 patients who received VIOXX in
controlled clinical trials of 6 weeks to one year duration (most were
enrolled in six month or longer studies) at a daily dose of 12.5 mg to
50 mg, a total of 4 patients experienced a serious upper GI event, using
protocol derived criteria. Two patients experienced an upper GI bleed
within three months (at day 62 and 87 respectively) (0.06%). One
additional patient experienced an obstruction within six months (Day
130) and the remaining patient developed an upper GI bleed within 12
months (Day 322) (0.12%). Approximately 23% of these 3357 patients were
in studies that required them to be free of ulcers at study entry. It is
unclear if this study population is representative of the general
population. Prospective, long-term studies required to compare the
incidence of serious, clinically significant upper GI adverse events in
patients taking VIOXX vs comparator NSAID products have not been
performed.

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.

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**

Anaphylactoid reactions were not reported in patients receiving VIOXX in
clinical trials. However, as with NSAIDs in general, anaphylactoid
reactions may occur in patients without known prior exposure to 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**

No safety information is available regarding the use of VIOXX in
patients with advanced kidney disease. Therefore, treatment with VIOXX
is not recommended in these patients. 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.

***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. 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
moderate or severe hepatic insufficiency (see **Pharmacokinetics** --
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.

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. Clinical trials with VIOXX at daily
doses of 12.5 and 25 mg have shown renal effects (e.g., hypertension,
edema) similar to those observed with comparator NSAIDs; these occur
with an increased frequency with chronic use of VIOXX at doses above the
12.5 to 25 mg range. (See ADVERSE REACTIONS.)

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).

***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).

***Fluid Retention and Edema:***

Fluid retention and edema have been observed in some patients taking
VIOXX (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.

***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**

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 (see WARNINGS,
Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding and
Perforation).

Patients should promptly report signs or symptoms of gastrointestinal
ulceration or bleeding, skin rash, unexplained weight gain, or edema 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. 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
TXB~2~ generation in clotting blood. VIOXX is not a substitute for
aspirin for cardiovascular prophylaxis.

***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. Thus, when VIOXX and
lithium are administered concurrently, subjects should be observed
carefully for signs of lithium toxicity.

***Methotrexate:*** VIOXX 75 mg administered once daily for 10 days
increased plasma concentrations by 23% as measured by AUC~0-24\ hr~ in
patients receiving methotrexate 7.5 to 15 mg/week for rheumatoid
arthritis. An equivalent magnitude of reduction in methotrexate renal
clearance was observed. 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).
The effects of the recommended doses for osteoarthritis (12.5 and 25 mg)
of VIOXX on plasma methotrexate levels are unknown. 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 600mg 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.

***Warfarin:*** Prothrombin time (measured as INR) increased in both
single and multiple dose cross-over studies in healthy individuals
receiving both warfarin and rofecoxib. In a 21 day multiple dose study
in healthy individuals stabilized on warfarin (2 to 8.5 mg daily),
administration of rofecoxib 25 mg QD was associated with mean increases
in INR of approximately 8% (range of INR on warfarin alone, 1.1 to 2.2;
range of INR on warfarin plus rofecoxib, 1.2 to 2.4). Somewhat greater
mean increases in INR of approximately 11% (range of maximum INR on
warfarin alone, 1.5 to 2.7; range of maximum INR on warfarin plus
rofecoxib, 1.6 to 4.4) were also seen in a single dose PK screening
study using a 30 mg dose of warfarin and 50 mg of rofecoxib. Standard
monitoring of INR values should be conducted when therapy with VIOXX is
initiated or changed, particularly in the first few days, in patients
receiving warfarin or similar agents.

## 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 10 and 75 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 5
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. 

***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 approximately 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 who were 75 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. Dosage
adjustment in the elderly is not necessary; however, therapy with VIOXX
should be initiated at the lowest recommended dose.

In one of these studies (a six-week, double-blind, randomized clinical
trial), VIOXX 12.5 or 25 mg once daily was administered to 174
osteoarthritis patients 80 years of age. The safety profile in this
elderly population was similar to that of younger patients treated with
VIOXX.

# 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 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 weeks to 6 months 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.

+-----------------+-----------+-------------+----------+-------------+
| Clinical        |           |             |          |             |
| Adverse         |           |             |          |             |
| Experiences     |           |             |          |             |
| occurring in    |           |             |          |             |
|                 |           |             |          |             |
| 2.0% of         |           |             |          |             |
| Patients        |           |             |          |             |
| Treated with    |           |             |          |             |
| VIOXX           |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+
|                 | Placebo   | VIOXX       | I        | Diclofenac  |
|                 |           |             | buprofen |             |
|                 |           | 12.5 or 25  |          | 150 mg      |
|                 |           | mg daily    | 2400 mg  |             |
|                 |           |             |          | daily       |
|                 |           |             | daily    |             |
+-----------------+-----------+-------------+----------+-------------+
|                 | (N = 783) | (N = 2829)  | (N =     | (N = 498)   |
|                 |           |             | 847)     |             |
+-----------------+-----------+-------------+----------+-------------+
| **Body As A     |           |             |          |             |
| Whole/Site      |           |             |          |             |
| Unspecified**   |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+
| Abdominal Pain  | 4.1       | 3.4         | 4.6      | 5.8         |
+-----------------+-----------+-------------+----------+-------------+
| A               | 1.0       | 2.2         | 2.0      | 2.6         |
| sthenia/Fatigue |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+
| Dizziness       | 2.2       | 3.0         | 2.7      | 3.4         |
+-----------------+-----------+-------------+----------+-------------+
| Influenza-Like  | 3.1       | 2.9         | 1.5      | 3.2         |
| Disease         |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+
| Lower Extremity | 1.1       | 3.7         | 3.8      | 3.4         |
| Edema           |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+
| Upper           | 7.8       | 8.5         | 5.8      | 8.2         |
| Respiratory     |           |             |          |             |
| Infection       |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+
| *               |           |             |          |             |
| *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      | 2.8       | 3.8         | 9.2      | 5.4         |
| Discomfort      |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+
| 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   | 2.7       | 2.8         | 2.5      | 3.6         |
| Infection       |           |             |          |             |
+-----------------+-----------+-------------+----------+-------------+

The general safety profile of VIOXX 50 mg QD in OA clinical trials up to
6 months (476 patients) was similar to that of VIOXX at the recommended
OA doses of 12.5 and 25 mg QD, except for a higher incidence of
gastrointestinal symptoms (abdominal pain, epigastric pain, heartburn,
nausea and vomiting), lower extremity edema (6.3%) and hypertension
(8.2%).

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 heart beat, 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, 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 Disorder:** 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

**Other serious adverse reactions which occur rarely (\<0.1%),
regardless of causality:** The following serious adverse events have
occurred rarely in patients taking VIOXX:

**Cardiovascular:** cerebrovascular accident, congestive heart failure,
deep venous thrombosis, myocardial infarction, pulmonary embolism,
transient ischemic attack, unstable angina

**Gastrointestinal:** colitis, colonic malignant neoplasm,
cholecystitis, duodenal ulcer, gastrointestinal bleeding, intestinal
obstruction, pancreatitis

**Hemic and lymphatic:** lymphoma

**Urogenital:** breast malignant neoplasm, prostatic malignant neoplasm,
urolithiasis

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.

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).

In 110 patients treated with VIOXX (average age approximately 65 years)
in the post-orthopedic surgery pain study, the most commonly reported
adverse experiences were constipation, fever, and nausea.

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.

Management of Acute Pain and Treatment of Primary Dysmenorrhea

The recommended initial dose of VIOXX is 50 mg once daily. Subsequent
doses should be 50 mg once daily as needed. Use of VIOXX for more than 5
days in management of pain has not been studied (See CLINICAL STUDIES,
*Analgesia, including primary dysmenorrhea*.)

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

No. 3810 -- Tablets VIOXX, 12.5 mg, are cream/off-white, round, shallow
cup tablets engraved MRK 74 on one side and VIOXX on the other. They are
supplied as follows:

**NDC** 0006-0074-31 unit of use bottles of 30

**NDC** 0006-0074-54 unit of use bottles of 90

**NDC** 0006-0074-28 unit dose packages of 100

**NDC** 0006-0074-68 bottles of 100

**NDC** 0006-0074-82 bottles of 1000

> **NDC** 0006-0074-80 bottles of 8000.

No. 3811 -- Tablets VIOXX, 25 mg, are yellow, round, tablets engraved
MRK 110 on one side and VIOXX on the other. They are supplied as
follows:

**NDC** 0006-0110-31 unit of use bottles of 30

**NDC** 0006-0110-54 unit of use bottles of 90

**NDC** 0006-0110-28 unit dose packages of 100

**NDC** 0006-0110-68 bottles of 100

**NDC** 0006-0110-82 bottles of 1000

**NDC** 0006-0110-80 bottles of 8000.

No. 3784 -- 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.

**NDC** 0006-3784-64 unit of use bottles containing 150 mL
(12.5 mg/5 mL).

No. 3785 -- 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.

**NDC** 0006-3785-64 unit of use bottles containing 150 mL (25 mg/5 mL).

Storage

*VIOXX Tablets*:

Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). \[See
USP Controlled Room Temperature.\]

*VIOXX Oral Suspension:*

Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). \[See
USP Controlled Room Temperature.\]

Rx only.

![](media/image4.wmf){width="3.1104166666666666in"
height="0.33819444444444446in"}

Issued Month Year

Printed in USA

[^1]: ^\*^ Registered trademark of MERCK & CO., Inc., Whitehouse
    Station, New Jersey, USA

    COPYRIGHT MERCK & CO., Inc., 1998

    All rights reserved.