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Description: Rofecoxib is a selective cyclooxygenase-2 (COX-2), nonsteroidal
anti-inflammatory drug (NSAID) which is indicated to relieve the signs
and symptoms of osteoarthritis (OA) and for the treatment of dysmenorrhea
or acute pain. Compared to celecoxib, another COX-2 selective NSAID, rofecoxib
lacks a sulfonamide chain and is not primarily dependent on CP450 enzymes
for metabolism. Rofecoxib demonstrates comparable efficacy to non-selective
NSAIDs (e.g. ibuprofen and diclofenac) in patients with OA or acute pain.
Rofecoxib exhibits anti-inflammatory, analgesic, and antipyretic activities
but does not inhibit platelet aggregation. Due to rofecoxib's specificity
for the COX-2 cyclooxygenase pathway, it has the potential to cause less
gastropathy and risk of gastrointestinal (GI) bleeding; however, serious
GI bleeding or obstruction has been reported in patients receiving rofecoxib
in clinical trials. The FDA currently requires warnings in the rofecoxib
labeling regarding the risk of GI ulceration, bleeding and perforation.
This warning also notes the lack of long-term, prospective studies which
are required to determine the incidence of serious, clinically significant
upper GI adverse outcomes versus traditional NSAIDs. Although it has been
hypothesized that COX-1 cyclooxygenase antagonism may contribute to the
renal adverse effects of NSAIDs, clinical trials have shown similar adverse
renal effects with rofecoxib and non-selective NSAIDs. Rofecoxib was approved
by the FDA on May 21, 1999. Mechanism of Action: Rofecoxib selectively
inhibits the cyclooxygenase-2 (COX-2) enzyme, resulting in analgesic,
antipyretic, and anti-inflammatory pharmacologic effects. The enzymes
cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion
of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and
thromboxane. The inducible isoform, COX-2, is demonstrated to be important
for the mediation of inflammation and pain. It is hypothesized that COX-1
produces prostaglandins that are beneficial to renal and gastric function.
However, because COX-2 is constitutively expressed in the kidney and clinical
trials with rofecoxib and celecoxib (another selective COX-2 inhibitor)
have shown similar renal effects to those observed with comparator NSAIDs,
the degree to which renal adverse effects of NSAIDs can be attributed
to COX-1 inhibition is uncertain. The exact localization of COX-1 and
COX-2 in renal tissues remains to be determined. Nonselective NSAIDs such
as ibuprofen inhibit both COX-1 and COX-2 cyclooxygenases. At therapeutic
concentrations in humans, rofecoxib does not significantly inhibit the
cyclooxygenase-1 (COX-1) isoenzyme. In contrast to non-selective NSAIDs,
rofecoxib does not inhibit platelet aggregation at therapeutic doses.
Pharmacokinetics: Rofecoxib is administered orally. Rofecoxib is well
absorbed, with peak plasma levels of rofecoxib occurring approximately
2—3 hrs after an oral dose. The bioavailability is approximately 93%.
Vioxx® tablets and oral suspension are bioequivalent. Both peak plasma
levels (Cmax) and area under the curve (AUC) are roughly dose proportional
across the clinical dose range of 12.5—50 mg. At higher doses, there is
a less than proportional increase in Cmax and AUC which is thought to
be due to the low aqueous solubility of the drug. When Vioxx® tablets
are taken with a high fat meal, peak plasma levels are delayed for about
one to two hours with no significant effect on the peak plasma concentration
(Cmax) or extent of absorption (AUC). Vioxx® tablets can be administered
without regard to the timing of meals. The food effect on the oral suspension
formulation has not been studied. Rofecoxib is highly bound to plasma
proteins (~87%). The apparent steady-state volume of distribution is 91
or 86 L following a 12.5 or 25 mg dose, respectively. Rofecoxib metabolism
is primarily mediated via reduction by cytosolic enzymes. The principal
metabolic products are the cis-dihydro and trans-dihydro derivatives of
rofecoxib, which account for nearly 56 percent of recovered radioactivity
in the urine. An additional 8.8 percent of the dose was recovered as the
glucuronide of the hydroxy derivative, a product of oxidative metabolism.
The biotransformation of rofecoxib and this metabolite is reversible in
humans to a limited extent (less than 5 percent). These metabolites are
inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 plays a minor role
in metabolism of rofecoxib. Inhibition of CYP 3A activity by administration
of ketoconazole does not affect rofecoxib disposition. However, induction
of general hepatic metabolic activity by administration of the non-specific
inducer rifampin significantly decreases rofecoxib plasma concentrations
(See Drug Interactions). Rofecoxib is eliminated predominantly by hepatic
metabolism with little (<1%) unchanged drug recovered in the urine and
14% unchanged drug recovered in the feces. The metabolites are primarily
eliminated by the renal route; 72% of the total dose is recovered in the
urine as metabolites. The apparent plasma clearance is about 140 and 120
mL/min after doses of 12.5 and 25 mg, respectively. Higher plasma clearance
rates are observed at doses below the therapeutic range, suggesting non-linear
metabolism. The mean effective half-life is 17 hours. Renal insufficiency,
race, and gender have minimal influence on the pharmacokinetics of rofecoxib.
Impaired hepatic function and advanced age may affect the pharmacokinetics
of rofecoxib. A pharmacokinetic study in mild (Child-Pugh score less than
or equal to 6) hepatic insufficiency patients indicated that rofecoxib
AUC was similar between these patients and healthy subjects. Limited data
in patients with moderate (Child-Pugh score 7-9) hepatic insufficiency
suggest a trend towards higher AUC (about 69 percent) of rofecoxib in
these patients, but more data are needed to evaluate pharmacokinetics
in these patients. Patients with severe hepatic insufficiency have not
been studied. Elderly subjects (over 65 years old) have a 34 percent increase
in rofecoxib AUC compared to younger subjects.
Indications...Dosage For the relief of the signs and symptoms of osteoarthritis:
Oral dosage: Adults: Initially, 12.5 mg PO once daily. The lowest effective
dose of rofecoxib should be sought for each patient. Some patients may
benefit by increasing the dose to 25 mg PO once daily. The maximum recommended
daily dose for chronic therapy is 25 mg. Elderly: Initiate therapy at
the lowest recommended adult dose. Dose adjustment in the elderly is not
generally necessary. Adolescents and Children: Safe and effective use
has not been established. For the treatment of acute mild pain or moderate
pain including bone pain, dental pain, and orthopedic surgical pain: Oral
dosage: Adults: The recommended initial dose of rofecoxib is 50 mg PO
one time, then 50 mg PO once daily as needed. Use of rofecoxib for more
than 5 days in management of pain has not been studied. Elderly: Initiate
therapy at the lowest recommended adult dose. Dose adjustment in the elderly
is not generally necessary. Adolescents and Children: Safe and effective
use has not been established. For the treatment of primary dysmenorrhea:
Oral dosage: Adults: The recommended initial dose of rofecoxib is 50 mg
PO one time, then 50 mg PO once daily as needed. Use of rofecoxib for
more than 5 days in management of pain has not been studied Adolescents
and Children: Safe and effective use has not been established. For the
treatment of rheumatoid arthritis†: NOTE: The maximum dose recommended
by the manufacturer for chronic therapy is 25 mg/day PO. Oral dosage:
Adults: In a limited 8 week trial, 25—50 mg PO once daily has been shown
to be effective in treating rheumatoid arthritis compared to placebo.
Patients in the rofecoxib 25 mg and 50 mg groups (171 and 161 patients,
respectively) showed significant improvement in key efficacy endpoints,
including patient global assessment of pain, patient and investigator
global assessment of disease activity, and Stanford Health Assessment
Questionnaire Disability Index.[2854] Elderly: Initiate therapy at the
lowest recommended adult dose. Dose adjustment in the elderly is not generally
necessary. Adolescents and Children: Safe and effective use has not been
established. Maximum Dosage Infomation: •Adults: 25 mg/day PO for chronic
therapy; 50 mg/day PO for acute therapy no more than 5 days. •Elderly:
25 mg/day PO for chronic therapy; 50 mg/day PO for acute therapy no more
than 5 days. •Adolescents: Safe and effective use has not been established.
•Children: Safe and effective use has not been established. Patients with
hepatic impairment: Initiate therapy at the lowest recommended dose in
patients with mild hepatic impairment (see Pharmacokinetics). Rofecoxib
is not recommended in patients with moderate or severe hepatic insufficiency.
Patients with renal impairment: No dosage adjustment needed; however,
rofecoxib has not been studied in patients with severe renal insufficiency.
The use of rofecoxib is not recommended in patients with advanced renal
disease.
Administration Oral Administration •Rofecoxib is adminstered orally
as tablets or suspension. •Rofecoxib tablets can be administered with
or without food. The effect of food on the oral suspension formulation
is unknown. •Rofecoxib oral suspension 12.5 mg/5 mL or 25 mg/5 mL may
be substituted for rofecoxib tablets 12.5 or 25 mg, respectively. Shake
before using.
Contraindications Rofecoxib is absolutely contraindicated in patients
with known rofecoxib hypersensitivity. Rofecoxib should not be given to
patients who have experienced salicylate hypersensitivity evidenced by
asthma, bronchospasm, urticaria, or allergic-type reactions (ie. bronchospasm)
after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like
reactions to NSAIDs have been reported in such patients. Anaphylactoid
reactions may occur in patients without known prior exposure to rofecoxib.
Rofecoxib should be used with caution in patients with preexisting asthma
since there is a higher risk for aspirin sensitivity (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. Emergency help
should be sought in cases where an anaphylactoid reaction occurs. Because
serious GI tract ulceration and bleeding can occur without warning or
symptoms in patients receiving NSAIDs, rofecoxib should be monitored for
the signs and symptoms of GI bleeding. A few cases of serious GI bleeding
and one case of obstruction has been reported in patients receiving rofecoxib
in clinical trials. NSAIDs should be prescribed with extreme caution in
patients with a prior history of GI bleeding, GI perforation or ulcerative
GI disease. Most spontaneous reports of fatal GI events with NSAID therapy
are in elderly or debilitated patients and therefore special care should
be taken in treating this population. Another caution for rofecoxib is
that elderly subjects (over 65 years old) have a 34 percent increase in
AUC compared to younger subjects. Although the safety profile of rofecoxib
was similar in elderly versus younger patients in a short-term study (see
Adverse Effects); experience with chronic NSAID therapy in elderly and
debilitated patients suggest greater potential for serious GI adverse
events. To minimize the potential risk for an adverse GI event, the lowest
effective dose should be used for the shortest possible duration. For
high risk patients, alternate therapies that do not involve NSAIDs should
be considered. Studies have shown that patients with a prior history of
peptic ulcer disease and/or GI bleeding 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: corticosteroid therapy, anticoagulant therapy, longer
duration of NSAID therapy, tobacco smoking, alcoholism, older age, and
poor general health status. Hepatic disease may decrease the metabolism
of rofecoxib (See Pharmacokinetics). Studies of rofecoxib in hepatic disease
are limited, therefore the use of rofecoxib is not recommended (by the
manufacturer) for patients with moderate or severe hepatic insufficiency.
In patients taking NSAIDs, elevations of liver tests can occur and in
rare cases progress to severe hepatic reactions including jaundice, fatal
fulminant hepatitis, liver necrosis and hepatic failure. A patient with
symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal
liver test has occurred, should be monitored carefully for evidence of
the development of a more severe hepatic reaction while on therapy with
rofecoxib. Caution is recommended in patients with pre-existing renal
disease. No information is available regarding the use of rofecoxib in
patients with advanced kidney disease. Therefore, treatment with rofecoxib
is not recommended; however, if rofecoxib therapy must be initiated, close
monitoring of renal function is advisable. Clinical trials with rofecoxib
have shown renal effects similar to those observed with comparator NSAIDs.
The risk of renal adverse effects (e.g. hypertension and peripheral edema)
increases with chronic use of rofecoxib at doses greater than the 12.5—25
mg range indicated for osteoarthritis. 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 renal impairment, renal failure,
heart failure, liver dysfunction, those taking diuretics and ACE inhibitors,
or older patients. Discontinuation of NSAID therapy is usually followed
by recovery. Fluid retention and peripheral edema have also been observed
in some patients taking rofecoxib. Therefore, rofecoxib should be used
with caution in patients with fluid retention, hypertension, or heart
failure. Anemia is sometimes seen in patients receiving rofecoxib; and
could potentially worsen pre-existing anemia. Patients on long-term treatment
with rofecoxib should have their hemoglobin or hematocrit assessed if
they exhibit any signs or symptoms of anemia or blood loss. Rofecoxib
does not generally affect platelet counts, prothrombin time (PT), or partial
thromboplastin time (PTT), and does not inhibit platelet aggregation at
indicated dosages. Caution should be used when initiating treatment with
rofecoxib in patients with considerable dehydration. Patients should be
rehydrated before starting therapy with rofecoxib. The pharmacological
activity of rofecoxib in reducing inflammation, and possibly fever, may
diminish the utility of these diagnostic signs in detecting unsuspected
infection which may accompany coexisting painful conditions. Rofecoxib
is classified as a FDA pregnancy category C drug. There are no studies
in pregnant women. Rofecoxib should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus; its use should
especially be avoided during the third trimester to avoid premature closure
of the ductus arteriosus. No studies have been conducted to evaluate the
effect of rofecoxib on the closure of the ductus arteriosus in humans.
The manufacturer maintains a registry to monitor the pregnancy outcomes
of women exposed to refecoxib while pregnant. Health care providers are
encouraged to report any prenatal exposure to rofecoxib by calling the
Pregnancy Registry at (800) 986-8999. Rofecoxib is excreted in animal
milk; however, it is not known whether it is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from rofecoxib, a decision
should be made whether to continue breast-feeding or to discontinue the
drug, taking into account the importance of the drug to the mother. Safety
and effectiveness of rofecoxib in children below the age of 18 years have
not been evaluated.
Interactions Cytochrome P450 plays a minor role in metabolism of rofecoxib
as a substrate. 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
percent 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. Rofecoxib reduced the renal clearance of methotrexate
resulting in a 23% increase in AUC when given for ten days to rheumatoid
arthritis patients receiving methotrexate 7.5 to 15 mg per week. Rofecoxib
would be expected to also reduce the clearance of methotrexate during
high dose methotrexate for oncology patients; the magnitude of the effect
on plasma methotrexate levels has not been studied. In general, NSAID
therapy can decrease the renal clearance of methotrexate, resulting in
elevated and prolonged serum methotrexate levels. Concomitant administration
of methotrexate and NSAID therapy can cause severe, possibly fatal methotrexate
toxicity, particularly when high-dose methotrexate (HD-MTX) therapy is
used. NSAID therapy can impair the renal excretion of methotrexate by
decreasing renal perfusion (due to the inhibition of prostaglandin synthesis)
or by competing for urinary elimination. When rofecoxib is administered
to patients receiving methotrexate, renal function and potential for methotrexate
accumulation and toxicity should be monitored (see Methotrexate Dosage).
Anticoagulant activity and signs and symptoms of GI bleeding should be
monitored, particularly in the first few days, after initiating or changing
rofecoxib therapy in patients receiving warfarin or similar agents. In
single and multiple dose studies, rofecoxib increased the mean INR by
8—11% in healthy subjects receiving stabilized warfarin doses. Postmarketing
reports of increases in INR, sometimes associated with bleeding events,
in predominantly elderly patients have been reported during concurrent
administration of rofecoxib and warfarin. Nonsteroidal antiinflammatory
agents, including another selective COX-2 inhibitor (celecoxib) have produced
an elevation of plasma lithium levels resulting from a reduction in lithium
clearance. Patients on lithium treatment should be closely monitored for
signs of lithium toxicity when rofecoxib is introduced or withdrawn. ACE
inhibitors have the potential to interact with COX-2 selective NSAIDs
based on experience with traditional NSAID therapy and rofecoxib data.
NSAID therapy may diminish the antihypertensive effect of ACE inhibitors.
Mean arterial blood pressure increased 3 mmHg in patients receiving ACE
inhibitor (benazepril 10—40 mg daily for 4 weeks) with rofecoxib 25 mg
once daily compared to the ACE inhibitor regimen alone. Patients should
be monitored for loss of ACE inhibitor activity if an NSAID including
rofecoxib or celecoxib is added. Diuretics may have reduced efficacy with
rofecoxib due to the inhibition of renal prostaglandin synthesis. Clinical
studies, as well as post marketing observations, have shown that NSAID
therapy can reduce the natriuretic effect of furosemide and thiazide diuretics
in some patients. Concomitant administration of NSAID therapy with diuretics
can also increase the risk for renal failure secondary to decreased renal
blood flow. Aspirin, ASA, in low doses, can be used with rofecoxib. However,
concomitant administration of aspirin with rofecoxib may result in an
increased rate of GI ulceration or other complications, compared to use
of rofecoxib alone. Because of its lack of platelet effects, rofecoxib
is not a substitute for aspirin for cardiovascular prophylaxis. Co-administration
of rofecoxib with rifampin 600 mg daily, a potent, non-specific inducer
of hepatic metabolism, produced a 50 percent decrease in rofecoxib plasma
concentrations. When rofecoxib is coadministered with rifampin, the patient
should be monitored for potential loss of rofecoxib efficacy and need
for a higher dosage requirement. The manufacturer recommends a higher
initial daily dosage of 25 mg of rofecoxib for the treatment of osteoarthritis
when rofecoxib is co-administered with rifampin or other potent inducers
of hepatic metabolism (unspecified). Rofecoxib has not been evaluated
for several potential interactions documented for other NSAIDs (including
corticosteroids) or for interactions with cyclosporine or ethanol. Patients
receiving rofecoxib concurrently with cyclosporine should be monitored
for potential renal failure. Patients on ethanol or corticosteroids along
with any NSAIDs should be monitored carefully for potential increased
risk of GI bleeding. Rofecoxib did not have a clinically significant effect
on the pharmacokinetics of prednisolone or prednisone; however, the potential
of rofecoxib to enhance the risk of GI ulceration when given with corticosteroids
has not been evaluated. Rofecoxib and NSAID therapy have antipyretic and
analgesic properties which may mask the signs of infection such as fever
and pain in patients who have bone marrow suppression following treatment
with antineoplastic agents. Drug interaction studies do not support the
potential for clinically important interactions between antacids or cimetidine
with rofecoxib. The manufacturer reported that coadministration of rofecoxib
with either a calcium carbonate antacid or an aluminum/magnesium antacid
to elderly subjects decreased rofecoxib AUC by 13% or 8%, respectively.
Either antacid decreased the peak plasma concentrations of rofecoxib by
about 20%. Co-administration with high doses of cimetidine (800 mg twice
daily) increased the Cmax of rofecoxib by 21 percent, the AUC by 23 percent
and the half-life by 15 percent. In a retrospective study, those women
taking an NSAID concomitantly with alendronate had a 70% increased risk
of developing a GI adverse event, such as gastric ulceration. The use
of rofecoxib may be an alternative to a traditional NSAID in these patients,
but the incidence of GI effects has not been evaluated with the combination
of rofecoxib and alendronate. The effects of rofecoxib on the pharmacokinetics
and/or pharmacodynamics of ketoconazole, oral contraceptives, and digoxin
have been studied in vivo and clinically important interactions have not
been found. Ketoconazole 400 mg daily did not have any clinically important
effect on the pharmacokinetics of rofecoxib. Rofecoxib did not have any
clinically important effect on the pharmacokinetics of ethinyl estradiol
and norethindrone. Rofecoxib 75 mg once daily for 11 days does not alter
the plasma concentration profile or renal elimination of digoxin after
a single 0.5 mg oral dose. Preclinical data suggest agents that inhibit
prostaglandin synthesis such as NSAIDs could decrease the efficacy of
porfimer or verteporfin photodynamic therapy.
Adverse Reactions Three cases of serious GI bleeding and one case of
GI obstruction have been reported in osteoarthritis patients receiving
rofecoxib in pre-marketing clinical trials. Rofecoxib premarketing clinical
trials also demonstrate that the incidence of endoscopically observed
GI ulceration is lower than that observed for the nonselective NSAID,
ibuprofen. Two identical placebo-controlled endoscopic trials compared
rofecoxib versus ibuprofen over 6 months in over 1,400 osteoarthritis
patients (age >50 years) with no endoscopic ulcers at baseline. The study
design allowed inclusion of patients at higher risk of GI complications
such as patients older than 65 years and patients with a prior history
of upper GI perforation, ulceration or bleeding; however, patients receiving
aspirin were excluded. Both trials reported a statistically lower incidence
of endoscopically observed gastroduodenal ulcers for rofecoxib compared
to ibuprofen. The incidence of endoscopic ulceration ranged from 4.1—5.3%
for rofecoxib 25 mg daily, 7.3—8.8% for rofecoxib 50 mg daily, 27.7—29.2%
for ibuprofen 2400 mg daily, and 5.1—9.9% for placebo. The correlation
between endoscopic findings and adverse GI adverse events has not been
fully established. Prospective, long-term outcome trials will be required
to determine the actual incidence of serious, clinically significant upper
GI adverse events with rofecoxib therapy During pre-marketing trials,
the most common gastrointestinal adverse reactions (>2%) to rofecoxib
12.5—25 mg daily were mild to moderate complaints including diarrhea (6.5%),
nausea/vomiting (5.2%), dyspepsia (3.5%), and abdominal pain (3.4%). Less
common GI effects (>0.1—1.9% incidence) which occurred with rofecoxib
regardless of causality included: anorexia, cholecystitis, constipation,
esophagitis, flatulence, gastritis, gastroenteritis, gastroesophageal
reflux disease (GERD), hemorrhoids, melena, pancreatitis, peptic ulcer,
stomatitis, and vomiting. NSAIDs in general may also cause esophageal
ulceration. The 50 mg daily dose of rofecoxib evaluated during osteoarthritis
pre-marketing trials was associated with a higher incidence of GI adverse
effects (abdominal pain, epigastric pain, heartburn, nausea, and vomiting).
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. Even
short-term NSAID therapy is not without risk. It is unclear how the GI
bleeding rates associated with traditional NSAIDs apply to rofecoxib.
Among 3,357 patients who received rofecoxib in controlled, pre-marketing
clinical trials of 6 weeks to 1 year duration (most were >=6 month studies)
at a daily dose of 12.5—50 mg; two patients (0.06%) experienced significant
upper GI bleeding at 3 months, one patient developed GI obstruction within
6 months, and one patient (0.12%) developed upper GI bleeding at 12 months
after initiation of dosing. Approximately 23% of these 3,357 patients
were in studies that required them to be free of ulcers by endoscopy at
study entry. Thus it is unclear if this study population is representative
of the general population. Patients receiving rofecoxib and their health
care providers should monitor for the signs and symptoms of GI perforation,
ulceration and bleeding, even in the absence of previous GI tract symptoms.
Experience with chronic NSAID therapy in elderly and debilitated patients
suggest greater potential for serious GI adverse events. Of the patients
who received rofecoxib in osteoarthritis clinical trials, 1455 were 65
years of age or older and 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 rofecoxib should be initiated at the lowest recommended dose.
In a six-week, controlled clinical trial, rofecoxib 12.5 or 25 mg once
daily was administered to 174 osteoarthritis patients greater than or
equal 80 years of age. The safety profile in this elderly population was
similar to that of younger patients. Due to the greater potential for
serious GI adverse events in elderly patients receiving NSAIDs; elderly
patients should be monitored closely for serious GI events, especially
those receiving chronic therapy or higher doses of rofecoxib. Slightly
elevated hepatic enzymes (borderline values) may occur in up to 15 percent
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 percent 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 rofecoxib, the incidence of borderline elevations of
liver tests at doses of 12.5 and 25 mg daily was comparable to the incidence
observed with ibuprofen and lower than that observed with diclofenac.
In placebo-controlled trials, approximately 0.5 percent of patients taking
rofecoxib (12.5 or 25 mg QD) and 0.1 percent of patients taking placebo
had notable elevations of ALT or AST. A patient with symptoms and/or signs
suggesting liver dysfunction, or in whom an abnormal liver test has occurred,
should be monitored carefully for evidence of the development of a more
severe hepatic reaction while on therapy with rofecoxib. Use of rofecoxib
is not recommended in patients with moderate or severe hepatic insufficiency
(see Pharmacokinetics). If clinical signs and symptoms consistent with
liver disease develop, or if systemic manifestations occur (e.g., eosinophilia,
rash, etc.), rofecoxib should be discontinued. Anemia is sometimes seen
in patients receiving rofecoxib. Patients on long-term treatment with
rofecoxib should have their hemoglobin or hematocrit assessed if they
exhibit any signs or symptoms of anemia or blood loss. Rofecoxib does
not generally affect platelet counts, prothrombin time (PT), or partial
thromboplastin time (PTT), and does not inhibit platelet aggregation at
indicated dosages. Anaphylactoid reactions were not reported with rofecoxib
during pre-marketing trials. However, patients with hypersensitivity to
salicylates are at higher risk for allergic reactions to NSAIDs in general.
Urticaria was reported rarely (>0.1—1.9%) in patients receiving rofecoxib.
Patients who develop urticaria, bronchospasm, or other signs and symptoms
of an anaphylactoid reaction should be advised to seek emergency care
immediately. Common effects (2% or greater) of rofecoxib, with an incidence
greater than placebo (regardless of causation), included: dizziness (3.0%
vs. placebo 2.2%), sinusitis (2.7% vs. 2.0%), back pain (2.5% vs. 1.9%),
fatigue (asthenia) (2.2% vs. placebo 1.0%), and bronchitis (2.0% vs. 0.8%).
Infrequent side effects which occurred infrequently (0.1—1.9%) but are
consistent with NSAID pharmacology included: headache, maculopapular rash,
dermatitis, and appetite changes (anorexia). Lower extremity edema (3.7%)
and hypertension (3.5%) occurred relatively frequently in patients receiving
12.5—25 mg daily of rofecoxib in pre-marketing trials. The incidence of
renal adverse effects (hypertension and peripheral edema) increases with
chronic daily dosage above 12.5—25 mg (the dosage range indicated for
osteoarthritis). The 50 mg daily dose of rofecoxib evaluated during osteoarthritis
pre-marketing trials was associated with a higher incidence of lower extremity
edema (6.3%) and hypertension (8.2%). Fluid retention (>0.1 to 1.9%),
weight gain (>0.1 to 1.9%), and congestive heart failure (<0.1%) have
also occurred in patients taking rofecoxib. Rare serious adverse reactions
(<0.1%) (without a causal relationship) and not related to the known pharmacology
of rofecoxib included: cerebrovascular accident (stroke), deep venous
thrombosis, myocardial infarction, pulmonary embolism, transient ischemic
attack, unstable angina, colitis, colonic malignant neoplasm, lymphoma,
breast malignant neoplasm, prostatic malignant neoplasm, and urolithiasis.
Approximately one thousand patients were treated with rofecoxib in analgesia
studies. All patients in the post-dental surgery pain studies received
only a single dose. Patients in primary dysmenorrhea studies may have
taken up to 3 daily doses of rofecoxib, and those in the post-orthopedic
surgery pain study were prescribed daily doses of rofecoxib for five days.
The adverse experience profile in the analgesia studies was generally
similar to those reported in the osteoarthritis studies. An additional
adverse experience (>=2%) with rofecoxib in the post-dental pain surgery
studies included post-dental extraction alveolitis (dry socket). In 110
patients treated with rofecoxib (average age approximately 65 years) in
the post-orthopedic surgery pain study, the most commonly reported adverse
experiences (regardless of causation) were constipation, fever, and nausea.
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