Etoricoxib
30mg Tablet
60mg Tablet
90mg Tablet
120mg Tablet
Drug Category: COX-2
Specific Inhibitor
Brand Name:
Arcoxia/Arcoxia Ac
Product Description:
Etoricoxib is a member of
a class arthritis/analgesia medications called, coxibs. Etoricoxib is
a highly selective inhibitor of cycloxygenase-2 (COX-2). Etoricoxib
tablets contain etoricoxib, which is described chemically as
5-chloro-6-methyl-3-[4-9methylsulfony)phenyl],-2,3`-bipyridine. The
empirical formula is C18H15CIN2OS.
The molecular weight is 358.84.
Etoricoxib is a white to
off-white powder. Etoricoxib is free soluble in methanol,
tetrahydrofuran, dimethyl sulfoxide, methyl ethyl ketone, dimethyl
formamide, and chloroform. Etoricoxib is soluble in isopropyl
acetate, ethanol and toluene, sparingly soluble in 2-propanol, and
practically insoluble in water.
Pharmacokinetics:
Absorption
Orally administered
etoricoxib is well absorbed. The mean oral bioavailability is
approximately 100%. Following 12mg once daily dosing to steady-state,
the peak plasma concentration (geometirc mean Cmax =
3.6mcg/ml) was observed at approximately 1 hour (Tmax)
after administration to fasted adults. The
geometric mean AUC0-24hr
was 37.8 mcg.hr/ml.
The pharmacokinetics of etoricoxib are linear across the clinical
dose range.
The standard meal had no
clinically meaningful effect on the extent or rate of absorption of a
dose of etoricoxib 120mg. In clinical trials, etoricoxib was
administered without regard to food.
The pharmacokinetics of
etoricoxib in 12 healthy subjects were similar (comparable AUC, Cmax
within approximately 20%) when administered alone, with a
magnesium/aluminum hydroxide antacid, or a calcium carbonated antacid
(approximately 50 mEq acid-neutralizing capacity).
Distribution
Etoricoxib is
approximately 92% bound to human plasma protein over the range of
concentration of 0.05 to 5mcg/ml. The volume of distribution at
steady-state (Vdss) is approximately 120L in humans.
Etoricoxib crosses the
placenta in rats and rabbits, and the blood-brain-barrier in rats.
Metabolism
Etoricoxib is extensively
metabolized with <1% of a dose recovered in urine as the parent
drug. The major route of metabolism to form the 6`-hydroxymethyl
derivative is catalyzed by cytochrome P450 (CYP) enzymes.
Five metabolites have
been identified in man. The principal metabolite in the 6`-carboxylic
acid derivative of etoricoxib formed by further oxidation of the
6`-hydroxymethyl derivative. These principal metabolites either
demonstrate no measurable activity or are only weakly active as COX-2
inhibitors. None of these metabolites inhibit COX-1.
Elimination
Following administration
of single 25mg radio labeled intravenous dose of etoricoxib to
healthy subjects, 70% of radioactivity was recovered in urine and 20%
in feces, mostly as metabolites. Less than 2% was recovered as
unchanged drug.
Elimination of etoricoxib
occurs almost exclusively through metabolism followed by renal
excretion. Steady-state concentration of etoricoxib are reached
within seven days of once-daily administration of 120mg, with an
accumulation ration of approximately 2, corresponding to an
accumulation half-life of approximately 22 hours. The plasma
clearance is estimated to be approximately 50ml/min.
Characteristic in
Patients (Special Populations)
Gender
The pharmacokinetics of
etoricoxib are similar between men women. (See recommended dose.)
Elderly
Pharmacokinetics in
elderly (65years of age and older) similar to those in the young. No
dosage adjustment is necessary for elderly patients. (See recommended
dose).
Race
There is no clinically
important effect of race on the pharmacokinetics of etoricoxib. (See
recommended dose).
Hepatic Insufficiency
Patients with mild
hepatic insufficiency (Child-Pugh score 5-6) administered etoricoxib
60mg once daily had an approximately 16% higher mean AUC as compared
to healthy subjects given the same regime. Patients with moderate
hepatic insufficiency (Child-Pugh score 7-9) administered etoricoxib
60m once daily; etoricoxib 30mg once daily has not been studied in
this population. There are no clinical or pharmacokinetic data in
patients with severe hepatic insufficiency (Child-Pugh score >9).
(See recommended dose, Hepatic Insufficiency).
Renal Insufficiency
The pharmacokinetics of a
single dose of etoricoxib 120mg in patients with moderate-to-severe
renal insufficiency and patients with end-stage renal disease on
hemodialysis were not significantly different from those in healthy
subjects. Hemodialysis contributed negligibly to elimination
(dialysis clearance approximately 50ml/min).
Pediatric Patients
The pharmacokinetic study
(N=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics
in adolescents weighing 40 to 60 kg given etoricoxib 60mg once daily
and in adolescents >60kg given etoricoxib 90mg once daily were
similar to the pharmacokinetics in adults given etoricoxib 90mg once
daily. Safety and effectiveness of etoricoxib in pediatric patients
have not been established.
Drug Interactions with
additional pharmacokinetic data:
The main pathway of
etoricoxib biotransformation is CYP-dependent oxidation to produce
6`-hydroxymethyl etoricoxib, which can undergo further metabolism to
the corresponding carboxylic acid or O-glucuronide. In vitro data
indicate that CYP3A4 plays a major role (approximately 60%) in the
hydroxylation of etoricoxib and that the remainder of the activity
(approximately 40%) is shared among CYP2C9, and 2D6. Administration
of a potent inhibitor of CYP3A (ketoconazole) did not increase
etoricoxib plasma concentrations to a clinically meaningful extent
(approximately 43% increase in AUC). Administration of a potent
inducer of CYP enzymes (rifampin) produced a 65% decrease in
etoricoxib plasma AUC.
The potential for
etoricoxib to inhibit or induce CYP3A4 activity was investigated in
human studies using the intravenous erythromycin breath test.
Compared to placebo, etoricoxib (120mg daily for 11 days) did not
produce any significant effect on erythromycin N-demethylation,
indicating no effect on hepatic CYP3A4 activity. Based on in vitro
studies, etoricoxib does not inhibit cytochromes P4501A2, 2C9, 2C19,
2D6, or 2E1.
Indications:
Etoricoxib is indicated
for:
- Acute and chronic treatment of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA)
- Treatment of ankylosing spondylitis (AS)
- Treatment of acute gouty arthritis
- Relief of acute pain
- Treatment of primary dysmenorrhea.
- Treatment of moderate to sever acute post-operative pain associated with dental surgery.
- Treatment of moderate to sever acute post-operative pain associated with abdominal gynecological surgery
The decision to prescribe
a selective COX-2 inhibitor should be based on an assessment of the
individual patient's overall risks (See Warnings and Precautions).
Recommended Dose:
Etoricoxib is
administered orally. Etoricoxib may be taken with or without food.
Etoricoxib should be administered for the shortest duration possible
and the lowest effective daily dose should be used.
Arthritis
Osteoarthritis
The recommended dose is
30mg or 60mg once daily.
Rheumatoid Arthritis
The recommended dose is
90mg once daily.
Ankylosing Spondylitis
The recommended dose is
90mg once daily.
Acute Pain
For acute pain
conditions, the recommended dose is 90mg or 120mg once daily.
Etoricoxib should be used only for the acute symptomatic period,
limited to a maximum of 8 days treatement.
Acute Gouty Arthritis
The recommended dose is
120mg once daily.
Primary Dysmenorrhea
The recommended dose is
120mg once daily.
Post-operative Dental
Pain
The recommended dose is
90mg once daily.
Post-operative
Gynecological Pain
The recommended dose is
90mg once daily. The initial dose should be administered shortly
before surgery. The dose can be increased to a maximum 120mg once
daily.
Doses greater than those
recommended for each indication have either no demonstrated
additional efficacy or have not been studied. Therefore:
The dose for OA should
not exceed 60mg daily.
The dose for RA should
not exceed 90mg daily.
The dose for ankylosing
spondylitis should not exceed 90mg daily.
The dose for acute gout
should not exceed 120mg daily.
The dose for acute pain
and primary dysmenorrhea should not exceed 120mg daily.
The dose for
post-operative acute dental surgery pain should not exceed 90mg
daily.
The dose for
post-operative acute gynecological surgery pain should not exceed
120mg daily.
As the cardiovascular
risks of selective COX-2 inhibitors may increase with dose and
duration of exposure, the shortest duration possible and the lowest
effective daily dose should be used. The patient's need for
symptomatic relief and response to therapy should be re-evaluated
periodically. (See Warnings and Precautions)
Elderly, Gender, Race
No dosage adjustment in
etoricoxib is necessary for the elderly or based on gender or race.
Hepatic Insufficiency
In patients with mild
hepatic insufficiency (Child-Pugh score 5-6), a dose of 60mg once
daily should not be exceeded. In patients with moderate hepatic
insufficiency (Child-Pugh score 7-9), the dose should be reduced; a
dose of 60mg every other day should
not be exceeded, administration of 30mg once daily can also be
considered. There are no clinical or pharmacokinetic data in patients
with severe hepatic insufficiency (Child-Pugh score >9). (See
WARNINGS AND PRECAUTIONS.)
Renal Insufficiency
In
patients with advanced renal disease (creatinine clearance <30
ml/min), treatment with etoricoxib is not recommended. No dosage
adjustment is necessary for patients with lesser degrees of renal
insufficiency (creatinine clearance ≥30ml/min).
(See WARNINGS AND PRECAUTIONS.)
Mode
of Administrations:
Etoricoxib
is administered orally. Etoricoxib may be taken with or without food.
Contraindications:
Hypersensitivity
to the active substance or to any of the excipients.
Active
peptic ulceration or active gastrointestinal (GI) bleeding.
Patients
who have experienced bronchospasm, acute rhinitis, nasal polyps,
angioneurotic edema, urticaria, or allergic-type reactions after
taking acetylsalicylic acid or NSAIDS including COX-2
(cyclooxygenase-2) inhibitors.
Pregnancy
and lactation.
Severe
hepatic dysfunction (serum albumin <25g/l or Child-Pugh score
≥10).
Estimate
renal creatinine clearance <30ml/min.
Children
and adolescents under 16 years of age.
Inflammatory
bowel disease.
Congestive
heart failure (NYHA II-IV)
Patients
with hypertension whose blood pressure has not been adequately
controlled.
Established
ischemic heart disease, peripheral arterial disease and/or
cerebrovascular disease.
Warnings
and Precautions:
Clinical
trials suggest that the selective COX-2 inhibitors class of drugs may
be associated with an increased risk of thrombotic events (especially
MI and stroke), relative to placebo and some NSAIDs (naproxen). As
the cardiovascular risks of selective COX-2 inhibitors may increase
with dose and duration of exposure, the shortest duration possible
and the lowest effective daily dose should be used. The patient's
need for symptomatic relief and response to therapy should be
re-evaluated periodically.
Patients
with significant risk factors for cardiovascular events (e.g.
hypertension, hyperlipidemia, diabetes mellitus, smoking) should only
be treated with etoricoxib after careful consideration.
Selective
COX-2 inhibitors are not a substitute for aspirin for cardiovascular
prophylaxis because of their lack of effect on platelets. Because
etoricoxib, a member of this class, does not inhibit platelet
aggregation, antiplatelet therapies should not be discontinued.
There
is a further increase in the risk of gastrointestinal adverse effects
(gastrointestinal ulceration or other gastrointestinal complications)
for etoricoxib, other selective COX-2 inhibitors and NSAIDs, when
taken concomitantly with acetylsalicylic acid (even at low doses).
The relative difference in gastrointestinal safety between selective
COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic
acid has not been adequately evaluated in long-term clinical trials.
Long-term
administration of NSAIDs has resulted in renal papillary necrosis and
other renal injury. Renal prostaglandins may play a compensatory role
in the maintenance of renal perfusion. Therefore, under conditions of
compromised renal perfusion, administration of Etoricoxib may cause a
reduction in prostaglandin formation and, secondarily, in renal blood
flow, and thereby impair renal function. Patients at greatest risk of
this response are those with preexisting significantly impaired renal
function, uncompensated heart failure, or cirrhosis. Monitoring of
renal function in such patients should be considered.
Caution
should be used when initiating treatment with etoricoxib in patients
with considerable dehydration. It is advisable to rehydrate patients
prior to starting therapy with etoricoxib.
As
with other drugs known to inhibit prostaglandin synthesis, fluid
retention, edema and hypertension have been observed in some patients
taking etoricoxib. The possibility of fluid retention, edema or
hypertension should be taken into consideration when etoricoxib is
used in patients with preexisting edema, hypertension or heart
failure. All Nonsteroidal Antiinflammatory Drugs (NSAIDs), including
etoricoxib, can be associated with the new onset or recurrent
congestive heart failure. (see Undesirable effects). Etoricoxib may
be associated with more frequent and severe hypertension than some
other NSAIDs and selective COX-2 inhibitors, particularly at high
doses. Therefore, special attention should be paid to blood pressure
monitoring during treatment with etoricoxib. If blood pressure rises
significantly, alternative treatment should be considered.
Physicians
should be aware that individual patients may develop upper
gastrointestinal (GI) ulcers/ulcer complications irrespective of
treatment. Although the risk of GI toxicity is not eliminated with
etoricoxib, the results of the MEDAL Program demonstrate that in
patients treated with etoricoxib, the risk of GI toxicity with
etoricoxib 60mg or 90mg once daily is significantly less than with
diclofenac 150mg daily. In clinical studies with ibuprofen and
naproxen, the risk of endoscopically detected upper GI ulcers was
lower in the patients treated with etoricoxib 120mg once daily than
in patients treated with non-selective NSAIDs. While the risk of
endoscopically detected ulcers was low in patients treated with
etoricoxib. These events can occur at any time during use and without
warning symptoms. Independent of treatment, patients with a prior
history of GI perforation, ulcers and bleeding (PUB) and patients
greater than 65 years of age are known to be at a higher risk for a
PUB.
Elevations
of alanine aminotransferase (ALT) and/or aspartate aminotransferase
(AST) (approximately three or more times the upper limit of normal)
have been reported in approximately 1% of patients in clinical trials
treated for up to one year with etoricoxib 30, 60, and 90 mg daily.
In active comparator portions of clinical trials, the incidence of
elevated AST and/or ALT in patients treated with etoricoxib 60 and 90
mg daily was similar to that of patients treated with naproxen 1000mg
daily, but notably less than the incidence in the diclofenac 150mg
daily group. These elevations resolved in patients treated with
etoricoxib, with approximately half resolving while patients remained
on therapy. In controlled clinical trials of etoricoxib 30mg daily
versus ibuprofen 2400mg daily or celecoxib 200mg daily, the incidence
of elevations of ALT or AST was similar.
A
patient with symptoms and/or signs suggesting liver dysfunction, or
in whom an abnormal liver function test has occurred, should be
evaluated for persistently abnormal liver function tests. If
persistently abnormal liver function test (three times the upper
limit of normal) are detected, etoricoxib should be discontinued.
When
using etoricoxib in the elderly and in patients with renal, hepatic,
or cardiac dysfunction, medically appropriate supervision should be
maintained. If these patients deteriorated during treatment
appropriate measures should be taken, including discontinuation of
therapy.
Serious
skin reactions, some of them fatal, including exfoliative
dermintitis, Stevens-Johnson syndrome, and toxic epidermal
necrolysis, have been reported very rarely in association with the
use of NSAIDs and some selective COX-2 inhibitors during
post-marketing surveillance (see Undesirable effects). These serious
events may occur without warning. Patients appear to be at highest
risk for these reactions early in the course of therapy: the onset of
the reaction occurring in the majority of cases within the first
month of treatment. Serious hypersensitivity reactions (such as
anaphylaxis and angioedema) have been reported in patients receiving
etoricoxib (see Undesirable effects). Some selective COX-2 inhibitors
have been associated with an increased risk of skin reactions in
patients with a history of any drug allergy. Etoricoxib should be
discontinued at the first appearance of skin rash, mucosal lesions,
or any other sign of hypersensitivity.
Etoricoxib
may mask fever, which is a sign of infection. The physician should be
aware of this when using etoricoxib in patients being treated for
infection.
Interactions
with other medicaments:
Warfarin:
In subjects stabilized on chronic warfarin therapy, the
administration of etoricoxib 120mg daily was associated with an
approximate 13% increase in prothrombin time International Normalized
Ration (INR). Standard monitoring of INR values should be conducted
when therapy with etoricoxib is initiated or changed, particularly in
the first few days, in patients receiving warfarin or similar agents.
Rifampin:
Co-administration of etoricoxib with rifampin, a potent inducer of
hepatic metabolism, produced a 65% decrease in etoricoxib plasma area
under the curve (AUC). This interaction should be considered when
etoricoxib is co-administered with rifampin.
Methotrexate:
Two studies investigated the effects of etoricoxib 60, 90, or 120mg
administered once daily for seven days in patients receiving
once-weekly methotrexate doses of 7.5 to 20mg for rheumatoid
arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate
plasma concentrations (as measured by AUC) or renal clearance. In one
study, etoricoxib 120mg had no effect on methotrexate plasma
concentrations (as measured by AUC) or renal clearance. In the other
study, etoricoxib 120mg increased methotrexate plasma concentrations
by 28% (as measured by AUC) and reduced renal clearance of
methotrexate by 13%. Monitoring for methotrexate-related toxicity
should be considered when etoricoxib at doses greater than 90 mg
daily and methotrexate are administered concomitantly.
Diuretics,
Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin II
Antagonists (AIIAs): Reports suggest that NSAIDs including selective
COX-2 inhibitors may diminish the anti-hypertensive effect of
diuretics, ACE inhibitors and AIIAs. This interaction should be given
consideration in patients taking etoricoxib concomitantly with these
products.
In
some patients with compromised renal function (e.g. elderly patients
or patients who are volume-depleted, including those on diuretic
therapy) who are being treated with non-steroidal anti-inflammatory
drugs, including selective COX-2 inhibitors, the co-administration of
ACE inhibitors or AIIAs may result in a further deterioration of
renal function, including possible acute renal failure. These effects
are usually reversible. Therefore, the combination should be
administered with caution especially in the elderly.
Lithium:
Reports suggest that non-selective NSAIDs and selective COX-2
inhibitors may increase plasma lithium levels. This interaction
should be given consideration in patients taking etoricoxib
concomitantly with lithium.
Aspirin:
Etoricoxib can be used concomitantly with low-dose aspirin at doses
for cardiovascular prophylaxis. At steady state, etoricoxib 120 mg
once daily had no effect on the anti-platelet activity of low-dose
aspiring with etoricoxib increased rate of GI ulceration or other
complications compared to use of etoricoxib alone. (See Warnings and
Precautions.)
Oral
Contraceptives:
Etoricoxib 60mg given concomitantly with an oral contraceptive
containing 35mcg ethinyl estradiol (EE) and 0.5 to 1mg norethindrone
for 21 days increased the steady sate AUC0-24hr
of EE by 37%. Etoricoxib 120mg given with the same oral contraceptive
concomitantly or separated by 12 hours, increased the steady state
AUC0-24hr
of
EE by 50% to 60%. This increase in EE concentration should be
considered when selecting an oral contraceptive for use with
etoricoxib. An increase in EE exposure can increase the incidence of
adverse events associated with oral contraceptives (e.g. venous
thromboembolic events in women at risk).
Hormone
Replacement Therapy: Administration of Etoricoxib 120mg with hormone
replacement therapy consisting of conjugated estrogens (0.625mg
Premarin) for 28 days, increased the mean steady state AUC0-24hr
of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol
(22%).
The
effects o the recommended chronic doses of etoricoxib (30, 60, and
90mg) has not been studied. The effects of etoricoxib 120mg on the
exposure ( AUC0-24hr)
to these estrogenic components of Premarin were less than half of
those observed when Premarin was administered alone and the dose was
increased from 0.625 to 1.25mg. The clinical significance of these
increases is unknown, and higher doses of Premarin were not studied
in combination with etoricoxib. These increases in estrogenic
concentration should be taken into consideration when selecting
prost-menopausal hormone therapy for use with etoricoxib.
Other:In
drug-interaction studies etoricoxib did not have clinical important
effects on the pharmacokinetics of prednisone/prednisolone or
digoxin.
Antacids
and ketoconazole (a potent inhibitor of CYP3A4) did not have
clinically important effects on the pharmacokinetics of etoricoxib.
Pregnancy
and Lactation:
The
use of etoricoxib, as with any drug substances known to inhibit
COX-2, is not recommended in women attempting to conceive.
No
clinical data on exposed pregnancies are available for etoricoxib.
Studies in animals have shown reproductive toxicity. The potential
for human risk in pregnancy in unknown. Etoricoxib, as with other
medicinal products inhibiting prostaglandin synthesis, may cause
uterine inertia and premature closure o the ductus arteriosus during
the last trimester. Etoricoxib is contraindicated in pregnancy. If a
woman becomes pregnant during treatment, etoricoxib must be
discontinued.
Reproductive
studies conducted in rats have demonstrated no evidence of
developmental abnormalities at doses up to 15mg/kg/day (approximately
1.5 times the human dose [90mg] based on systemic exposure). At doses
approximately 2 times the adult human exposure (90mg) based on
systemic exposure, a low incidence of cardiovascular malformations
and increases in post implantation loss were observed in
etoricoxib-treated rabbits. No developmental effects were seen at
systemic exposure of approximately equal to or less than the daily
human dosage (90mg). However, animal reproduction studies are not
always predictive of human response. There are no adequate and
well-controlled studies in pregnant women.
It
is not known whether etoricoxib is excreted in human milk. Etoricoxib
is excreted in the milk of lactating rats. Women who use etoricoxib
should not breast feed.
Pediatric
Use:
Safety
and effectiveness of etoricoxib in pediatric patients have not been
established.
Use
in the Elderly:
Pharmacokinetics
in the elderly (65 years of age and older) are similar to those in
the young. In clinical studies, a higher incidence of adverse
experiences was seen in older patients, compared to younger patients:
the relative differences between etoricoxib and control groups were
similar in the elderly and the young. Greater sensitivity of some
older individuals cannot be ruled out.
Undesirable
Effects:
In
clinical trials, etoricoxib was evaluated for safety in 7152
individuals, including 4488 patients with OA, RA or chronic low back
pain (approximately 600 patients with OA or RA were treated for one
year or longer).
The
following drug-related adverse experiences were reported in clinical
studies in patients with OA, RA or chronic low back pain treated for
up to 12 weeks. These occurred in ≥1% of patients treated with
etoricoxib and at an incidence greater than placebo:
asthenia/fatigue, dizziness, lower extremity edema, hypertension,
dyspepsia, heartburn, nausea headache, ALT increased, AST increased.
The
adverse experience profile was similar in patients with OA or RA
treated with etoricoxib for one year or longer.
In
the MEDAL Study, an endpoint driven CV outcomes trial involving
23,504 patients, the safety of etoricoxib 60 or 90 mg daily was
compared to diclofenac 150mg daily in patients with OA or RA (mean
duration of treatment was 20 months). In this large trial, only
serious adverse events and discontinuations due to any adverse events
were recorded. The rates of confirmed thrombotic cardiovascular
serious adverse events were similar between etoricoxib and
diclofenac. The incidence of discontinuations for
hypertension-related adverse events was less than 3% in each
treatment group; however, etoricoxib 60 and 90mg demonstrated
significantly higher rates of discontinuations for these events than
diclofenac. The incidence of congestive heart failure adverse event
(discontinuations and serious events) and the incidence of
discontinuations due to edema occurred at similar rate on etoricoxib
60mg compared to diclofenac; however, the incidences for these events
were higher for etoricoxib 90mg compared to diclofenac. The incidence
of discontinuations due to atrial fibrillation was higher for
etoricoxib compared to diclofenac.
The
EDGE and EDGE II studies compared the GI tolerability of etoricoxib
90mg daily (1.g to 3 times the doses recommended for OA) and
diclofenac 150mg daily in 7111 patients with OA (EDGE Study; mean
duration of treatment 9 months) and 4086 patients with RA (EDGE II;
mean duration of treatment 19 months). In each of these studies, the
adverse experience profile of etoricoxib was generally similar to
that reported in the phase IIb/III placebo-controlled clinical
studies; however, hypertension and edema-related adverse experiences
occurred at a higher rate on etoricoxib 90 mg than on diclofenac 150
mg daily. The rate of confirmed thrombotic cardiovascular serious
adverse events occurring in the two treatment groups was similar.
In
combined analysis of phase IIb to V clinical studies 4 weeks duration
or longer (excluding the MEDAL Program Studies), there was no
discernible difference in the rate of confirmed thrombotic
cardiovascular serious adverse events between patients receiving
etoricoxib ≥30mg or non-naproxen NSAIDs. The rate of these events
was higher in patients receiving etoricoxib compared with those
receiving with those of naproxen 500mg twice daily.
In
a clinical study for ankylosing spondilitis, patients were treated
with etoricoxib 90mg once daily for up to 1 year (N=126). The adverse
experience profile in this study was generally similar to that
reported in chronic studies in OA, RA and chronic low back pain.
In
a clinical study for acute gouty arthritis, patients were treated
with etoricoxib 120mg once daily for eight days. The adverse
experience profile in these studies was generally similar to that
reported in chronic studies in OA, RA and chronic low back pain.
In
initial clinical studies for acute analgesia, patients were treated
with etoricoxib 120mg once daily for one to sever days. The adverse
experience profile in these studies was generally similar to that
reported in chronic studies in OA, RA and chronic low back pain.
In
the additional clinical studies for acute post-operative pain
associated with dental and abdominal gynecological surgeries
including 1222 patients treated with etoricoxib (90 or 120mg), the
adverse experience profile was generally similar to that reported in
the combined OA, RA, and chronic low back pain studies.
In
the combined studies for acute post-operative dental pain, the
incidence of post-dental extraction alveolitis (dry socket) reported
in patients treated with etoricoxib was similar to that of patients
treated with active comparators.
Post-marketing
experiences
The
following adverse reactions have been reported in post-marketing
experience.
Blood
and lymphatic systems disorders:
thrombocytopenia.
Immune
system disorders:
hypersensitivity reactions, including anaphylactic/anaphylactoid
reactions including shock.
Metabolism
and nutrition disorders:
hyperkalemia.
Psychiatric
disorders:
anxiety insomnia, confusion, hallucinations, depression,
restlessness.
Nervousness
system disorders:
dysgeusia, somnolence.
Eye
disorders:
blurred vision.
Cardiac
disorders:
congestive heart failure, palpitation, angina, arrhythmia.
Vascular
disorders:
hypersensitive crisis.
Respiratory,
thoracic and mediastinal disorders:
bronchospasm.
Gastrointestinal
disorders:
abdominal pain, oral ulcers, peptic ulcers including perforation and
bleeding (mainly in elderly patients) vomiting, diarrhea.
Hepatobiliary
disorders:
hepatitis, jaundice, hepatic failure.
Skin
and subcutaneous tissue disorders:
angioedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic
epidermal necrolysis, urticaria, fixed drug eruption.
Renal
and urinary disorders: renal
insufficiency, including renal failure (see Warnings and
precautions).
Overdosage
and Treatment:
In
clinical studies, administration of etoricoxib at single doses up to
500mg and multiple doses up to 150mg/day for 21 days did not result
in significant toxicity. There have been reports of acute overdosage
with etoricoxib, although adverse experiences were not reported in
the majority of cases. The most frequently observed adverse
experiences were consistent with the safety profile for etoricoxib
(e.g. gastrointestinal events, renovascular events).
In
the event of overdosage, 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.
Etoricoxib
is not dialyzable by hemodialysis; it is not known whether etoricoxib
is dialyzable by peritoneal dialysis.
Storage
Condition:
Store
ate temperatures not exceeding 30oC.
Protect from light. Store in the original package.
