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SIDE EFFECTS
Of the CELEBREX treated patients in controlled
trials, approximately 4,250 were patients with OA, approximately
2,100 were patients with RA, and approximately 1,050 were
patients with post-surgical pain. More than 8,500 patients
have received a total daily dose of CELEBREX of 200 mg
(100 mg BID or 200 mg QD) or more, including more than
400 treated at 800 mg (400 mg BID). Approximately 3,900
patients have received CELEBREX at these doses for 6 months
or more; approximately 2,300 of these have received it
for 1 year or more and 124 of these have received it for
2 years or more.
Adverse events from controlled trials: Table 4 lists all
adverse events, regardless of causality, occurring in
³2% of patients receiving CELEBREX from 12 controlled
studies conducted in patients with OA or RA that included
a placebo and/or a positive control group.
|
Table 4
Adverse Events Occurring in ³
2% Of Celebrex Patients |
| |
Celebrex
(100-200mg
BID)
and
(200mg QD) |
Placebo
|
Naproxen
500 mg
BID |
Ibuprofen
800 mg
TID |
Diclofenac
75 mg
BID |
| |
(N=4146)
|
(N=1864)
|
(N=1366)
|
(N=387)
|
(N=345)
|
| Gastrointestinal
|
| Abdominal
pain |
4.1%
|
2.8%
|
7.7%
|
9.0%
|
9.0%
|
| Diarrhea
|
5.6%
|
3.8%
|
5.3%
|
9.3%
|
5.8%
|
| Dyspepsia
|
8.8%
|
6.2%
|
12.2%
|
10.9%
|
12.8%
|
| Flatulence
|
2.2%
|
1.0%
|
3.6%
|
4.1%
|
3.5%
|
| Nausea
|
3.5%
|
4.2%
|
6.0%
|
3.4%
|
6.7%
|
| Body
as a whole |
| Back
Pain |
2.8%
|
3.6%
|
2.2%
|
2.6%
|
0.9%
|
| Peripheral
edema |
2.1%
|
1.1%
|
2.1%
|
1.0%
|
3.5%
|
| Injury-accidental
|
2.9%
|
2.3%
|
3.0%
|
2.6%
|
3.2%
|
| Central
and peripheral nervous system |
| Dizziness
|
2.0%
|
1.7%
|
2.6%
|
1.3%
|
2.3%
|
| Headache
|
15.8%
|
20.2%
|
14.5%
|
15.5%
|
15.4%
|
| Psychiatric
|
| Insomnia
|
2.3%
|
2.3%
|
2.9%
|
1.3%
|
1.4%
|
| Respiratory
|
| Pharyngitis
|
2.3%
|
1.1%
|
1.7%
|
1.6%
|
2.6%
|
| Rhinitis
|
2.0%
|
1.3%
|
2.4%
|
2.3%
|
0.6%
|
| Sinusitis
|
5.0%
|
4.3%
|
4.0%
|
5.4%
|
5.8%
|
| Upper
resp. tract Infection |
8.1%
|
6.7%
|
9.9%
|
9.8%
|
9.9%
|
| Skin
|
| Rash
|
2.2%
|
2.1%
|
2.1%
|
1.3%
|
1.2%
|
In placebo- or active-controlled clinical trials, the discontinuation
rate due to adverse events was 7.1% for patients receiving
CELEBREX and 6.1% for patients receiving placebo. Among
the most common reasons for discontinuation due to adverse
events in the CELEBREX treatment groups were dyspepsia and
abdominal pain (cited as reasons for discontinuation in
0.8% and 0.7% of CELEBREX patients, respectively). Among
patients receiving placebo, 0.6% discontinued due to dyspepsia
and 0.6% withdrew due to abdominal pain.
The following adverse events occurred in 0.1 - 1.9% of patients
regardless of causality.
| |
Celebrex
(100 - 200 mg BID or 200 mg QD) |
| Gastrointestinal |
Constipation,
diverticulitis, dysphagia, eructation, esophagitis,
gastritis, gastroenteritis, gastroesophageal reflux,
hemorrhoids, hiatal hernia, melena, stomatitis,
tooth disorder, vomiting |
| Cardiovascular |
Aggravated
hypertension, dry mouth, glaucoma, tenesmus |
| General |
Allergy
aggravated, allergic reaction, asthenia, chest pain,
cyst NOS, Edema generalized, face edema, fatigue,
fever, hot flushes, influenza-like symptoms, pain,
peripheral pain |
| Resistance
Mechanism Disorders |
Herpes
simplex, herpes zoster, infection bacterial, infection
Fungal, infection soft tissue, infection viral,
moniliasis, moniliasis genital, otitis media |
| Central,
peripheral nervous system |
Leg
cramps, hypertonia, hypoesthesia, migraine, neuralgia,
neuropathy, Paresthesia, vertigo |
| Female
reproductive |
Breast
fibroadenosis, breast neoplasm, breast pain, dysmenorrhea,
menstrual disorder, vaginal hemorrhage, vaginitis |
| Male
reproductive |
Prostatic
disorder |
| Hearing
and vestibular |
Deafness,
ear abnormality, earache, tinnitus |
| Heart
rate and rhythm |
Angina
pectoris, coronary artery disorder, myocardial infarction,
palpitation, tachycardia |
| Liver
and biliary system |
Hepatic
function abnormal, SGOT increased, SGPT increased |
| Metabolic
and nutritional |
BUN
increased, CPK increased, diabetes mellitus, hypercholesterolemia,
Hyperglycemia, hypokalemia, NPN increase, creatinine
increased,Alkaline phosphatase increased, weight
increase |
| Musculoskeletal |
Arthralgia,
arthrosis, bone disorder, fracture accidental, myalgia,
neck stiffness, synovitis, tendinitis |
| Platelets
(bleeding or clotting) |
Ecchymosis,
epistaxis, thrombocythemia |
| Psychiatric
|
Anorexia,
anxiety, appetite increased, depression, nervousness,
somnolence |
| Hemic
|
Anemia
|
| Respiratory
|
Bronchitis,
bronchospasm, bronchospasm aggravated, coughing,
dyspnea, Laryngitis, pneumonia |
| Skin
and appendages |
Alopecia,
dermatitis, nail disorder, photosensitivity reaction,
pruritus, rash erythematous, rash maculopapular,
skin disorder, skin dry, sweating increased, urticaria |
| Application
site disorders |
Cellulitis,
dermatitis contact, injection site reaction, skin
nodule |
| Special
senses |
Taste
perversion |
| Urinary
system |
Albuminuria,
cystitis, dysuria, hematuria, micturition frequency,
renal calculus, urinary incontinence, urinary tract
infection |
| Vision
|
Blurred
vision, cataract, conjunctivitis, eye pain |
Other serious adverse reactions which occur rarely (£0.1%),
regardless of causality: The following serious adverse events
have occurred rarely in patients, taking CELEBREX.
| Cardiovascular:
|
Syncope,
congestive heart failure, ventricular fibrillation,
pulmonary embolism, cerebrovascular accident, peripheral
gangrene, thrombophlebitis |
| Gastrointestinal:
|
Intestinal
obstruction, intestinal perforation, gastrointestinal
bleeding, colitis with bleeding, esophageal perforation,
pancreatitis, cholelithiasis, ileus |
| Hemic
and lymphatic: |
Thrombocytopenia |
| Nervous
system: |
Ataxia |
| Renal: |
Acute
renal failure |
| General: |
Sepsis,
sudden death |
DRUG INTERACTIONS
General: Significant interactions may occur when
celecoxib is administered together with drugs that inhibit
P450 2C9. Celecoxib metabolism is predominantly mediated
via cytochrome P450 2C9 in the liver. Co-administration
of celecoxib with drugs that are known to inhibit 2C9 should
be done with caution. In vitro studies indicate that celecoxib
is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.
In vitro studies also indicate that celecoxib, although
not a substrate, is an inhibitor of cytochrome P450 2D6.
Therefore, there is a potential for an in vivo drug interaction
with drugs that are metabolized by P450 2D6.
Clinical studies with celecoxib have identified potentially
significant interactions with fluconazole and lithium. Experience
with nonsteroidal anti-inflammatory drugs (NSAIDs) suggests
the potential for interactions with furosemide and ACE inhibitors.
The effects celecoxib on the pharmacokinetics and/or pharmacodynamics
of glyburide, ketoconazole, methotrexate, phenytoin, tolbutamide,
and warfarin have been studied in vivo and clinically important
interactions have not been found.
ACE
inhibitors: Reports suggest that NSAIDs may diminish
the antihypertensive effect of Angiotensin Converting Enzyme
(ACE) inhibitors. This interaction should be given consideration
in patients taking CELEBREX concomitantly with ACE-inhibitors.
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.
Aspirin:
CELEBREX can be used with low dose aspirin. However, concomitant
administration of aspirin with CELEBREX may result in an
increased rate of GI ulceration or other complications,
compared to use of CELEBREX alone (see CLINICAL PHARMACOLOGY
- CLINICAL STUDIES: Special Studies - Gastrointestinal).
Because of its lack of platelet effects, CELEBREX is not
a substitute for aspirin for cardiovascular prophylaxis.
Fluconazole: Concomitant administration
of fluconazole at 200 mg QD resulted in a two-fold increase
in celecoxib plasma concentration. This increase is due
to the inhibition of celecoxib metabolism via P450 2C9 by
fluconazole (see CLINICAL PHARMACOLOGY - Pharmacokinetics:
Metabolism). CELEBREX should be introduced at the lowest
recommended dose in patients receiving fluconazole.
Lithium: In a study conducted in
healthy subjects, mean steady-state lithium plasma levels
increased approximately 17% in subjects receiving lithium
450 mg BID with CELEBREX 200 mg BID as compared to subjects
receiving lithium alone. Patients on lithium treatment should
be closely monitored when CELEBREX is introduced or withdrawn.
Methotrexate: In an interaction study
of rheumatoid arthritis patients taking methotrexate, CELEBREX
did not have a significant effect on the pharmacokinetics
of methotrexate.
Warfarin: The
effect of celecoxib on the anti-coagulant effect of warfarin
was studied in a group of healthy subjects receiving daily
doses of 2-5 mg of warfarin. In these subjects, celecoxib
did not alter the anticoagulant effect of warfarin as determined
by prothrombin time. However, caution should be used when
administering CELEBREX with warfarin since these patients
are at increased risk of bleeding complications.
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