ע עבקנ הז ןולע טמרופ " רשואו קדבנ ונכותו תואירבה דרשמ י

Transcription

Celebra, Israel 28 Dec 2011
‫פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר‬
The format of this leaflet was determined by the Ministry of Health and its content was checked and approved
CELEBRA
celecoxib capsules
Cardiovascular Risk
 CELEBRA may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase
with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may
be at greater risk (see WARNINGS and CLINICAL STUDIES).

CELEBRA is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
 NSAIDs, including CELEBRA, cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These
events can occur at any time during use and without warning symptoms. Elderly patients are at greater
risk for serious gastrointestinal events (see WARNINGS).
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 100 mg capsule contains 100 mg celecoxib.
Each 200 mg capsule contains 200 mg celecoxib.
PHARMACEUTICAL FORM
100 mg Capsules: Opaque, white capsules with two blue bands marked 7767 and 100
200 mg Capsules: Opaque, white capsules with two gold bands marked 7767 and 200
DESCRIPTION
CELEBRA (celecoxib) is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]
benzenesulfonamide and is a diaryl-substituted pyrazole. It has the following chemical structure:
O
NH2
S
O
N
CH3
1
N
CF3
The empirical formula for celecoxib is C17H14F3N3O2S, and the molecular weight is 381.38.
CELEBRA oral capsules contain either 100 mg or 200 mg of celecoxib.
The inactive ingredients in CELEBRA capsules include:
lactose monohydrate, sodium lauryl sulphate, polyvidone K30, croscarmellose sodium, and magnesium stearate.
Capsule shells contain gelatin, titanium dioxide; ink contains yellow ferric oxide E172 (200 mg capsule) or FD&C
blue #2 Aluminum Lake E132 (100 mg capsule).
CLINICAL PHARMACOLOGY
Pharmacotherapeutic group
M01AH Coxibs
Mechanism of Action
Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and
antipyretic activities in animal models. The mechanism of action of celecoxib is believed to be due to inhibition of
prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations
in humans, celecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. COX-2 is induced in response
to inflammatory stimuli. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular
prostaglandin E2, causing inflammation, edema and pain. Celecoxib acts as an anti-inflammatory, analgesic, and
antipyretic agent in animal models by blocking the production of inflammatory prostanoids via COX-2 inhibition.
In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
In vivo and ex vivo studies show that celecoxib has a very low affinity for the constitutively expressed
cyclooxygenase 1 enzyme (COX-1). Consequently at therapeutic doses celecoxib has no effect on prostanoids
synthesized by activation of COX-1 thereby not interfering with normal COX-1 related physiological processes in
tissues, particularly the stomach, intestine and platelets.
Pharmacodynamics
Platelets
In clinical trials using normal volunteers, CELEBRA at single doses up to 800 mg and multiple doses of 600 mg
twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of
platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, CELEBRA is not a
substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of CELEBRA on
platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events
associated with the use of CELEBRA.
Fluid Retention
Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal
medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting
ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.
Pharmacokinetics
Absorption
The pharmacokinetics of celecoxib has been evaluated in approximately 1500 individuals. When given under
fasting conditions celecoxib is well absorbed reaching peak plasma levels after approximately 2-3 hrs after an
oral dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly
dose proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in Cmax
and AUC (see Food Effects). Oral bioavailability from capsules is about 99% relative to administration in
suspension (optimally available oral dosage form). Absolute bioavailability studies have not been conducted.
With multiple dosing, steady state conditions are reached on or before day 5. The pharmacokinetic parameters
of celecoxib in a group of healthy subjects are shown in Table 1.
2
Table 1
Summary of Single Dose (200 mg) Disposition
Kinetics of Celecoxib in Healthy Subjects1
Mean (%CV) PK Parameter Values
Cmax, ng/mL
Tmax, hr
Effective t1/2, hr
Vss/F, L
CL/F, L/hr
705 (38)
2.8 (37)
11.2 (31)
429 (34)
27.7 (28)
1
Subjects under fasting conditions (n=36, 19-52 yrs.)
Food Effects
When CELEBRA capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2
hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200
mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of
the drug in aqueous media. Coadministration of CELEBRA with an aluminum- and magnesium-containing
antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in
AUC. CELEBRA, at doses up to 200 mg twice daily, can be administered without regard to timing of meals.
Higher doses (400 mg twice daily) should be administered with food to improve absorption.
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib
was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant
alterations in Cmax, Tmax or T1/2 after administration of capsule contents on applesauce.
Distribution
Plasma protein binding, which is concentration independent, is about 97% at therapeutic plasma concentrations.
In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, 1-acid glycoprotein.
The apparent volume of distribution at steady state (Vss/F) is approximately 400 L, suggesting extensive
distribution into the tissues. Celecoxib is not preferentially bound to red blood cells.
Metabolism
Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, a primary alcohol, the
corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These
metabolites are inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 2C9 activity is reduced in individuals
with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3
polymorphism.
In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as
either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median Cmax and AUC 0-24 of celecoxib on day 7
were approximately 4-fold and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other
genotypes. In three separate single dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3,
single-dose AUC 0-24 increased by approximately 3-fold compared to normal metabolizers. It is estimated that
the frequency of the homozygous *3/*3 genotype is 0.3 – 1.0% among different ethnic groups.
Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience
with other CYP2C9 substrates should be administered celecoxib with caution. Consider starting treatment at half
the lowest recommended dose. (See Sections DOSAGE AND ADMINISTRATION and DRUG
INTERACTIONS.)
Excretion
Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the
urine and feces. Following a single oral dose of radio labeled drug, approximately 57% of the dose was excreted
in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the
carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It
appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t1/2)
determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The
apparent plasma clearance (CL/F) is about 500 mL/min. After multiple dosing, elimination half-life is 8-12 hours.
With multiple dosing steady state plasma concentrations are reached before day 5. The intersubject variability
on the main pharmacokinetic parameters (AUC, Cmax, elimination half-life) is about 30%. The mean steady
state volume of distribution is about 500 L/70kg in young healthy adults indicating wide distribution of celecoxib
into the tissues. Preclinical studies indicate that the drug crosses the blood/brain barrier.
Special Populations
3
Elderly
At steady state, elderly subjects (over 65 years old) had one and a half to two-fold increase in mean Cmax and
AUC for celecoxib, compared to the young subjects. This is a predominantly weight-related rather than agerelated change, celecoxib levels being higher in lower weight individuals and consequently higher in the elderly
population who are generally of lower mean weight than the younger population. Therefore, elderly females tend
to have higher drug plasma concentrations than elderly males.Dose adjustment in the elderly is not generally
necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended
dose.
Pediatric
The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was
evaluated in 152 juvenile idiopathic arthritis (JIA) patients 2 years to 17 years of age weighing 10 kg with
oligoarticular, oligoarticular extended, or polyarticular rheumatoid factor positive or negative) course JIA and in
patients with systemic onset JIA (with currently inactive systemic features). Population pharmacokinetic analysis
indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to
increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively,
compared with a 70 kg adult RA patient.
Twice-daily administration of 50 mg capsules to JIA patients weighing 10 to 25 kg and twice daily
administration of 100 mg capsules to JIA patients weighing >25 kg should achieve plasma concentrations similar
to those observed in the clinical trial that demonstrated the non-inferiority of celecoxib to naproxen 7.5 mg/kg
twice daily (see DOSAGE AND ADMINISTRATION). Celecoxib has not been studied in JIA patients under the
age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks.
Race
Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in
Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown and therefore
treatment should be initiated at the lowest recommended dose.
Hepatic Insufficiency
A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic
impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above
that seen in healthy control subjects. Therefore, the daily recommended dose of CELEBRA capsules should be
reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with
severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of CELEBRA in patients with
severe hepatic impairment is not recommended (see DOSAGE AND ADMINISTRATION).
Renal Insufficiency
In elderly volunteers with age related reductions in glomerular filtration rate (GFR) (mean
GFR>65mL/min/1.73m2) and in patients with chronic stable renal insufficiency (GFR 35-60mL/min/1.73m2)
celecoxib pharmacokinetics were comparable to those seen in patients with normal renal function. No significant
relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not
been studied. Similar to other NSAIDs, CELEBRA is not recommended in patients with severe renal
insufficiency (see WARNINGS – Advanced Renal Disease).
Renal Effects
At the present time the relative roles of COX-1 and COX-2 in renal physiology is not completely understood.
Celecoxib reduces the urinary excretion of PGE2 and 6-keto-PGF1 (a prostacyclin metabolite) but leaves
serum thromboxane B2 (TXB2) and urinary excretion of 11-dehydro-TXB2, a thromboxane metabolite (both
COX-1 products) unaffected. Specific studies have shown celecoxib produces no decreases in GFR in the
elderly or those with chronic renal insufficiency. These studies have also shown transient reductions in fractional
excretion of sodium. In studies in patients with arthritis a comparable incidence of peripheral edema has been
observed to that seen with non-specific COX-inhibitors (which also possess COX-2 inhibitory activity). This was
most evident in patients receiving concomitant diuretic therapy. However increased incidences of hypertension
and cardiac failure have not been observed and the peripheral edema has been mild and self-limiting.
CLINICAL STUDIES
Osteoarthritis (OA)
4
CELEBRA has demonstrated significant reduction in joint pain compared to placebo. CELEBRA was evaluated
for treatment of the signs and the symptoms of OA of the knee and hip in approximately 4,200 patients in
placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with
CELEBRA 100 mg twice daily or 200 mg once daily resulted in improvement in the WOMAC (Western Ontario
and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA.
In three 12-week studies of pain accompanying OA flare, CELEBRA doses of 100 mg twice daily and 200 mg
twice daily provided significant reduction of pain within 24–48 hours of initiation of dosing. At doses of 100 mg
twice daily or 200 mg twice daily the effectiveness of CELEBRA was shown to be similar to that of naproxen 500
mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice
daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg
twice daily or 200 mg once daily.
Rheumatoid Arthritis (RA)
CELEBRA has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to
placebo. CELEBRA was evaluated for treatment of the signs and symptoms of RA in approximately 2,100
patients in placebo- and active-controlled clinical trials of up to 24 weeks in duration. CELEBRA was shown to
be superior to placebo in these studies, using the ACR20 Responder Index, a composite of clinical, laboratory,
and functional measures in RA. CELEBRA doses of 100 mg twice daily and 200 mg twice daily were similar in
effectiveness and both were comparable to naproxen 500 mg twice daily. Although CELEBRA 100 mg twice
daily and 200 mg twice daily provided similar overall effectiveness, some patients derived additional benefit from
the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with
100–200 mg twice daily.
Juvenile Idiopathic Arthritis (JIA)
In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non-inferiority study, 242
patients, 2 years to 17 years of age with oligoarticular, oligoarticular extended, or polyarticular (rheumatoid factor
positive or negative) course JIA and in patients with systemic onset JIA (with currently inactive systemic
features), received the following treatments: CELEBRA 3 mg/kg (to a maximum of 150 mg) twice daily;
CELEBRA 6 mg/kg (to a maximum of 300 mg) twice daily; naproxen 7.5 mg/kg (to a maximum of 500 mg) twice
daily. The response rates were based upon the ACR Pediatric 30 criterion, which is a composite of clinical,
laboratory, and functional measures of JIA. The ACR Pediatric 30 response rates at week 12 were 69%, 80%
and 67% in the CELEBRA 3 mg/kg, CELEBRA 6 mg/kg, and naproxen treatment groups, respectively,
demonstrating non-inferiority of both doses to naproxen. Persistence of treatment effect was observed during a
12-week open-label extension to the 12-week double-blind study, in which 202 patients received CELEBRA 6
mg/kg to a maximum of 300 mg twice daily.
The efficacy and safety of CELEBRA for JIA have not been studied beyond 6 months. The long-term
cardiovascular toxicity in children exposed to CELEBRA has not been evaluated and it is unknown if the longterm risk may be similar to that seen in adults exposed to CELEBRA or other COX-2 selective and non-selective
NSAIDs. (See Section Cardiovascular Effects.)
Analgesia, including Primary Dysmenorrhea
In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea,
CELEBRA relieved pain that was rated by patients as moderate to severe. Single doses (see Section
POSOLOGY AND METHOD OF ADMINISTRATION) of CELEBRA provided pain relief within 60 minutes.
Ankylosing Spondylitis (AS)
CELEBRA was evaluated in AS patients in two placebo- and active- (naproxen, or ketoprofen) controlled clinical
trials of 6 and 12 weeks duration. CELEBRA at doses of 100mg twice daily, 200mg once daily and 400mg once
daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures
assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and
functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no
difference in the extent of improvement between the 200 mg and 400 mg CELEBRA doses in a comparison of
mean change from baseline, but there was a greater percentage of patients who responded to CELEBRA 400
mg, 53%, than to CELEBRA 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria
(ASAS 20). The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute
improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient
global, pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also
demonstrated no change in the responder rates beyond 6 weeks.
5
Special Studies
Celecoxib Long-Term Arthritis Safety Study (CLASS)
The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a prospective long-term safety outcome study
conducted postmarketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received
CELEBRA 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg
TID or diclofenac 75 mg BID (common therapeutic doses). Median exposures for CELEBRA (n = 3,987) and
diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this
outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction).
Patients were allowed to take concomitant low-dose ( 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis
(ASA subgroups: CELEBRA, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of
complicated ulcers between CELEBRA and the combined group of ibuprofen and diclofenac were not statistically
significant.
Those patients on CELEBRA and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of
complicated ulcers compared to those not on ASA (N=3105). The Kaplan Meier rate for complicated ulcers at 9
months was 1.12% versus 0.32% for those on low dose ASA and those not on ASA, respectively (see
WARNINGS — Gastrointestinal Effects).
The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with
CELEBRA 400 mg BID are described in Table 2. Table 2 also displays results for patients less than or greater than
65 years of age. The difference in rates between CELEBRA alone and CELEBRA with ASA groups may be due to
the higher risk for GI events in ASA users.
Table 3
Complicated and Symptomatic Ulcer Rates in Patients Taking CELEBRA 400 mg BID (Kaplan-Meier Rates
at 9 months [%]) Based on Risk Factors
Complicated and Symptomatic
Ulcer Rates
All Patients
Celebra alone (n=3105)
Celebra with ASA (n=882)
0.78
2.19
Patients <65 Years
0.47
1.26
Patients 65 Years
1.40
3.06
In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in
patients taking CELEBRA alone or CELEBRA with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48
weeks. These results are to be expected in patients with a prior history of ulcer disease (see WARNINGS –
Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation and ADVERSE
REACTIONS – Safety Data from CLASS Study – Hematological Events).
Cardiovascular Safety Long-Term Study of Alzheimer's Disease Anti-Inflammatory Prevention Trial
(ADAPT)
Data from a another long-term study ADAPT (The Alzheimer's Disease Anti-inflammatory Prevention Trial) did
not show a significantly increased cardiovascular risk with celecoxib 200 mg twice daily compared to placebo.
The relative risk compared to placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95% CI
0.61 - 2.12) with celecoxib 200 mg twice daily
6
Cardiovascular Safety - Meta-Analysis from Chronic Usage Studies
No long-term controlled clinical study specifically designed to assess the CV safety of chronic celecoxib dosing of
any duration has been conducted. However, a meta-analysis of safety data (adjudicated, investigator-reported
serious adverse events) from 39 completed celecoxib clinical studies of up to 65 weeks in duration has been
conducted, representing 41,077 patients [23,030 (56.1 %) patients exposed to celecoxib 200-800 mg total daily
dose (TDD), 13,990 (34.1 %) patients exposed to non-selective NSAIDs, and 4,057 (9.9 %) patients exposed to
placebo].
In this analysis, the adjudicated event rate for the composite endpoint of CV death, non-fatal myocardial
infarction and non-fatal stroke was similar between celecoxib (N = 19,773; 0.96 events/100 patient-years) and
non-selective NSAID (N = 13,990; 1.12 events/100 patient-years) treatment (RR = 0.90, 95% CI 0.60 - 1.33).
This pattern of effect was maintained with or without ASA use (≤ 325mg). The adjudicated event rate of non-fatal
myocardial infarction trended higher (RR = 1.76, 95% CI 0.93 - 3.35); however that of non-fatal stroke trended
lower (RR = 0.51, 95% CI 0.23 - 1.10), and that of cardiovascular death was comparable (RR = 0.57, 95% CI
0.28 - 1.14) for celecoxib compared to combined non-selective NSAIDs.
In this analysis, the adjudicated event rate for the composite endpoint of CV death, non-fatal myocardial
infarction and non-fatal stroke was 1.42/100 patient-years for celecoxib (N = 7,462) and 1.20/100 patient-years
for placebo (N = 4,057) treatment (RR = 1.11, 95% CI 0.47 - 2.67). This pattern of effect was maintained with or
without ASA use (≤325mg). The incidence of non-fatal myocardial infarction trended higher (RR = 1.56, 95% CI
0.21 - 11.90), as did that of cardiovascular death (RR = 1.26, 95% CI 0.33 - 4.77), and that of non-fatal stroke
was similar (RR = 0.80, 95% CI 0.19 - 3.31) for celecoxib compared to placebo.
Cardiovascular Safety
Cardiovascular safety outcomes were evaluated in the CLASS trial. Kaplan-Meier cumulative rates for
investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism,
deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents)
demonstrated no differences between the CELEBRA, diclofenac, or ibuprofen treatment groups. The cumulative
rates in all patients at nine months for CELEBRA, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%,
respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were
less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the
three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the
ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the
risk to a similar degree.
Cardiovascular Safety - Long-Term Studies Involving Patients With Sporadic Adenomatous Polyps
Two studies involving patients with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC
trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous
Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death,
myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The
PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the hazard ratios compared to placebo for a composite endpoint of cardiovascular death,
myocardial infarction, or stroke (adjudicated) were 3.4 (95% CI 1.4 - 8.5) with celecoxib 400 mg twice daily and
2.8 (95% CI 1.1 - 7.2) with celecoxib 200 mg twice daily (cumulative rates for this composite endpoint over
3 years were 20/671 subjects, 3.0%, and 17/685 subjects, 2.5%, respectively, compared to 6/679 subjects, 0.9%,
for placebo). The increases for both celecoxib dose groups versus placebo were mainly driven by myocardial
infarction.
In the PreSAP trial, the hazard ratio compared to placebo for this same composite endpoint was 1.2 (95% CI 0.6
- 2.4) with celecoxib 400 mg once daily (cumulative rates for this composite endpoint over 3 years were 21/933
subjects, 2.3%, compared to 12/628 subjects, 1.9%, for placebo).
Endoscopic Studies
Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients who were enrolled in
five controlled randomized 12-24 week trials using active comparators, two of which also included placebo
controls. There was no consistent relationship between the incidence of gastroduodenal ulcers and the dose of
CELEBRA over the range studied.
7
Table 4 summarizes the incidence of endoscopic ulcers in two 12-week studies that enrolled patients in whom
baseline endoscopies revealed no ulcers.
Table 4
Incidence of Gastroduodenal Ulcers from Endoscopic Studies in OA and RA Patients
3 Month Studies
Study 1 (n = 1108)
Study 2 (n= 1049)
Placebo
2.3% (5/217)
2.0% (4/200)
Celecoxib 50 mg Twice Daily
3.4% (8/233)
Celecoxib100 mg Twice Daily
3.1% (7/227)
4.0% (9/223)
5.9% (13/221)
2.7% (6/219)
---
4.1% (8/197)
Naproxen 500 mg Twice Daily
---
16.2% (34/210)*
17.6% (37/210)*
*p0.05 vs. all other treatments
Table 5 summarizes data from two 12-week studies that enrolled patients in whom baseline endoscopies
revealed no ulcers. Patients underwent interval endoscopies every 4 weeks to give information on ulcer risk over
time.
Table 5
Incidence of Gastroduodenal Ulcers from 3-Month Serial Endoscopy Studies in OA and RA Patients
Week 4
Week 8
Week 12
Final
CELECOXIB
4.0%
2.2%
1.5%
7.5%
200 mg twice daily
(10/252)*
(5/227)*
(3/196)*
(20/266)*
Naproxen
19.0%
14.2%
9.9%
34.6%
500 mg twice daily
(47/247)
(26/182)
(14/141)
(89/257)
CELECOXIB
3.9%
2.4%
1.8%
7.0%
200 mg twice daily
(13/337) †
(7/296) †
(5/274) †
(25/356) †
Diclofenac
5.1%
3.3%
2.9%
9.7%
75 mg twice daily
(18/350)
(10/306)
(8/278)
(36/372)
Ibuprofen
13.0%
6.2%
9.6%
23.3%
800 mg three times daily
(42/323)
(15/241)
(21/219)
(78/334)
Study 3 (n=523)
Study 4 (n=1062)
*p 0.05 celecoxib vs. naproxen based on interval and cumulative analyses
† p0.05 celecoxib vs. ibuprofen based on interval and cumulative analyses
One randomized and double-blind 6-month study in 430 RA patients was conducted in which an endoscopic
examination was performed at 6 months.
The incidence of endoscopic ulcers in patients taking celecoxib 200 mg twice daily was 4% vs. 15% for patients
taking diclofenac SR 75 mg twice daily (p<0.001).
In 4 of the 5 endoscopic studies, approximately 11% of patients (440/4,000) were taking aspirin (325 mg/day).
In the celecoxib groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users.
8
However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed
in the active comparator groups, with or without aspirin.
The correlation between findings of endoscopic studies, and the relative incidence of clinically significant serious
upper GI events has not been established. Serious clinically significant upper GI bleeding has been observed in
patients receiving celecoxib in controlled and open-labeled trials, albeit infrequently (see Section Gastrointestinal
Effects).
Gastrointestinal Safety Meta-Analysis from Osteoarthritis and Rheumatoid Arthritis Studies
An analysis of 31 randomized controlled clinical studies in osteoarthritis and rheumatoid arthritis, involving
39,605 patients with osteoarthritis (N=25,903), rheumatoid arthritis (N=3,232) or patients with either condition
(N=10,470) compared the incidence of GI adverse events in celecoxib treated patients with placebo or NSAIDs
(including naproxen, diclofenac and ibuprofen). The incidence of clinical ulcers and ulcer bleeds with celecoxib
200-400 mg total daily dose was 0.2% compared with an incidence of 0.6% with NSAIDs (RR=0.35; 95% CI
0.22-0.56).
Use with Aspirin
The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a prospective long-term safety outcome study
conducted postmarketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received celecoxib
400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three
times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for celecoxib (n =
3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The Kaplan-Meier
cumulative rates at 9 months are provided for all analyses. The primary endpoint of this outcome study was the
incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to
take concomitant low-dose ( 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis (ASA
subgroups:celecoxib, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of
complicated ulcers between celecoxib and the combined group of ibuprofen and diclofenac were not statistically
significant. Those patients on celecoxib and concomitant low-dose ASA experienced 4-fold higher rates of
complicated ulcers compared to those not on ASA (see Section Gastrointestinal Effects). The results for
celecoxib are displayed in Table 6.
Table 6
Effects of Co-Administration of Low-Dose Aspirin on Complicated Ulcer Rates with CELECOXIB 400 mg
Twice Daily (Kaplan-Meier Rates at 9 months [%])
Complicated Ulcers
Non-Aspirin Users
Aspirin Users
n=3105
n=882
0.32
1.12
Platelet Function
In healthy volunteers, celecoxib at therapeutic doses and at multiple doses of 600 mg twice daily (three times the
highest recommended dose) had no effect on platelet aggregation and bleeding time compared to placebo.
Active controls (non-specific COX inhibitors) all significantly reduced platelet aggregation and prolonged bleeding
time.
9
% Platelet Aggregation to Arachidonate
(Mean + SE) After Multiple Doses
Bleeding Time After Multiple Doses
- Change From Baseline
360
*
**
100
240
Sec
% 50
120
*
**
0
n=8
Placebo
0
n=8
n=8
celecoxib Non-Specific
COX Inhibitor
600mg
twice
(Naproxen
daily
500 mg twice
daily)
n=8
Placebo
n=8
n=8
celecoxib Non-Specific
COX Inhibitor
600mg
twice daily
(Naproxen
500 mg twice
daily)
* Significantly different from placebo; p<0.05
** Significantly different from celecoxib; p<0.05
Preclinical safety data
Preclinical safety data reveal no special hazard for humans based on conventional studies of repeated dose
toxicity, mutagenicity or carcinogenicity. Conventional embryo-fetal toxicity studies resulted in dose dependent
occurrences of diaphragmatic hernia in rat fetuses and cardiovascular malformations in rabbit fetuses. In both
species, these effects were observed at systemic exposure levels 5-6 times those seen at the highest
recommended clinical dose (400 mg daily).
In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and postimplantation losses, and reduced embryo/fetal survival. These effects, which were seen at oral dosages of
approximately 6-fold human systemic exposure, are expected following inhibition of prostaglandin synthesis.
Animal Toxicology
An increase in the incidence of background findings of spermatocele with or without secondary changes such as
epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile
rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with
dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not
observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of
this observation is unknown.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of CELEBRA and other treatment options before deciding to
use CELEBRA. Use the lowest effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).
CELEBRA is indicated for symptomatic treatment of inflammation and pain in osteoarthritis and
rheumatoid arthritis:
CONTRAINDICATIONS
CELEBRA is contraindicated in patients with known hypersensitivity to celecoxib or any other ingredient of the
product.
CELEBRA should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.
CELEBRA should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions
after taking aspirin or other NSAIDs including other cyclooxygenase-2 (COX-2) specific inhibitors. Severe, rarely
10
fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS –
Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma).
CELEBRA is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft
(CABG) surgery (see WARNINGS).
WARNINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
CELEBRA may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and
stroke, which can be fatal. In the APC trial, the relative risk for the composite endpoint of cardiovascular death,
MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for CELEBRA 400 mg twice daily and 2.5 (95% CI 1.0 – 6.4) for the
CELEBRA 200 mg twice daily compared to placebo (see Special Studies – Adenomatous Polyp Studies).
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. This risk may increase with dose,
duration of use, and baseline cardiovascular risk factors. Patients with known CV disease or risk factors for CV
disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with
CELEBRA, the lowest effective dose should be used for the shortest duration possible. Physicians and patients
should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur.
CELEBRA is not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases
because of the lack of effect on platelet function. Because CELEBRA does not inhibit platelet aggregation,
antiplatelet therapies (e.g., acetylsalicylic acid) should not be discontinued. The concurrent use of aspirin and
CELEBRA does increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 1014 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see
CONTRAINDICATIONS).
Hypertension
As with all NSAIDS, CELEBRA can lead to the onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including
CELEBRA, should be used with caution in patients with hypertension. Blood pressure should be monitored
closely during the initiation of therapy with CELEBRA and throughout the course of therapy. The rates of
hypertension from the CLASS trial in the CELEBRA, ibuprofen and diclofenac treated patients were 2.4%, 4.2%
and 2.5%, respectively (see Special Studies - CLASS).
Congestive Heart Failure, fluid retention and Edema
As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in
some patients taking CELEBRA. In the CLASS study (see Special Studies – CLASS), the Kaplan-Meier
cumulative rates at 9 months of peripheral edema in patients on CELEBRA 400 mg twice daily (4-fold and 2-fold
the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg
twice daily were 4.5%, 6.9% and 4.7%, respectively.
Therefore, patients with pre-existing congestive heart failure or hypertension should be closely monitored.
CELEBRA should be used with caution in patients with compromised cardiac function, pre-existing edema, or
other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or
otherwise at risk of hypovolemia.
Gastrointestinal Effects–Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including CELEBRA, can cause serious gastrointestinal adverse events including inflammation,
bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which may be fatal.
These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with
NSAIDs Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is
symptomatic. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS
trial, and 2.19% for the subgroup on low dose ASA. Patients 65 years of age and older had an incidence of
1.40% at nine months, 3.06% when also taking ASA (see Special Studies - CLASS). With longer duration of
use of NSAIDs, there is a trend for 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.
11
NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease,
gastrointestinal bleeding or inflamation. Patients with a prior history of peptic ulcer disease and/or
gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in
patients treated with NSAIDs include concomitant use of oral corticosteroids, anticoagulants or aspirin, longer
duration of NSAID therapy, smoking, use of alcohol, older age, cardiovascular disease,and poor general health
status. 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 in patients treated with CELEBRA, the lowest effective
dose should be used for the shortest possible duration. Physicians and patients should remain alert for signs
and symptoms of GI ulceration and bleeding during CELEBRA therapy and promptly initiate additional evaluation
and treatment if a serious GI adverse event is suspected. For high risk patients, alternate therapies that do not
involve NSAIDs should be considered.
Renal Effects
NSAIDs, including CELEBRA may cause renal toxicity. Clinical trials with CELEBRA have shown renal effects
similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with
impaired renal function, heart failure, liver dysfunction, and the elderly. Such patients should be carefully
monitored while receiving treatment with CELEBRA.
Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate
patients first and then start therapy with CELEBRA.
Advanced Renal Disease
Renal function should be closely monitored in patients with advanced renal disease who are administered
CELEBRA. (See DOSAGE AND ADMINISTRATION)
Anaphylactoid Reactions
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to
CELEBRA. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been
reported in patients receiving CELEBRA. CELEBRA 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.
Serious Skin Reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic
epidermal necrolysis, have been reported very rarely in association with the use of CELEBRA. These serious
events can occur without warning and in patients without prior known sulfa allergy. Patients appear to be at
highest risk for these events early in the course of therapy: the onset of the event occurring in the majority of
cases within the first month of treatment. CELEBRA should be discontinued at the first appearance of skin rash,
mucosal lesions, or any other sign of hypersensitivity.
Systemic Onset Juvenile Idiopathic Arthritis
NSAIDs including celecoxib should be used only with caution in patients with systemic onset JIA, due to the risk
of disseminated intravascular coagulation. Patients receiving celecoxib who have systemic onset JIA should be
monitored for the development of abnormal coagulation tests.
Pregnancy
In late pregnancy all NSAIDS, including CELEBRA, should be avoided because they may cause premature
closure of the ductus arteriosus.
PRECAUTIONS
General
CELEBRA 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.
12
The pharmacological activity of CELEBRA in reducing inflammation, and possibly fever, may diminish the utility
of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.
The concomitant use of CELEBRA and a non-aspirin NSAID should be avoided.
Elderly Use
Of the total number of patients who received CELEBRA in clinical trials, more than 3,300 were 65-74 years of
age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in
effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal
function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and
platelet aggregation, the results were not different between elderly and young volunteers. However, as with
other NSAIDS, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing
reports of fatal GI events and acute renal failure in the elderly than in younger patients (see WARNINGS –
Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation).
Hepatic Effects
Borderline elevations of one or more liver associated enzymes may occur in up to 15% of patients taking
NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have
been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may
progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic
reactions, including jaundice and fatal fulminant hepatitis (some with fatal outcome), liver necrosis and hepatic
failure (some with fatal outcome or requiring liver transplant) have been reported with CELEBRA. In controlled
clinical trials of CELEBRA, the incidence of borderline elevations (greater than or equal to 1.2 times and less
than 3 times the upper limit of normal) of liver associated enzymes was 6% for CELEBRA and 5% for placebo,
and approximately 0.2% of patients taking CELEBRA and 0.3% of patients taking placebo had notable elevations
of ALT and AST.
Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of CELEBRA in
patients with severe hepatic impairment is not recommended. CELEBRA should be used with caution when
treating patients with moderate hepatic impairment (Child-Pugh Class B), and initiated at the lowest
recommended dose.
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 CELEBRA. If clinical signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), CELEBRA should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving CELEBRA. In controlled clinical trials the incidence of anemia
was 0.6% with CELEBRA and 0.4% with placebo. Patients on long-term treatment with CELEBRA should have
their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.
CELEBRA 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 PHARMACOLOGY – Platelets).
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive
asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including
bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
CELEBRA 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
Patients should be informed of the following information before initiating therapy with CELEBRA and periodically
during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide
that accompanies each prescription dispensed.
1. CELEBRA, like other NSAIDs, may cause serious CV side effects such as MI or stroke which may result
in hospitalization and even death. Although serious CV events can occur without warning symptoms,
patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of
speech, and should ask for medical advice if they observe any of these signs or symptoms. Patients should
be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
2. CELEBRA, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as
13
ulcers and bleeding, which may result in hospitalization and even death. 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 including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be
apprised of the importance of this follow-up (see WARNINGS – Gastrointestinal Effects – Risk of
Gastrointestinal Ulceration, Bleeding and Perforation).
3. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their
physicians as soon as possible. CELEBRA is a sulfonamide and can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TENS, which may result in hospitalizations and even death. These reactions
can occur with all NSAIDs, even non-sulfonamides. Although serious skin reactions may occur without
warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of
hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or
symptoms. Patients with prior history of sulfa allergy should not take CELEBRA.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. 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). Patients should be
instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms
occur.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of
the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop
any of these signs and symptoms (see WARNINGS – Anaphylactoid Reactions).
7. Patients should be informed that in late pregnancy CELEBRA 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. Patients on long-term treatment with NSAIDs, should have their
CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen,
CELEBRA should be discontinued.
In controlled clinical trials, elevated BUN occurred more frequently in patients receiving CELEBRA compared
with patients on placebo. This laboratory abnormality was also seen in patients who received comparator
NSAIDs in these studies. The clinical significance of this abnormality has not been established.
DRUG INTERACTIONS
General
Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver.
Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience
with other CYP2C9 substrates should be administered CELEBRA with caution as they may have abnormally high
plasma levels due to reduced metabolic clearance. Consider starting treatment at half the lowest recommended
dose (See DOSAGE AND ADMINISTRATION, PHARMACOKINETICS- metabolism).
In vitro studies 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.
Drug Specific
ACE-inhibitors and Angiotensin II antagonists
Inhibition of prostaglandins may diminish the antihypertensive effect of angiotensin converting enzyme (ACE)
inhibitors and/or angiotensin II antagonists. This interaction should be given consideration in patients taking
CELEBRA concomitantly with ACE-inhibitors and/or angiotensin II antagonists. However, a clinical study with
lisinopril showed no significant pharmacodynamic interaction with respect to blood pressure.
14
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Aspirin
CELEBRA does not interfere with the anti-platelet effect of low-dose aspirin. However, concomitant
administration of aspirin with CELEBRA increases the rate of GI ulceration or other complications, compared to
use of CELEBRA alone. (see CLINICAL STUDIES – Special Studies –CLASS, WARNINGS –
Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation, and WARNINGS –
Cardiovascular Effects).
Because of its lack of platelet effects, CELEBRA is not a substitute for aspirin for cardiovascular prophylaxis.
Diuretics
Clinical studies have shown that NSAIDs, in some patients, can reduce the natriuretic effect of furosemide and
thiazides by inhibition of renal prostaglandin synthesis.
Fluconazole and ketoconazole
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.
CELEBRA should be introduced at the lowest recommended dose in patients receiving the CYP2C9 inhibitor
fluconazole (see PHARMACOKINETICS – Metabolism). Ketoconazole, a CYP3A4 inhibitor, showed no
clinically relevant inhibition in the metabolism of CELEBRA.
Lithium
In healthy subjects, lithium plasma levels increased approximately 17% in subjects receiving lithium together with
CELEBRA. Patients on lithium treatment should be closely monitored when CELEBRA is introduced or
withdrawn.
Warfarin or Similar Agents
In patients on concurrent therapy with warfarin or similar agents, serious bleeding events, some of them fatal,
have been reported. Because increases in prothrombin time (INR) have been reported, anticoagulant activity
should be monitored after initiating treatment with CELEBRA or changing the dose.
Oral contraceptives
In an interaction study, CELEBRA had no clinically relevant effects on the pharmacokinetics of a prototype
combination oral contraceptive (1 mg norethindrone/ 0.035 mg ethinyl estradiol).
Other drugs
No clinically important interactions have been observed with celecoxib and antacids (aluminum and magnesium),
omeprazole, methotrexate, glibenclamide (glyburide), phenytoin, or tolbutamide.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females
(approximately 2- to 4-fold the human exposure as measured by the AUC0-24 at 200 mg twice daily) or in mice
given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately equal to human exposure as
measured by the AUC0-24 at 200 mg twice daily) for two years.
Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor
clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow.
Celecoxib did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day (approximately 11fold human exposure at 200 mg twice daily based on the AUC0-24).
15
PREGNANCY AND LACTATION
Pregnancy
There are no studies in pregnant women. Studies in animals have shown reproductive toxicity (See Section
PRECLINICAL SAFETY DATA). The relevance of these data for humans is unknown.
CELEBRA, as with other drugs inhibiting prostaglandin synthesis, may cause uterine inertia and premature
closure of the ductus arteriosus and should be avoided during the third trimester of pregnancy.
CELEBRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk
to the fetus.
Lactation
Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Administration of
celecoxib to lactating women has shown very low transfer of celecoxib into breast milk.Because of the potential
for serious adverse reactions in nursing infants from CELEBRA, 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.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
The effect of CELEBRA on ability to drive or use machinery has not been studied, but based on its
pharmacodynamic properties and overall safety profile it is unlikely to have an effect.
ADVERSE REACTIONS
Clinical Trials
1) The following adverse reactions in Table 7 were reported at incidence rates greater than 0.01% and greater
than those reported for placebo during 12 placebo- and/or active-controlled clinical trials of duration up to 12
weeks at daily doses from 100 mg up to 800 mg in adults. Adverse reactions are listed by system organ class
and ranked by frequency. Frequencies are defined as: common ( 1% and < 10%), uncommon ( 0.1% and <
1%), rare ( 0.01% and < 0.1%).
Table 7.
Adverse Reactions From the 12 Placebo- and/or Active-Controlled Clinical Trials of
Duration up to 12 Weeks and Daily Doses of 100mg – 800mg in Adults
System Organ Class
Frequency
Infections and infestations
Common
Blood and lymphatic system disorders
Uncommon
Immune system disorders
Common
Psychiatric disorders
Common
Uncommon
Rare
Nervous system disorders
Common
Uncommon
Eye disorders
Uncommon
Ear and labyrinth disorders
Uncommon
Cardiac disorders
Uncommon
Adverse Drug Reaction
Bronchitis, pharyngitis, rhinitis, sinusitis, upper
respiratory tract infection, urinary tract infection
Anemia, thrombocytopenia
Allergy aggravated
Insomnia
Anxiety
Confusion
Dizziness, hypertonia
Somnolence
Blurred vision
Tinnitus
Arrhythmia, palpitation, tachycardia
16
Table 7.
Adverse Reactions From the 12 Placebo- and/or Active-Controlled Clinical Trials of
Duration up to 12 Weeks and Daily Doses of 100mg – 800mg in Adults
System Organ Class
Frequency
Rare
Vascular disorders
Uncommon
Respiratory, thoracic and mediastinal
disorders
Common
Gastrointestinal disorders
Common
Uncommon
Rare
Hepatobiliary disorders
Rare
Skin and subcutaneous tissue disorders
Common
Uncommon
Rare
General disorders and administration site
conditions
Common
Injury, poisoning and procedural conditions
Common
Congestive heart failure
Aggravated hypertension, flushing, hypertension
Coughing
Abdominal pain, diarrhea, dyspepsia, flatulence, tooth
disorder
Vomiting
Gastric ulcer, duodenal ulcer, esophageal ulceration,
intestinal perforation, pancreatitis
Elevation of hepatic enzymes
Pruritus, rash
Alopecia, ecchymosis, urticaria
Angioedema, bullous eruption
Flu-like symptoms, peripheral edema
Accidental injury
Pediatric Population
Generally, the adverse reactions observed in the pivotal pediatric study (see Section CLINICAL STUDIES;
Juvenile Idiopathic Arthritis [JIA]) were similar to those observed in adult arthritis studies (see Table 7).
Additionally, the following adverse reactions are not listed in Table 7 and were attributed by the investigator in
the pivotal pediatric study as possibly related to treatment with celecoxib: headache (2 reports, 1.3%),
exacerbation of hematuria (1 report, 0.6%) and asthma [1 patient who had controlled asthma at baseline] (1
report, 0.6%).Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily had no observable
deleterious effect on growth and development during the course of the 12-week double-blind study.
2) The following additional adverse reactions* in Table 8 were reported at incidence rates greater than placebo in
long-term polyp prevention studies of duration up to 3 years at daily doses from 400 mg up to 800 mg (see
Section CLINICAL STUDIES; Cardiovascular Safety – Long-Term Studies Involving Patients With Sporadic
Adenomatous Polyps). Adverse reactions are listed by system organ class and ranked by frequency.
Frequencies are defined as: very common ( 10%), common ( 1% and < 10%), uncommon ( 0.1% and < 1%).
Table 8.
Adverse Reactions From Polyp Prevention Studies of Duration up to 3 Years and Daily
Doses of 400mg - 800mg
System Organ Class
Frequency
Infections and infestations
Common
Uncommon
Ear infection, fungal infection**
Helicobacter infection, herpes zoster, erysipelas, wound
infection, gingival infection, labyrinthitis, bacterial infection
*Hypertension, vomiting and diarrhea are included in Table 2 because they were reported more frequently in
these studies, which were of 3-year duration, compared to Table 1, which includes adverse reactions from
studies of 12-week duration.
** Fungal infections were primarily non-systemic.
17
Table 8.
System Organ Class
Frequency
Neoplasms benign, malignant, and
unspecified
Uncommon
Psychiatric disorders
Uncommon
Nervous system disorders
Uncommon
Eye disorders
Uncommon
Ear and labyrinth disorders
Uncommon
Cardiac disorders
Common
Uncommon
Vascular disorders
Very common
Uncommon
Respiratory, thoracic and mediastinal
disorders
Common
Uncommon
Gastrointestinal disorders
Very common
Common
Uncommon
Hepatobiliary disorders
Rare
Skin and subcutaneous tissue disorders
Uncommon
Musculoskeletal and connective tissue
disorders
Common
Uncommon
Renal and urinary disorders
Common
Uncommon
Reproductive system and breast disorders
Common
Uncommon
General disorders and administration site
conditions
Uncommon
Investigations
Common
Uncommon
Lipoma
Sleep disorder
Cerebral infarction
Vitreous floaters, conjunctival hemorrhage
Hypoacusis
Angina pectoris, myocardial infarction
Angina unstable, aortic valve incompetence, coronary
artery atherosclerosis, sinus bradycardia, ventricular
hypertrophy
Hypertension*
Deep vein thrombosis, hematoma
Dyspnea
Dysphonia
Diarrhea*
Nausea, gastroesophageal reflux disease, diverticulum,
vomiting*, dysphagia, irritable bowel syndrome
Hemorrhoidal hemorrhage, frequent bowel movements,
mouth ulceration, stomatitis
Elevation of hepatic enzymes
Dermatitis allergic
Muscle spasms
Ganglion
Nephrolithiasis
Nocturia
Benign prostatic hyperplasia, prostatitis
Vaginal hemorrhage, breast tenderness, dysmenorrhea,
ovarian cyst, menopausal symptoms
Edema
Blood creatinine increased, prostatic specific antigen
increased, weight increased
Blood potassium increased, blood sodium increased, blood
testosterone decreased, hematocrit decreased,
hemoglobin increased
18
Table 8.
System Organ Class
Frequency
Injury, poisoning and procedural
complications
Uncommon
Foot fracture, lower limb fracture, epicondylitis, tendon
rupture, fracture
Post-marketing Experience
Adverse reactions reported from post-marketing experience include the following:
Immune system disorders: anaphylaxis
Psychiatric disorders: hallucinations
Nervous system disorders: ageusia, anosmia, aseptic meningitis
Eye disorders: Conjunctivitis
Vascular disorders: vasculitis, cerebral hemorrhage
Gastrointestinal disorders: gastrointestinal hemorrhage
Hepato-biliary disorders: hepatitis, liver failure, fulminant hepatitis, liver necrosis (See Section PRECAUTIONS;
Hepatic Effects)
Renal and urinary disorders: acute renal failure (See Section WARNINGS; Renal Effects), interstitial nephritis,
hyponatremia
Skin and subcutaneous tissue disorders: photosensitivity reaction, exfoliative dermatitis, erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms
(DRESS, or hypersensitivity syndrome)
Reproductive system and breast disorders: menstrual disorder
Respiratory, thoracic and mediastinal disorders: pulmonary embolism
General disorders and administration site conditions: chest pain
OVERDOSAGE
No overdoses of CELEBRA were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12
patients did not result in serious toxicity. Symptoms following acute NSAID overdoses are usually limited to
lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care.
Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may
occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no
specific antidotes. No information is available regarding the removal of celecoxib by hemodialysis, but based on
its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or
activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in
patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis,
alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of CELEEBRA and other treatment options before deciding to
use CELEBRA. Use the lowest effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).
For osteoarthritis and rheumatoid arthritis, the lowest dose of CELEBRA should be sought for each patient.
19
Celecoxib capsules, at doses up to 200 mg twice per day can be taken with or without food.
As the cardiovascular risks of celecoxib may increase with dose and duration of exposure, the shortest duration
possible and the lowest effective daily dose should be used.
Symptomatic Treatment of Osteoarthritis
The recommended oral dose is 200 mg per day administered as a single dose or as 100 mg twice per day.
Symptomatic Treatment of Rheumatoid arthritis
The recommended oral dose is 100 to 200 mg twice per day.
Special Populations
Hepatic insufficiency
No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). The daily
recommended dose of CELEBRA capsules in patients with moderate hepatic impairment (Child-Pugh Class B)
should be reduced by approximately 50%. The use of CELEBRA in patients with severe hepatic impairment is
not recommended since they have not been studied (see CLINICAL PHARMACOLOGY – Special
Populations).
CYP2C9 Poor Metabolizers
Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience
with other CYP2C9 substrates should be administered celecoxib with caution. Consider starting treatment at half
the lowest recommended dose.
At a dose of 400 mg twice per day, poor metabolism in patients with the CYP2C9*3*3 genotype may result in
exposures to celecoxib that are higher than those for which safety has been studied in clinical trials. Therefore,
the risk for high celecoxib exposure in poor metabolizers should be considered carefully when treating patients.
Renal Impairment
No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical
experience in patients with severe renal impairment. (See Section WARNINGS - Renal Effects.)
Coadministration with Fluconazole
Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole, a CYP2C9
inhibitor. Caution is advised when coadministering celecoxib with other CYP2C9 inhibitors. (See Section DRUG
INTERACTIONS)
Elderly
No dosage adjustment is generally necessary. However, for elderly patients weighing less than 50kg, it is
advisable to initiate therapy at the lowest recommended dose.
METHOD OF ADMINISTRATION
For patients who have difficulty swallowing capsules, the contents of a celecoxib capsule can be added to
applesauce, rice gruel, yogurt or mashed banana. To do so, the entire capsule contents must be carefully
emptied onto a level teaspoon of cool or room temperature applesauce, rice gruel, yogurt or mashed banana and
should be ingested immediately with water. The sprinkled capsule contents on applesauce, rice gruel or yogurt
are stable for up to 6 hours under refrigerated conditions (2-8° C). The sprinkled capsule contents on mashed
banana should not be stored under refrigerated conditions and should be ingested immediately.
PHARMACEUTICAL PARTICULARS
Special precautions for storage
Store below 30oC.
Nature and content of container
PVC/Aclar blisters. Pack of 2, 4, 10, 20, 30, 50 cps
Instructions for use and handling, and disposal (if appropriate)
None
20
Manufacturer: Pfizer Pharmaceuticals LLC, Puerto Rico.
Packaged by: Pfizer Manuf. Deutschland GmbH, Illertissen Germany
License Holder: Pfizer Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725
21

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ע עבקנ הז ןולע טמרופ " רשואו קדבנ ונכותו תואירבה דרשמ י