CELEBREX – data sheet Page 1 of 35
NEW ZEALAND DATA SHEET
1. PRODUCT NAME
Celebrex
®
100 mg and 200 mg capsules.
2. QUALITATIVE AND QUANTITATIVE COMPOISTION
Celebrex 100 mg contains 100 mg celecoxib.
Celebrex 200 mg contains 200 mg celecoxib.
Excipient(s) with Known Effect
Each 100 mg and 200 mg capsule contains 149.7 mg and 49.8 mg lactose monohydrate,
respectively. For the full list of excipients, see section 6.1 List of Excipients.
3. PHARMACEUTICAL FORM
100 mg capsules: Opaque, white capsules with 2 blue bands marked 7767 and 100.
200 mg capsules: Opaque, white capsules with 2 gold bands marked 7767 and 200.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Symptomatic treatment of pain and inflammation in osteoarthritis, rheumatoid arthritis and
ankylosing spondylitis.
For the management of acute pain and treatment of primary dysmenorrhoea in adults.
The decision to prescribe a selective cyclooxygenase 2 (COX-2) inhibitor should only be made:
• if non-pharmacological interventions and simple analgesic therapies have been tried and
found to lack analgesic efficacy or to have unacceptable adverse effects in the individual
patient, and
• after assessment of the individual patient’s overall risks.
As the cardiovascular (CV) risks of the 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. Patients on long-term treatment should be reviewed regularly, such as every three
months, with regards to efficacy, risk factors and ongoing need for treatment.
4.2 Dose and Method of Administration
Dose
All patients taking celecoxib should commence therapy at the lowest recommended dose, and
be titrated to the lowest dose compatible with effective control of symptoms for the shortest
possible period.
CELEBREX – data sheet Page 2 of 35
Patients on long-term treatment should be reviewed regularly with regards to efficacy, risk
factors and ongoing need for treatment.
The following doses can be given without regard to timing of meals (also see section 5.2
Pharmacokinetic Properties - Absorption for full description of food effect).
Osteoarthritis
The recommended daily dose is 200 mg taken once daily (OD) or in two divided doses. A dose
of 200 mg twice daily (BD) may be used if needed.
Rheumatoid Arthritis
The recommended daily dose is 200 mg - 400 mg taken in two divided doses.
Ankylosing Spondylitis
The recommended daily dose is 200 mg taken OD or in two divided doses. Some patients may
benefit from a total daily dose (TDD) of 400 mg.
Management of Acute Pain and Treatment of Primary Dysmenorrhoea
The recommended dose is 400 mg as a single dose on the first day, followed by 200 mg OD
on subsequent days. Patients may be instructed to take an additional dose of 200 mg on any
given day, if needed. The maximum recommended dose is 400 mg per day. Celebrex can be
administered up to 2 hours prior to surgery.
Special Population
Elderly (>65 years old)
No dosage adjustment is generally necessary. However, for elderly patients with a lower than
average body weight (<50 kg), it is advisable to initiate therapy at the lowest recommended
dose.
Children and Adolescents
Celebrex is not approved for use in patients under 18 years of age.
Hepatic Impairment
No dosage adjustment is necessary in patients with mild hepatic impairment. In arthritis
patients with moderate hepatic impairment, Celebrex should be introduced at the lowest
recommended dose.
There is no clinical experience in patients with severe hepatic impairment. Therefore, the use
of Celebrex in patients with severe hepatic impairment (Child-Pugh score ≥10) is
contraindicated (see section 4.3 Contraindications, 4.4 Special Warnings and Precautions for
Use, and 5.2 Pharmacokinetic Properties).
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 4.3
Contraindications, and 4.4 Special Warnings and Precautions for Use ).
CELEBREX – data sheet Page 3 of 35
CYP2C9 Poor Metabolisers
Patients who are known, or suspected to be CYP2C9 poor metabolisers 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 section 4.5
Interaction with Other Medcines and Other Forms of Interaction, and 5.2 Pharmacokinetic
Properties).
Method of Administration
Oral use. Swallow the capsules whole with a glass of fluid.
4.3 Contraindications
Known hypersensitivity to Celebrex or any of the excipients contained in the Celebrex capsules
(see list in section 6.1 List of Excipients).
Demonstrated allergic-type reactions to sulfonamides.
Celebrex should not be given to patients who have experienced asthma, urticaria, or
allergic-type reactions after taking acetylsalicylic acid (ASA) or other non-steroidal anti-
inflammatory drugs (NSAIDs), including other COX-2 specific inhibitors. Severe, rarely fatal,
anaphylactoid reactions to NSAIDs have been reported in such patients (see section 4.4 Special
Warnings and Precautions for Use - Anaphylactoid Reactions).
Celebrex should not be used with other NSAIDs because of the absence of any evidence
demonstrating synergistic benefits and the potential for additive adverse reactions.
Celebrex is contraindicated for the peri-operative treatment of pain in patients undergoing
coronary artery bypass graft (CABG) surgery (see section 4.4 Special Warnings and
Precautions for Use - Cardiovascular Effects).
Celebrex is contraindicated in:
• Patients with unstable ischaemic heart disease of thrombus aetiology, documented
myocardial infarction (MI) or stroke within 3 months
• Patients with active peptic ulceration or gastrointestinal (GI) bleeding
• Patients with estimated creatinine clearance <30 mL/min
• Patients with congestive heart failure (NYHA II-IV).
• Patients with severe hepatic impairment (Child-Pugh
#
score ≥10). See section 4.2 Dose
and Method of Administration, and 5.2 Pharmacokinetic Properties.
#
Child-Pugh is a classification of the severity of liver disease.
Parameter
Points Assigned
1
2
3
Ascites
Absent
Slight
Moderate
Bilirubin (mg/dL)
<2
2-3
>3
Albumin (g/dL)
>3.5
2.8-3.5
<2.8
Prothrombin time (seconds over control)
<4
4-6
>6
CELEBREX – data sheet Page 4 of 35
Parameter
Points Assigned
1
2
3
INR
<1.7
1.7-2.3
>2.3
Encephalopathy
None
Grade1-2
Grade3-4
Modified Child-Pugh classification of the severity of liver disease according to the degree of
ascites, the plasma concentrations of bilirubin and albumin, the prothrombin time, and the
degree of encephalopathy. A total score of 5-6 is considered grade A (well-compensated
disease); 7-9 is grade B (significant functional compromise); and 10-15 is grade C
(decompensated disease). These grades correlate with one- and two-year patient survival:
grade A - 100 and 85 percent; grade B - 80 and 60 percent; and grade C - 45 and 35 percent.
4.4 Special Warnings and Precautions for Use
Cardiovascular Effects
COX-2 inhibitors, including celecoxib, have been associated with an increased risk of serious
CV thrombotic adverse events, myocardial infarction and stroke, which can be fatal (see section
5.1 Pharmacodynamic Properties - Clinical Efficacy and Safety, Cardiovascular Safety).
All NSAIDs, both COX-2 selective and non-selective, may cause an increased risk of serious
CV thrombotic events. This risk may increase with dose and duration of use. The relative
increase of this risk appears to be similar in those with or without known CV disease or CV
risk factors. However, patients with CV disease or CV risk factors may be at greater risk in
terms of absolute incidence, due to their increased rate at baseline.
Two large, controlled clinical trials of a different COX-2 selective inhibitor for the treatment
of pain in the first 10-14 days following CABG surgery found an increased incidence of
myocardial infarction and stroke. In the absence of comparable data with celecoxib, it may be
assumed that patients at high risk of CV disease (including patients with diabetes, ischaemic
heart disease, cardiac failure, hyperlipidaemia, hypertension, or smokers) who are undergoing
any major surgery may face an increased risk of developing a CV event. Patients with
significant established ischaemic heart disease, peripheral arterial disease and/or
cerebrovascular disease as well as patients at high risk for CV disease including those with
significant and multiple risk factors for CV events should only be treated with celecoxib after
careful consideration of the patient’s overall risk and the potential risks and benefits of
alternative analgesic therapies (See section 4.3 Contraindications).
To minimise the potential risk for an adverse CV event in patients treated with celecoxib, the
lowest effective dose should be used for the shortest duration possible (see section 4.2 Dose
and Method of Administration).
Prescribers should inform the individual patient of the possible increased risks when
prescribing celecoxib for patients at high risk of CV adverse events. Physicians and patients
should remain alert for such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and symptoms of serious CV toxicity and the steps to take
if they occur. Celecoxib is not a substitute for CV prophylaxis because of its lack of effect on
platelets; therefore, concurrent anti-platelet therapies should not be discontinued. There is no
evidence that concurrent use of aspirin decreases the risk of CV adverse events associated with
COX-2 inhibitors, including celecoxib.
CELEBREX – data sheet Page 5 of 35
Gastrointestinal Effects
Infrequently, serious gastrointestinal (GI) toxicity such as bleeding, ulceration, and upper and
lower GI perforation (including perforations of the stomach or intestine) has been observed in
patients treated with Celebrex.
Celebrex (celecoxib) exhibited a low incidence of gastroduodenal ulceration and serious
clinically significant GI events within clinical trials (see section 5.1 Pharmacodynamic
Properties - Clinical Efficacy and Safety, Special Studies).
Serious GI toxicity, such as peptic ulceration, perforation and bleeding, sometimes severe and
occasionally fatal, can occur at any time, with or without warning symptoms, in patients treated
with NSAIDs. Minor upper GI problems, such as dyspepsia, are common, and may also occur
at any time during NSAID therapy. Therefore, physicians should remain alert for ulceration
and bleeding in patients treated with NSAIDs, even in the absence of previous GI tract
symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity
and the steps to take if they occur.
Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is
symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation,
caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months,
and in about 2-4% of patients treated for one year. These trends continue thus, increasing the
likelihood of developing a serious GI event at some time during the course of therapy.
However, even short-term therapy is not without risk.
Patients most at risk of developing GI complications with NSAIDs are elderly patients; patients
with CV disease; patients using concomitant anti-platelet drugs (such as aspirin, even at low
doses) or corticosteroids; patients who consume alcohol; or patients with a prior history of GI
disease (such as ulceration, GI bleeding or inflammatory conditions). In addition
pharmacoepidemiological studies have identified several other co-therapies or co-morbid
conditions that may increase the risk for GI bleeding such as: treatment with anticoagulants,
longer duration of NSAID therapy, smoking and poor general health status. Celebrex should
be prescribed with extreme caution in these patients. Physicians and patients should remain
alert for ulceration and GI bleeding, even in the absence of symptoms.
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 minimise the potential risk of an
ulcer complication, the lowest effective dose of Celebrex should be used for the shortest
possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should
be considered.
Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding and
who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than
patients with neither of these risk factors. It is unclear how this finding applies to Celebrex.
There is no definitive evidence that the concomitant administration of histamine H2-receptor
antagonists and/or antacids will either prevent the occurrence of GI side effects or allow the
continuation of Celebrex if these adverse reactions appear.
Anaphylactoid Reactions
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known
prior exposure to Celebrex. In post-marketing experience, rare cases of anaphylactoid
reactions and angioedema have been reported in patients receiving Celebrex. Celebrex should
CELEBREX – data sheet Page 6 of 35
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 section 4.3
Contraindications, and 4.4 Special Warnings and Precautions for Use - Pre-existing Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Serious Skin Reactions
Serious skin reactions, some of them fatal, including drug reaction with eosinophilia and
systemic symptoms (DRESS syndrome), exfoliative dermatitis, Stevens-Johnson syndrome,
and toxic epidermal necrolysis, have been reported very rarely in association with the use of
celecoxib. 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.
Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any
other sign of hypersensitivity.
Hypertension
As with all NSAIDs, celecoxib 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 celecoxib, should be used with caution in patients with hypertension.
Blood pressure should be monitored closely during the initiation of therapy with celecoxib and
throughout the course of therapy.
Use with ACE Inhibitors, Angiotensin Receptor Antagonists, Anti-inflammatory Drugs
and Thiazide Diuretics
The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), and an
anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time,
increases the risk of renal impairment. This includes use in fixed-combination products
containing more than one class of drug. Concomitant use of all three classes of these
medications should be accompanied by increased monitoring of serum creatinine, particularly
at the initiation of the treatment. The concomitant use of drugs from these three classes should
be used with caution particularly in elderly patients or those with pre-existing renal impairment.
Use with Oral Anticoagulants
The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and
should be given with caution (see section 4.5 Interaction with Other Medcines and Other Forms
of Interaction - Oral Anticoagulants).
Use with Drugs Metabolised by CYP2D6
Celecoxib has shown to be a moderately potent CYP2D6 inhibitor. For drugs that are
metabolised by CYP2D6, a dose reduction during initiation of celecoxib treatment or a dose
increase upon termination of celecoxib treatment may be necessary (see section 4.5 Interaction
with Other Medcines and Other Forms of Interaction - Dextromethorphan and Metoprolol).
Use with Other NSAIDs
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking
NSAIDs, and notable elevations of ALT or AST (approximately three or more times the upper
CELEBREX – data sheet Page 7 of 35
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, fatal fulminant hepatitis, liver
necrosis and hepatic failure (some with fatal outcome or requiring liver transplant), have been
reported with NSAIDs, including Celebrex (see section 4.8 Undesirable Effects).
In controlled clinical trials of Celebrex, the incidence of borderline elevations of liver tests was
6% for Celebrex and 5% for placebo, and approximately 0.2% of patients taking Celebrex and
0.3% of patients taking placebo had notable elevations of ALT and AST.
Physician and patients should remain alert for hepatotoxicity. Patients should be informed
about the signs and/or symptoms of hepatotoxicity. A patient with symptoms and/or signs
suggesting liver dysfunction (e.g., nausea, fatigue, lethargy, pruritis, jaundice, abdominal
tenderness in the right upper quadrant and “flu-like” symptoms), 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 Celebrex.
If clinical signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), Celebrex should be discontinued.
The incidence of elevations in ALT and/or AST may be increased in patients treated with
celecoxib at doses greater than 400 mg daily.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal
injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients, administration of
a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Such patients should
be carefully monitored while receiving treatment with celecoxib. Patients at greatest risk of
this reaction are those with impaired renal function, heart failure, liver dysfunction, those
taking diuretics and ACE inhibitors (see section 4.4 Special Warnings and Precautions for Use
- Use with ACE Inhibitors, Angiotensin Receptor Antagonists, Anti-inflammatory Drugs and
Thiazide Diuretics), and the elderly. Discontinuation of NSAID therapy is usually followed
by recovery to the pretreatment state.
Clinical trials with Celebrex have shown renal effects similar to those observed with
comparator NSAIDs. The relative roles of cyclooxygenase 1 (COX-1) and COX-2 in renal
physiology are not completely understood. Celecoxib reduces the urinary excretion of PGE
2
and 6-keto-PGF
1α
(a prostacyclin metabolite) but leaves serum thromboxane B
2
(TXB
2
) and
urinary excretion of 11-dehydro-TXB
2
, a thromboxane metabolite (both COX-1 products)
unaffected.
Caution should be used when initiating treatment with Celebrex in patients with considerable
dehydration. It is advisable to rehydrate patients first and then start therapy with Celebrex.
No information is available regarding the use of Celebrex in patients with advanced kidney
disease. Therefore, treatment with Celebrex is not recommended in these patients. If Celebrex
therapy must be initiated, close monitoring of the patient's kidney function is advisable.
CELEBREX – data sheet Page 8 of 35
Haematological Effects
Anaemia is sometimes seen in patients receiving Celebrex. In controlled clinical trials the
incidence of anaemia was 0.6% with Celebrex and 0.4% with placebo. Patients on long-term
treatment with Celebrex should have their haemoglobin or haematocrit checked if they exhibit
any signs or symptoms of anaemia or blood loss. Celebrex does not generally affect platelet
counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not appear to
inhibit platelet aggregation at indicated dosages (see section 5.1 Pharmacodynamic Properties
- Special Studies, Platelet Function).
Pre-existing 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, Celebrex should not be administered to patients with
this form of aspirin sensitivity and should be used with caution in patients with pre-existing
asthma.
Fluid Retention and Oedema
Fluid retention and oedema have been observed in some patients taking Celebrex (see section
4.8 Undesirable Effects). As with all NSAIDs, celecoxib may exacerbate pre-existing
hypertension, cardiac failure or oedema, and the treatment of these conditions may be
compromised. Therefore, Celebrex should be used with caution in patients with fluid retention,
hypertension, heart failure, compromised cardiac function, pre-existing oedema or other
conditions predisposing to, or worsened by, fluid retention including those taking diuretic
treatment or otherwise at risk of hypovolaemia. Patients with pre-existing congestive heart
failure or hypertension should be closely monitored.
Use in Patients Being Treated with Corticosteroids
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.
Use in Patients with Inflammatory Bowel Disease (IBD)
Short-term exposure of celecoxib to patients with ulcerative colitis (UC) in remission has not
shown an exacerbation of IBD in spondyloarthropathies, but the implications of longer term
exposure remain unknown. NSAIDs have been associated with an exacerbation of IBD
associated with spondyloarthropathies.
Effects on Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms,
physicians should monitor for signs or symptoms of GI bleeding.
During the controlled clinical trials, there was an increased incidence of hyperchloremia in
patients receiving celecoxib compared with patients on placebo. Other laboratory
abnormalities that occurred more frequently in the patients receiving celecoxib included
hypophosphatemia, and elevated BUN. These laboratory abnormalities were also seen in
patients who received comparator NSAIDs in these studies. The clinical significance of these
abnormalities has not been established.
CELEBREX – data sheet Page 9 of 35
Detecting Infections
By reducing inflammation, celecoxib may diminish the utility of diagnostic signs, such as
fever, in detecting infections.
4.5 Interaction with Other Medcines and Other Forms of Interaction
Oral Anticoagulants
The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and
should be given with caution. Oral anticoagulants include warfarin/coumarin-type and novel
oral anticoagulants (e.g., apixaban, dabigatran, and rivaroxaban). In patients on concurrent
therapy with warfarin or similar agents, serious bleeding events, some of them fatal,
predominantly in elderly have been reported. Because increases in prothrombin time (INR)
have been reported, anticoagulation/INR should be monitored, in patients taking a
warfarin/coumarin-type anticoagulant after initiating treatment with celecoxib or changing the
dose. If INR increases, it may be sufficient to reduce the dose of the oral anticoagulant in order
to manage the interaction (see section 4.4 Special Warnings and Precautions for Use -
Gastrointestinal Effects).
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 section 5.1 Pharmacodynamic Properties - Special Studies, Upper
Gastrointestinal Complications). Because of its lack of platelet effects, Celebrex is not a
substitute for aspirin for CV prophylaxis.
Antihypertensives including Angiotensin Converting Enzyme (ACE) Inhibitors,
Angiotensin II Antagonists, Diuretics and Beta-blockers
Inhibition of prostaglandins may diminish the effect of antihypertensives including ACE
inhibitors, angiotensin II antagonists (also known as angiotensin receptor blockers or ARBs)
diuretics and beta-blockers. This interaction should be given consideration in patients taking
Celebrex concomitantly with these drugs.
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, angiotensin II antagonists or diuretics, may result in
deterioration of renal function, including possible acute renal failure. These effects are usually
reversible. Therefore, the concomitant administration of these drugs should be done with
caution. Patients should be adequately hydrated and the clinical need to monitor the renal
function should be assessed at the beginning of the concomitant treatment and periodically
thereafter.
In a clinical study, approximately half of patients who received the ACE inhibitor, lisinopril,
in combination with celecoxib were unresponsive to lisinopril at the final clinic visit, compared
to under one third of patients who received lisinopril in combination with placebo; and this
difference was statistically significant.
Ciclosporin
Because of their effect on renal prostaglandins, NSAIDs may increase the risk of
nephrotoxicity with ciclosporin.
CELEBREX – data sheet Page 10 of 35
Effects of Celecoxib on Other Drugs
CYP2D6 Inhibition
Clinical pharmacokinetics study and 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 metabolised by P450 2D6.
Dextromethorphan and Metoprolol
Concomitant administration of celecoxib resulted in increases in plasma concentrations of
dextromethorphan and metoprolol (CYP2D6 substrates). These increases are due to celecoxib
inhibition to the CYP2D6 substrate metabolism via CYP2D6. Therefore, the dose of drugs
which are CYP2D6 substrate may need to be reduced when treatment with celecoxib is initiated
or increased when treatment with celecoxib is terminated (see section 4.4 Special Warnings
and Precautions for Use - Use with Drugs Metabolised by CYP2D6).
Digoxin
Concomitant use of Celebrex with digoxin has been reported to increase serum concentration
and prolong half-life of digoxin. During concomitant use of Celebrex and digoxin, serum
digoxin levels should be monitored.
Methrotrexate
Celebrex did not have a significant effect on the pharmacokinetics of methotrexate.
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity
(e.g., neutropenia, thrombocytopenia, renal dysfunction). During concomitant use of Celebrex
and methotrexate, patients should be monitored for methotrexate toxicity.
Lithium
In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased
approximately 17% in subjects receiving lithium 450 mg BD with Celebrex 200 mg BD as
compared to subjects receiving lithium alone. Patients on lithium treatment should be closely
monitored when Celebrex is introduced or withdrawn.
Oral Hypoglycaemics
The effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glibenclamide
and tolbutamide has been studied and clinically important interactions have not been found.
Effects of Other Drugs on Celecoxib
CYP2C9 Inhibitors
Concomitant administration of celecoxib with inhibitors of CYP2C9 can lead to increases in
plasma concentrations of celecoxib. Therefore, a dose reduction of celecoxib may be necessary
when celecoxib is co-administered with CYP2C9 inhibitors.
CYP2C9 Inducers
Concomitant administration of celecoxib with inducers of CYP2C9 (such as rifampicin,
carbamazepine and barbiturates) can lead to decreases in plasma concentrations of celecoxib.
Therefore, a dose increase of celecoxib may be necessary when celecoxib is co-administered
with CYP2C9 inducers.
CELEBREX – data sheet Page 11 of 35
Fluconazole
Concomitant administration of fluconazole at 200 mg once daily 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 section 5.2 Pharmacokinetic Properties -
Biotransformation). Celebrex should be introduced at the lowest recommended dose in patients
receiving fluconazole.
Ketoconazole
Celebrex did not have a significant effect on the pharmacokinetics of ketoconazole.
Phenytoin
Celebrex did not have a significant effect on the pharmacokinetics of phenytoin.
Glucocorticoids
Oral glucocorticoids should be used with caution since they increase the risk of GI side effects
such as ulceration and bleeding. This is especially the case in older (>65 years of age)
individuals.
Antacids
Co-administration of Celebrex with an aluminium- and magnesium-containing antacid resulted
in a reduction in plasma celecoxib concentrations with a decrease of 37% in C
max
and 10% in
AUC.
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.
4.6 Fertility, Pregnancy and Lactation
Pregnancy - Pregnancy Category: B3
There is no information on the use of celecoxib in pregnant women. Celebrex use is not
recommended in pregnancy unless it is considered clinically essential (see below for
information on studies conducted in animals).
No studies have been done to evaluate the effect of celecoxib on the closure of the ductus
arteriosus in humans. In animal studies, both COX-1 and COX-2 have been shown to be
present in the ductus arteriosus of fetal lambs and to contribute to maintenance of patency.
Therefore, use of Celebrex during the third trimester of pregnancy should be avoided and
Celebrex should not be used during the first and second trimesters of pregnancy unless the
potential benefit to the mother justifies the potential risk to the fetus. The effects of Celebrex
on labour and delivery in pregnant women are not known.
If used during second or third trimester of pregnancy, NSAIDs may cause fetal renal
dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in
severe cases. Such effects may occur shortly after treatment initiation and are usually
reversible upon discontinuation. Pregnant women on celecoxib should be closely monitored
for amniotic fluid volume.
CELEBREX – data sheet Page 12 of 35
In rats, celecoxib caused early embryonic death at doses greater than 30 mg/kg/day
administered before mating and during early gestation (approximately 2-fold human exposure
based on AUC
0-24 h
at 400 mg BD, which is twice the recommended maximum daily dose).
This effect is attributable to inhibition of prostaglandin production, and is not associated with
permanent alteration of reproductive function. Celecoxib was shown to cross the placenta in
rats. Teratology studies disclosed an increased incidence of wavy ribs in one study in rats
dosed at 100 mg/kg/day, increased incidences of diaphragmatic hernias at 30 and
100 mg/kg/day in another rat study; and increased incidences of rib and sternebral
abnormalities in rabbits at doses of 60 mg/kg/day or greater and CV abnormalities in rabbits at
doses of 150 mg/kg/day or greater. At the no-effect dose in rats (10 mg/kg/day), AUC
0-24 h
was
similar to that in humans dosed at 400 mg BD. At the threshold dose of 60 mg/kg/day in
rabbits, AUC
0-24 h
was slightly below that in humans dosed at 400 mg BD. Celecoxib had a
marginal effect on parturition in rats, causing slight prolongation of gestation and parturition
and increased incidence of still births at oral doses of 10 mg/kg/day or greater (slightly greater
than human exposure based on AUC
0-24 h
at 400 mg BD).
Inhibition of prostaglandin synthesis might adversely affect pregnancy. Epidemiological
studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis
inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors
has been shown to result in increased pre- and post-implantation loss.
Lactation
Studies in rats show that celecoxib is excreted in milk 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 adverse reactions to celecoxib in
nursing infants, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the expected benefit of the drug to the mother.
Fertility
Celecoxib did not affect male or female fertility in rats at oral doses up to 600 mg/kg/day
(approximately 7-fold human exposure based on AUC
0-24 h
at 400 mg BD, which is twice the
recommended maximum daily dose).
Based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or
prevent rupture of ovarian follicles, which has been associated with reversible infertility in
some women. In women who have difficulties conceiving or who are undergoing investigation
of infertility, withdrawal of NSAIDs, including celecoxib, should be considered.
4.7 Effects on Ability to Drive and Use Machinery
The effect of Celebrex 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.
4.8 Undesirable 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 TDD of Celebrex of 200 mg
(100 mg BD or 200 mg OD) or more, including more than 400 treated at 800 mg (400 mg BD).
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.
CELEBREX – data sheet Page 13 of 35
Of the total number of patients who received Celebrex in clinical trials, more than 3,300 were
65-74 years of age, while approximately 1,300 additional patients were 75 years and over.
While the incidence of adverse experiences tended to be higher in elderly patients, no
substantial differences in safety and effectiveness were observed between these subjects and
younger subjects.
Adverse Events From Original Celebrex Arthritis Trials
Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving
Celebrex from 12 controlled studies conducted in patients with OA or RA that included a
placebo and/or an active control group.
Table 1: Adverse Events Occurring in ≥2% of Celebrex Patients From Original Celebrex
Arthritis Trials
Celebrex
(100-200 mg BD
or 200 mg OD)
(N=4146)
(N=1864)
Naproxen
(500 mg BD)
(N=1366)
Diclofenac
(75 mg BD)
(N=387)
Ibuprofen
(800 mg three
times a day
(TDS))
(N=345)
Infections and Infestations
Upper respiratory
tract infection
8.1%
9.9%
9.8%
9.9%
Psychiatric Disorders
Insomnia
2.3%
2.9%
1.3%
1.4%
Nervous system Disorders
Dizziness
2.0%
2.6%
1.3%
2.3%
Headache
15.8%
14.5%
15.5%
15.4%
Respiratory, Thoracic and Mediastinal Disorders
Pharyngitis
2.3%
1.7%
1.6%
2.6%
Rhinitis
2.0%
2.4%
2.3%
0.6%
Sinusitis
5.0%
4.0%
5.4%
5.8%
Gastrointestinal Disorders
Abdominal pain
4.1%
7.7%
9.0%
9.0%
Diarrhoea
5.6%
5.3%
9.3%
5.8%
Dyspepsia
8.8%
12.2%
10.9%
12.8%
Flatulence
2.2%
3.6%
4.1%
3.5%
Nausea
3.5%
6.0%
3.4%
6.7%
Skin and Subcutaneous Tissue Disorders
Rash
2.2%
2.1%
1.3%
1.2%
Musculoskeletal and Connective Tissue Disorders
Back pain
2.8%
2.2%
2.6%
0.9%
General Disorders and Administration Site Conditions
Oedema
peripheral
2.1%
2.1%
1.0%
3.5%
Injury, Poisoning and Procedural Complications
Injury
2.9%
3.0%
2.6%
3.2%
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
CELEBREX – data sheet Page 14 of 35
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 adverse event profile from the Celecoxib Long-term Arthritis Safety Study (at 4- and 2-
fold the recommended doses for OA and RA, respectively) was similar to those reported in the
arthritis controlled trials.
The following adverse events occurred in 0.1% - 1.9% of patients taking Celebrex
(100 mg-200 mg BD or 200 mg OD) regardless of causality.
Blood and Lymphatic System
Disorders
Anaemia, thrombocythaemia
Infections and Infestations
Herpes simplex, herpes zoster, infection bacterial,
infection fungal, infection soft tissue, infection
viral, moniliasis, moniliasis genital, otitis media,
cellulitis, cystitis, urinary tract infection
Neoplasms Benign, Malignant and
Unspecified (incl cysts and polyps)
Breast neoplasm
Immune System Disorders
Hypersensitivity
Metabolism and Nutritional
Disorders
Diabetes mellitus, hypercholesterolaemia,
hyperglycaemia, hypokalaemia
Psychiatric Disorders
Anorexia, anxiety, appetite increased, depression,
nervousness, somnolence
Nervous system Disorders
Hypertonia, hypoaesthesia, migraine, neuralgia,
neuropathy, paraesthesia dysgeusia
Eye Disorders
Vision blurred, cataract, conjunctivitis, eye pain,
glaucoma.
Ear and Labyrinth Disorders
Deafness, ear abnormality, earache, tinnitus, vertigo
Cardiac Disorders
Aggravated hypertension, angina pectoris, coronary
artery disorder, myocardial infarction, arrhythmia,
Palpitation, tachycardia
Vascular Disorders
Hot flushes
Respiratory, Thoracic and
Mediastinal Disorders
Bronchitis, bronchospasm, bronchospasm
aggravated, cough, dyspnoea, laryngitis,
pneumonia, epistaxis
Gastrointestinal Disorders
Constipation, diverticulitis, dysphagia, eructation,
oesophagitis, gastritis, gastroenteritis,
gastroesophageal reflux, haemorrhoids, hiatal
hernia, melaena, dry mouth, stomatitis, tenesmus,
tooth disorder, vomiting
Hepatobiliary Disorders
Hepatic function abnormal, AST increased, ALT
increased
Skin and Subcutaneous Tissue
Disorders
Alopecia, dermatitis, nail disorder, photosensitivity
reaction, pruritus, rash erythematous, rash
maculopapular, skin disorder, skin dry,
CELEBREX – data sheet Page 15 of 35
hyperhidrosis, urticarial, ecchymosis, dermatitis
contact, skin mass
Musculoskeletal and Connective
tissue Disorders
Arthralgia, arthrosis, bone disorder, myalgia, neck
stiffness, synovitis, tendinitis, leg cramps
Renal and Urinary System
Disorders
Albuminuria, dysuria, haematuria, pollakiuria,
nephrolithiasis, urinary incontinence
Reproductive System and Breast
Disorders
Breast fibroadenosis, breast pain, dysmenorrhoea,
menstrual disorder, vaginal haemorrhage, vaginitis,
prostatic disorder
General Disorders and
Administration Site Conditions
Asthenia, chest pain, cyst, oedema generalised, face
oedema, fatigue, pyrexia, influenza-like illness,
pain, peripheral pain, injection site reaction
Investigations
BUN increased, CPK increased, blood alkaline
phosphatase increased, blood urea increased, blood
creatinine increased, weight increased
Injury, Poisoning and Procedural
Complications
Fracture accidental
Other Serious Adverse Events Which Occur Rarely (<0.1%), Regardless of Causality
The following serious adverse events have occurred rarely in patients, taking Celebrex.
Blood and Lymphatic Disorders
Thrombocytopenia
Infection and Infestation
Peripheral gangrene , meningitis aseptic
Psychiatric Disorders
Suicide, confusional state
Nervous System Disorders
Ataxia, epilepsy, cerebrovascular accident
Ear and Labyrinth Disorders
Decreased hearing
Cardiac Disorders
Syncope, cardiac failure congestive, ventricular
fibrillation
Vascular Disorders
Thrombophlebitis
Respiratory, Thoracic, and
Mediastinal Disorders
Pulmonary embolism
Gastrointestinal Disorders:
Intestinal obstruction, intestinal perforation,
gastrointestinal bleeding, colitis with bleeding,
oesophageal perforation, pancreatitis, ileus,
oesophageal ulcer, gastric ulcer, duodenal ulcer
Hepatobiliary Disorders
Cholelithiasis
Renal and Urinary Disorders
Renal failure acute
General Disorders and
Administration Site Conditions
Sepsis, sudden death
* In a pooled analysis of 20 placebo-controlled studies with duration greater than 2 weeks up to 1 year in patients
with OA and RA, the excess rate of myocardial infarction in patients treated with celecoxib 200 or 400 mg daily
over placebo was 0.7 events per 1000 patients (Rare) and there was no excess of strokes.
CELEBREX – data sheet Page 16 of 35
In preliminary data from two studies in patients with colorectal polyps treated with celecoxib
400 mg daily (see section 5.1 Pharmacodynamic Properties - Clinical Trials, Cardiovascular
Safety) the excess rate over placebo of myocardial infarction over 3 years was 7 events per
1000 patients (Uncommon). In the same studies, the excess rate for clearly identified ischaemic
stroke for the 400 mg daily dose (not including events that were haemorrhagic or of unknown
aetiology) was 0.5 event per 1000 over 3 years (Rare). For all strokes, there was no increased
event rate with celecoxib compared with placebo.
Adverse Events from Analgesia and Dysmenorrhoea Studies
Approximately 1,700 patients were treated with Celebrex in analgesia and dysmenorrhoea
studies. All patients in post-oral surgery pain and dysmenorrhoea studies received a single
dose of study medication. Doses up to 600 mg/day were studied in primary dysmenorrhoea
and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and
dysmenorrhoea studies were similar to those reported in arthritis studies. In approximately
700 patients treated with Celebrex in the post-general and orthopedic surgery pain studies, the
most commonly reported adverse events were nausea, vomiting, headache, dizziness and fever.
Adverse Drug Reactions from Polyp Prevention Trials
The following additional adverse drug reactions in Table 2 were identified with 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 5.1 Pharmacodynamic Properties - Clinical
Efficacy and Safety, Cardiovascular Safety). Frequencies of ADRs in Table 2 were determined
based on long-term polyp prevention studies and are defined as: very common (≥10%),
common (≥1% and <10%), uncommon (≥0.1% and <1%). The ADRs in Table 2 are listed by
system organ class are ranked by frequency in descending order.
Table 2: Adverse Reactions Occurring In Celebrex Patients From Long-term Studies
Involving Patients with Sporadic Adenomatous Polyps
System Organ Class
Frequency
Adverse Drug Reaction
Infections and Infestations
Common
Ear infection, fungal infection (primarily non-systemic)
Uncommon
Helicobacter infection, herpes zoster, erysipelas, wound
infection, gingivitis, labyrinthitis, bacterial infection
Neoplasms Benign,
Mmalignant, and Unspecified
(incl cysts and polyps)
Uncommon
Lipoma
Psychiatric Disorders
Uncommon
Sleep disorder
Nervous System Disorders
Uncommon
Cerebral infarction
Eye Disorders
Uncommon
Vitreous floaters, conjunctival haemorrhage
CELEBREX – data sheet Page 17 of 35
System Organ Class
Frequency
Adverse Drug Reaction
Ear and Labyrinth Disorders
Uncommon
Hypoacusis
Cardiac Disorders
Common
Angina pectoris, myocardial infarction
Uncommon
Angina unstable, aortic valve incompetence,
arteriosclerosis coronary artery, sinus bradycardia,
ventricular hypertrophy
Vascular Disorders
Very Common
Hypertension*
Uncommon
Deep vein thrombosis, haematoma
Respiratory, Thoracic, and
Mediastinal Disorders
Common
Dyspnoea
Uncommon
Dysphonia
Gastrointestinal Disorders
Very Common
Diarrhoea*
Common
Nausea, gastro-oesophageal reflux disease,
diverticulum, vomiting*, dysphagia, irritable bowel
syndrome
Uncommon
Haemorrhoidal haemorrhage, frequent bowel
movements, mouth ulceration, stomatitis
Hepatobiliary Disorders
Common
Hepatic enzyme increased (includes alanine
aminotransferase increased and aspartate
aminotransferase increased)*
Skin and Subcutaneous Tissue
Disorders
Uncommon
Dermatitis allergic
Musculoskeletal and
Connective Tissue Disorders
Common
Muscle spasms
Uncommon
Synovial cyst
Renal and Urinary Disorders
Common
Nephrolithiasis
Uncommon
Nocturia
CELEBREX – data sheet Page 18 of 35
System Organ Class
Frequency
Adverse Drug Reaction
Reproductive System and
Breast Disorders
Common
Vaginal haemorrhage, benign prostatic hyperplasia,
prostatitis
Uncommon
Breast tenderness, dysmenorrhoea, ovarian cyst,
menopausal symptoms
General Disorders and
Administration Site
Conditions
Uncommon
Oedema
Investigations
Common
Blood creatinine increased, prostatic specific antigen
increased, weight increased
Uncommon
Blood potassium increased, blood sodium increased,
blood testosterone decreased, haematocrit decreased,
haemoglobin increased
Injury, Poisoning and
Procedural Complications
Uncommon
Foot fracture, lower limb fracture, epicondylitis, tendon
rupture, fracture
*
Hypertension, vomiting, diarrhoea and hepatic enzyme increased are included in Table 2 because these events
were reported more frequently in these studies, which were of 3-year duration, compared to Table 1, which
includes adverse events from studies of 12-week duration.
Other Adverse Events
Intestinal anastomotic ulceration was observed in 3 of 58 patients enrolled in familial
adenomatous polyposis clinical trials and who had prior intestinal surgery, one at 100 mg BD,
and two at 400 mg BD.
Post-marketing experience
The following adverse reactions have been identified during post approval use of Celebrex.
Blood and Lymphatic system Disorders: Agranulocytosis, aplastic anaemia, pancytopenia,
leukopenia.
Immune System Disorders: Anaphylactic reaction.
Metabolism and Nutrition Disorders: Hypoglycemia, hyponatremia.
Psychiatric Disorders: Hallucination.
Nervous System Disorders: Ageusia, anosmia, intracranial haemorrhage (including fatal
intracranial haemorrhage), cerebral haemorrhage.
Vascular Disorders: Vasculitis.
CELEBREX – data sheet Page 19 of 35
Respiratory, Thoracic and Mediastinal Disorders: Pneumonitis.
Hepatobiliary Disorders: Hepatic necrosis, hepatitis, jaundice, hepatic failure, hepatitis
fulminant, cholestasis, hepatitis cholestatic, liver transplant, hepatic enzyme increased.
Skin and Subcutaneous Tissue Disorders: Angioedema, photosensitivity reaction, erythema
multiforme, dermatitis exfoliative, Stevens-Johnson syndrome, toxic epidermal necrolysis,
drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised
exanthematous pustulosis (AGEP), dermatitis bullous.
Musculoskeletal and Connective Tissue Dsorders: Myositis.
Renal and Urinary Disorders: Tubulointerstitial nephritis, nephrotic syndrome,
glomerulonephritis minimal lesion.
Reproductive System and Breast Disorders: Menstrual Disorders, infertility female (female
fertility decreased).
Reporting of Suspected Adverse Reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
allows continued monitoring of the benefit/risk balance of the medicine. Healthcare
professionals are asked to report any suspected adverse reactions
https://nzphvc.otago.ac.nz/reporting/.
4.9 Overdosage
Clinical experience of overdose is limited. No overdoses of Celebrex 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.
Signs and Symptoms
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness,
nausea, vomiting, epigastric pain and other gastrointestinal adverse effects, 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.
Treatment of Overdosage
There are no specific antidotes. Patients should be managed by symptomatic and supportive
care following an NSAID overdose. Monitor patients for signs and symptoms of
gastrointestinal ulceration and/or haemorrhage. Monitor serum electrolytes, renal function and
urinalysis after significant overdose.
Consider activated charcoal in the event of a potentially toxic ingestion. Activated charcoal is
most effective when administered within one or two hours of ingestion and may reduce
absorption of the drug. In patients who are not fully conscious or have impaired gag reflex,
consideration should be given to administering activated charcoal via a nasogastric tube, once
the airway is protected.
No information is available regarding the removal of celecoxib by haemodialysis, but based on
its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose.
CELEBREX – data sheet Page 20 of 35
Forced diuresis, alkalinisation of urine, haemodialysis, or haemoperfusion may not be useful
due to high protein binding.
For advice on the management of overdose please contact the National Poisons Centre on 0800
POISON (0800 764766).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: M01AH Coxibs.
The chemical name is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]
benzenesulfonamide. Celecoxib is weakly acidic with a pKa in water of 11.1 and is practically
insoluble in water.
Celecoxib is chemically unrelated to anti-inflammatory agents of steroidal or non-steroidal
nature. Celecoxib does not contain a chiral centre.
Celecoxib is a member of a class of agents which has a mechanism of action that inhibits
prostaglandin synthesis primarily by inhibition of COX-2. At therapeutic concentrations in
humans celecoxib does not inhibit COX-1. 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, oedema and pain. In animal models, celecoxib acts
as an anti-inflammatory, analgesic and antipyretic agent by blocking the production of
inflammatory prostanoids via COX-2 inhibition.
In-vivo and ex-vivo studies show that celecoxib has a very low affinity for the constitutively
expressed COX-1. Consequently at therapeutic doses celecoxib has no effect on prostanoids
synthesised by activation of COX-1 thereby not interfering with normal COX-1-related
physiological processes in tissues, particularly the stomach, intestine and platelets.
Clinical Efficacy and Safety
Osteoarthritis (OA)
Celebrex has demonstrated significant reduction in joint pain compared to placebo. Celebrex
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 Celebrex 100 mg BD or 200 mg OD resulted in
improvement in 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, Celebrex doses of 100 mg BD or 200 mg BD provided significant
reduction of pain within 24-48 hours of initiation of dosing. At doses of 100 mg BD or 200 mg
BD the efficacy of Celebrex was shown to be similar to that of naproxen 500 mg BD. Doses
of 200 mg BD provided no additional benefit above that seen with 100 mg BD. A TDD of
200 mg has been shown to be equally effective whether administered as 100 mg BD or 200 mg
OD.
Rheumatoid Arthritis (RA)
Celebrex has demonstrated significant reduction in joint tenderness/pain and joint swelling
compared to placebo. Celebrex 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
CELEBREX – data sheet Page 21 of 35
24 weeks in duration. Celebrex was shown to be superior to placebo in these studies, using the
American College of Rheumatology 20 (ACR20) Responder Index, a composite of clinical,
laboratory, and functional measures in RA. Celebrex doses of 100 mg BD and 200 mg BD
were similar in efficacy and both were comparable to naproxen 500 mg BD.
Although Celebrex 100 mg BD and 200 mg BD provided similar overall efficacy, some
patients derived additional benefit from the 200 mg BD dose. Doses of 400 mg BD provided
no additional benefit above that seen with 100 mg - 200 mg BD.
Ankylosing spondylitis (AS)
Celebrex has been investigated in 896 patients in placebo and active-controlled (diclofenac,
naproxen or ketoprofen) clinical trials of 6 weeks (one trial) and 12 weeks (three trials) duration
for the symptomatic treatment of ankylosing spondylitis. At doses of 100 mg BD, 200 mg OD,
and 400 mg OD, Celebrex was statistically superior to placebo for all measures of efficacy
including global pain intensity, global disease activity and functional impairment. In two
12-week studies of celecoxib at 200 mg TDD and 400 mg TDD, non-inferiority was
demonstrated relative to diclofenac 150 mg TDD for global pain intensity. Results for global
pain intensity are presented below.
Table 3: Global Pain Intensity
a
in Celebrex Ankylosing Spondylitis Clinical Trials
Study
Placebo
Celecoxib
200 mg
TDD
b
Celecoxib
400 mg
TDD
b
Ketoprofen
100 mg BD
Naproxen
500 mg
BD
Diclofenac
150 mg TDD
b
Study 193
N=156
N=137
N=161
--
N=157
--
Week 12
-9.9
-30.0*
-30.4*
--
-36.3*
--
Study 137
N=76
N=80
--
N=90
--
--
Week 6
-11.9
-25.7*
--
-22.5
--
--
Study 243
--
N=126
N=124
--
--
N=123
Week 12
--
-29.1**
-31.7**
--
--
-32.7
Study 247
--
N=107
N=108
--
--
N=115
Week 12
--
-25.8**
-30.6**
--
--
-28.2
* Statistically significant difference vs. placebo (p<0.01), based on Analysis of Covariance model with the
effects of treatment and centre, and baseline value as covariate. Differences between celecoxib 200 mg TDD
and celecoxib 400 mg TDD were not statistically significant.
** Differences compared to diclofenac were not statistically significant (p
>0.50), based on Analysis of
Covariance model (for Study 243, baseline value and age as covariates and treatment, gender and centres as
factors; for Study 247, baseline value as a covariate and treatment and centres as factors. Differences
between celecoxib 200 mg TDD and celecoxib 400 mg TDD were not statistically significant.
a
As measured using 100 mm Visual Analog Scale. All values represent least squares mean changes from
baseline to the end of treatment, with last observation carried forward for patients who withdrew prior to the
end of treatment.
b
TDD = Total daily dose: celecoxib 200 mg TDD was administered as 100 mg BD (Study 137) or 200 mg OD
(Studies 193, 243, and 247); celecoxib 400 mg TDD was administered as 200 mg BD (Study 243 and 247)
or 400 mg OD (study 193); diclofenac 150 mg TDD was administered as Sustained Release 75 mg BD in
Study 243, or 50 mg TDS in Study 247.
CELEBREX – data sheet Page 22 of 35
Analgesia including Dysmenorrhoea
In acute analgesic models of post-oral surgery pain, post-orthopaedic surgery pain, and primary
dysmenorrhoea, Celebrex relieved pain that was rated by patients as moderate to severe. Single
doses of Celebrex provided pain relief within 30-60 minutes. In replicate multiple dose studies
of post-orthopaedic surgery pain, Celebrex was effective in reducing pain without additional
analgesic medication.
Special Studies
Celecoxib Long-term Athritis Safety Study (CLASS)
Study Design
A prospective long-term outcome study was conducted in approximately 5,800 OA patients
and 2,200 RA patients. The primary endpoint of this outcome study was the incidence of
complicated ulcers (gastrointestinal bleeding, perforation or obstruction) in Celebrex treated
patients compared to each comparator. Patients received Celebrex 400 mg BD (4-fold and
2-fold greater than the recommended OA and RA doses, respectively), ibuprofen 800 mg TDS
(approved maintenance dose is 1600 mg daily) or diclofenac 75 mg BD (approved maintenance
dose is 75-100 mg daily) for a median exposure of 9 months for Celebrex and diclofenac, and
6 months for ibuprofen. Patients were allowed to take concomitant low-dose aspirin ≤325 mg
mostly for CV prophylaxis.
Study Results
No statistically significant differences were demonstrated for the incidence of complicated
ulcers among the three treatment groups in all patients. In an additional non-protocol specified
analysis, there was no difference in the incidence of complicated and symptomatic ulcers in
patients on Celebrex vs. those on diclofenac, although the incidence was significantly lower
for Celebrex than for ibuprofen in all patients, and in those patients not taking aspirin (ASA)
(Figure 1). Approximately 22% of patients were taking low-dose aspirin. Concomitant low-
dose aspirin use increased the risk of complicated and symptomatic ulcers on Celebrex,
diclofenac and ibuprofen (see Use with Aspirin later in this section). The incidence rates for
diclofenac may be underestimated because of a higher incidence of early withdrawals due to
GI adverse events than Celebrex and ibuprofen.
Figure 1: Incidence of Symptomatic Ulcers and Ulcer Complications.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
All Patients Non-ASA Patients All Patients Non-ASA Patients
Incidence (12 months, %)
___________________
Ulcer Complications
_____________________
Symptomatic Ulcers and
Ulcer Complications
Celecoxib Diclofenac Ibuprofen
400 mg BD 75 mg BD 800 mg TDS
All (n) 3987 1996 1985
Non ASA (n) 3105 1551 1573
*
**
***
* p = 0.037 vs ibuprofen
** p = 0.017 vs ibuprofen
*** p < 0.01 vs ibuprofen
CELEBREX – data sheet Page 23 of 35
Celebrex (4-fold and 2-fold greater than the recommended OA and RA doses, respectively)
was also associated with a significantly lower incidence of clinically relevant decreases in
haemoglobin (>20 g/L) or haematocrit (≥10 points) than ibuprofen and diclofenac regardless
of aspirin use (Figure 2).
The incidence of clinically relevant decreases in haemoglobin and haematocrit in Celebrex
patients taking aspirin was lower than in ibuprofen and diclofenac patients taking aspirin.
Figure 2: Incidence of Clinically Relevant Decreases in Haemoglobin and/or
Haematocrit.
Upper Gastrointestinal Complications
In the original registration studies, the incidence of serious upper gastrointestinal complications
(bleeding, perforation, gastric outlet obstruction) with Celebrex was not significantly different
from placebo and is approximately 8-fold less than with non-specific COX inhibitors.
Endoscopic Studies
Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients
who were enrolled in five controlled randomised 12-24 week trials using active comparators,
two of which also included placebo controls. Twelve-week endoscopic ulcer data are available
on approximately 1,400 patients and 24-week endoscopic ulcer data are available on 184
patients on Celebrex at doses ranging from 50-400 mg BD. In all three studies that included
naproxen 500 mg BD, and in the study that included ibuprofen 800 mg TDS, Celebrex was
associated with a statistically significantly lower incidence of endoscopic ulcers over the study
period. Two studies compared Celebrex with diclofenac 75 mg BD; one study revealed a
statistically significantly higher prevalence of endoscopic ulcers in the diclofenac group at the
study endpoint (6 months on treatment), and one study revealed no statistically significant
difference between cumulative endoscopic ulcer incidence rates in the diclofenac and Celebrex
groups after 1, 2, and 3 months of treatment. There was no consistent relationship between the
incidence of gastroduodenal ulcers and the dose of Celebrex over the range studied.
Figure 3 and Table 4 summarise the incidence of endoscopic ulcers in two 12-week studies that
enrolled patients in whom baseline endoscopies revealed no ulcers.
*p<0.05 celecoxib vs ibuprofen and
diclofenac
CELEBREX – data sheet Page 24 of 35
Figure 3: Incidence of Endoscopically Observed Gastroduodenal Ulcers After Twelve
Weeks of Treatment.
Celebrex 100 mg BD, 200 mg OD or 200 mg BD are the recommended doses.
These studies were not powered to compare the endoscopic ulcer rates of Celebrex vs. placebo.
Study 1: placebo ulcer rate = 2.3%; Study 2: placebo ulcer rate = 2.0%
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)
Celebrex 50 mg BD
3.4% (8/233)
Celebrex 100 mg BD
3.1% (7/227)
4.0% (9/223)
Celebrex 200 mg BD
5.9% (13/221)
2.7% (6/219)
Celebrex 400 mg BD
4.1% (8/197)
Naproxen 500 mg BD
16.2% (34/210)*
17.6% (37/210)*
*p≤0.05 vs. all other treatments
Figure 4 and Table 5 summarise 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.
CELEBREX – data sheet Page 25 of 35
Figure 4: Cumulative Incidence of Gastroduodenal Ulcers Based on 4 Serial Endoscopies
Over 12 Weeks
C = Celebrex 200 mg BD D = Diclofenac 75 mg BD
N = Naproxen 500 mg BD I = Ibuprofen 800 mg TDS
Table 5: Incidence of Gastroduodenal Ulcers from 3-Month Serial Endoscopy Studies in
OA and RA Patients
Week 4
Week 8
Week 12
Final
Study 3 (n=523)
Celebrex
200 mg BD
4.0% (10/252)*
2.2% (5/227)*
1.5% (3/196)*
7.5% (20/266)*
Naproxen
500 mg BD
19.0% (47/247)
14.2% (26/182)
9.9% (14/141)
34.6% (89/257)
Study 4 (n=1062)
Celebrex
200 mg BD
3.9% (13/337)†
2.4% (7/296)†
1.8% (5/274)†
7.0% (25/356)†
Diclofenac
75 mg BD
5.1% (18/350)
3.3% (10/306)
2.9% (8/278)
9.7% (36/372)
Ibuprofen
800 mg TDS
13.0% (42/323)
6.2% (15/241)
9.6% (21/219)
23.3% (78/334)
* p≤0.05 Celebrex vs. naproxen based on interval and cumulative analyses
† p≤0.05 Celebrex vs. ibuprofen based on interval and cumulative analyses
One randomised and double-blinded 6-month study in 430 RA patients was conducted in which
an endoscopic examination was performed at 6 months. The results are shown in Figure 5.
C
N C D I
0
10
20
30
40
Study 3; n=523
Study 4; n=1062
*
*
p<0.001 vs. naproxen
**
p<0.001 vs. ibupr ofen
**
CELEBREX – data sheet Page 26 of 35
Figure 5: Prevalence of Endoscopically Observed Gastroduodenal Ulcers After Six
Months of Treatment in Patients with RA
The correlation between findings of endoscopic studies and the relative incidence of clinically
serious upper GI events that may be observed with different products, has not been fully
established.
Serious clinically significant upper GI bleeding has been observed in patients receiving
Celebrex in controlled and open-labelled trials, albeit infrequently. Among 5,285 patients who
received Celebrex in the original arthritis controlled clinical trials of 1 to 6 months duration
(most were 3 month studies) at a daily dose of 200 mg or more, 2 patients (0.04%) experienced
significant UGI bleeding. Patients most at risk of developing an ulcer complication were the
elderly (≥75 years), patients in poor health or with CV disease, aspirin users and patients with
a history of a GI ulcer or upper GI bleeding.
Use with Aspirin
Approximately 11% of patients (440/4,000) enrolled in 4 of the 5 endoscopic studies were
taking aspirin (≤325 mg/day). In the Celebrex groups, the endoscopic ulcer rate appeared to
be higher in aspirin users than in non-users. 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.
Platelet Function
At TDD of 1200 mg (three times the highest recommended therapeutic dose) for up to 7 days
duration, Celebrex had no effect on platelet aggregation and bleeding time compared to
placebo. Active controls (non-specific COX inhibitors i.e. naproxen, diclofenac, ibuprofen) all
significantly reduced platelet aggregation and prolonged bleeding time (see Figure 6).
CELEBREX – data sheet Page 27 of 35
Figure 6: Effect of High Dose Celecoxib (600 mg BD) on Patelet Aggregation and Bleeding
Time in Healthy Individuals
* Significantly different from placebo; p<0.05
** Significantly different from Celebrex; p<0.05
Gastrointestinal Safety - Meta-Analysis from OA and RA Studies
An analysis of 31 randomised 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 to the incidence in patients administered placebo
or NSAIDs (including naproxen, diclofenac and ibuprofen). The incidence of clinical ulcers
and ulcer bleeds with celecoxib 200 mg - 400 mg TDD was 0.2% compared to an incidence of
0.6% with NSAIDs (RR = 0.35; 95% CI 0.22-0.56).
Cardiovascular Safety - Prospective Randomized Evaluation of Celecoxib Integrated Safety vs
Ibuprofen Or Naproxen (PRECISION)
Study Design
The PRECISION study was a double blind study of CV safety in OA or RA patients with or at
high risk for CV disease comparing Celecoxib (200-400 mg daily) with Naproxen (750-1000
mg daily) and Ibuprofen (1800-2400 mg daily). The primary endpoint, Antiplatelet Trialists
Collaboration (APTC), was an independently adjudicated composite of CV death (including
haemorrhagic death), non-fatal myocardial infarction or non-fatal stroke. The study was
planned with 80% power to evaluate non-inferiority. All patients were prescribed open label
esomeprazole (20-40 mg) for gastro protection. Patients who were taking low dose Aspirin
were permitted to continue therapy.
Other independently adjudicated secondary and tertiary endpoints included CV,
gastrointestinal and renal outcomes. Additionally, there was a 4 month sub study focusing on
the effects of the three drugs on blood pressure as measured by ambulatory monitoring
(ABPM).
% Platelet Aggregation to Arachidonate
(Mean + SE) After Multiple Doses
0
50
100
%
n=8 n=8 n=8
Placebo Celebrex Non-Specific
600mg BID COX Inhibitor
(Naproxen
500 mg BID)
*
* *
Bleeding Time After Multiple Doses
- Change From Baseline
0
120
240
360
Sec
n=8 n=8 n=8
Placebo Celebrex Non-Specific
600mg BID COX Inhibitor
(Naproxen
500 mg BID)
*
* *
CELEBREX – data sheet Page 28 of 35
Study Results
Table 6: Population and Treatment Dose
Analysis Set
CELEBREX
100-200 mg bid
Ibuprofen
600-800 mg
tid
Naproxen
375-500 mg
bid
Total
Randomised (ITT)
8,072
8,040
7,969
24,081
On-Treatment (mITT)
8,030
7,990
7,933
23,953
Average Dose
1
(mg/day)
209±37
2045±246
852±103
NA
1
Average dose dispensed
ITT – Intent to Treat; All randomised subjects
mITT – Modified Intent to Treat: All randomised subjects with at least one dose of study medication and one post
baseline visit
Primary Endpoint
Celecoxib, as compared with either naproxen or ibuprofen, met all four pre-specified non-
inferiority requirements (P<0.001 for non-inferiority in both comparisons). Non-inferiority is
established when the hazard ratio (HR) ≤1.12 in both ITT and mITT analyses, and upper 95%
CI ≤1.33 for ITT analysis and ≤1.40 for mITT analysis.
The primary analysis for ITT and mITT are described below in Table 7.
Table 7: Primary Analysis of the Adjudicated APTC Composite Endpoint
Intent-To-Treat Analysis (ITT, through month 30)
CELEBREX
100 - 200 mg bid
Ibuprofen
600 - 800 mg tid
Naproxen
375 - 500 mg bid
N
8,072
8,040
7,969
Subjects with Events
188 (2.3%)
218 (2.7%)
201 (2.5%)
Pairwise Comparison
CELEBREX vs.
Naproxen
CELEBREX vs.
Ibuprofen
Ibuprofen vs.
Naproxen
HR (95% CI)
0.93 (0.76, 1.13)
0.86 (0.70, 1.04)
1.08 (0.89, 1.31)
Modified Intent-To-Treat Analysis (mITT, on treatment through month 43)
CELEBREX
100 - 200 mg bid
Ibuprofen
600 - 800 mg tid
Naproxen
375 - 500 mg bid
N
8,030
7,990
7,933
Subjects with Events
134 (1.7%)
155 (1.9%)
144 (1.8%)
Pairwise Comparison
CELEBREX vs.
Naproxen
CELEBREX vs.
Ibuprofen
Ibuprofen vs.
Naproxen
HR (95% CI)
0.90 (0.72, 1.14)
0.81 (0.64, 1.02)
1.12 (0.889, 1.40)
Key Secondary and Tertiary Endpoints
The analysis of Major Adverse Cardiovascular Events (MACE)
*
for mITT are described below
in Table 8.
Table 8: On-treatment Adjudicated Major Adverse CV events
CELEBREX
100 - 200 mg bid
Ibuprofen
60 - 800 mg tid
Naproxen
375 - 500 mg bid
N
8,030
7,990
7,933
Number of Subjects with Events (%)
MACE
247 (3.1%)
284 (3.6%)
253 (3.2%)
CELEBREX – data sheet Page 29 of 35
CV death
35 (0.4%)
51 (0.6%)
49 (0.6%)
Nonfatal MI
58 (0.7%)
76 (1.0%)
53 (0.7%)
Nonfatal stroke
43 (0.5%)
32 (0.4%)
45 (0.6%)
Hospitalisation for
unstable angina
46 (0.6%)
49 (0.6%)
44 (0.6%)
Revascularisation
132 (1.6%)
158 (2.0%)
122 (1.5%)
Hospitalisation for TIA
12 (0.1%)
21 (0.3%)
16 (0.2%)
Pairwise Comparison
HR (95%CI)
CELEBREX vs.
Naproxen
CELEBREX vs.
Ibuprofen
Ibuprofen vs.
Naproxen
MACE
0.95 (0.80, 1.13)
0.82 (0.69, 0.97)
1.17 (0.98, 1.38)
CV death
0.69 (0.45, 1.07)
0.64 (0.42, 0.99)
1.08 (0.73, 1.60)
Nonfatal MI
1.06 (0.73, 1.54)
0.72 (0.51, 1.01)
1.48 (1.04, 2.11)
Nonfatal stroke
0.93 (0.61, 1.42)
1.26 (0.79, 1.98)
0.74 (0.47, 1.16)
Hospitalisation for
unstable angina
1.02 (0.67, 1.54)
0.89 (0.59, 1.33)
1.16 (0.77, 1.74)
Revascularisation
1.06 (0.83, 1.35)
0.78 (0.62, 0.99)
1.35 (1.07, 1.72)
Hospitalisation for TIA
0.73 (0.35, 1.55)
0.54 (0.26, 1.09)
1.38 (0.72, 2.64)
*MACE = APTC composite endpoint plus coronary revascularization, or hospitalization for unstable angina or
transient ischaemic attack
In the ITT population for the MACE endpoint there were no significant differences, in the pairwise comparisons
between treatment regimens
The analysis of gastrointestinal events for mITT are described below in Table 9.
Table 9: On-treatment Adjudicated Gastrointestinal Endpoints
CELEBREX 100-200
mg bid
Ibuprofen
600-800 mg tid
Naproxen
375-500 mg bid
N
8,030
7,990
7,933
Subjects with Events, n(%)
CSGIE
27 (0.3%)
59 (0.7%)
52 (0.7%)
IDA of GI Origin
27 (0.3%)
58 (0.7%)
66 (0.8%)
Pairwise Comparison,
HR (95%CI)
CELEBREX vs.
Naproxen
CELEBREX vs.
Ibuprofen
Ibuprofen vs.
Naproxen
CSGIE
0.51 (0.32, 0.81)
0.43 (0.27, 0.68)
1.16 (0.80, 1.69)
IDA of GI Origin
0.39 (0.25, 0.62)
0.43 (0.27, 0.68)
0.91 (0.64, 1.29)
*CSGIE (Clinically Significant Gastrointestinal Events) = composite of the following; gastroduodenal
haemorrhage; gastric outlet obstruction; gastroduodenal, small bowel or large bowel perforation; large bowel
haemorrhage; small bowel haemorrhage; Acute GI haemorrhage of unknown origin, including presumed small
bowel haemorrhage; symptomatic gastric or duodenal ulcer.
**IDA (Iron Deficiency Anaemia) = clinically significant iron deficiency anaemia of GI origin or decrease in Hct
and/or Hgb (defined as Hct ≥ 10 points and or Hgb of ≥ 2g/dl from baseline.
In the ITT population for the CSGIE endpoint there were no significant differences, in the
pairwise comparisons between treatment regimens (data not shown). For the endpoint of iron
deficiency anaemia of GI origin, significant differences (celecoxib vs naproxen; celecoxib vs
ibuprofen) and non-significant differences (ibuprofen vs naproxen) were observed in a manner
consistent with the data presented above.
The analysis of clinically significant renal events
*
, hospitalisation for CHF and hypertension
for mITT are described below in Table 10.
CELEBREX – data sheet Page 30 of 35
Table 10: On-treatment Adjudicated Renal Events, Hospitalisation for CHF and
Hypertension
CELEBREX
100-200 mg bid
Ibuprofen
600-800 mg tid
Naproxen
375-500 mg bid
N
8,030
7,990
7,933
Subjects with Events, n(%)
Renal events
42 (0.5%)
73 (0.9%)
62 (0.8%)
Hospitalisation for CHF
28 (0.3%)
38 (0.5%)
35 (0.4%)
Hospitalisation for
hypertension
25 (0.3%)
37 (0.5%)
32 (0.4%)
Any of the Above
89 (1.1%)
139 (1.7%)
120 (1.5%)
Pairwise Comparison,
HR (95%CI)
CELEBREX vs.
Naproxen
CELEBREX vs.
Ibuprofen
Ibuprofen vs.
Naproxen
Renal events
0.66 (0.44, 0.97)
0.54 (0.37, 0.79)
1.21 (0.86, 1.70)
Hospitalisation for CHF
0.77 (0.47, 1.27)
0.70 (0.43, 1.13)
1.12 (0.71, 1.77)
Hospitalisation for
hypertension
0.76 (0.45, 1.28)
0.64 (0.39, 1.07)
1.18 (0.74, 1.90)
Any of the Above
0.72 (0.55, 0.95)
0.60 (0.46, 0.79)
1.19 (0.93, 1.52)
*N.B:Renal events included a composite of pre-defined rises in creatinine levels (verified serum creatinine of
≥2.0mg/dL (177μmol/L) and an increase of ≥0.7mg/ml (62μmol/L)) , or hospitalisation for acute renal failure
(defined as a doubling in serum creatinine, or confirmation of hyperkalaemia with ≥ 50% elevation in serum
creatinine), or the initiation of haemodialysis or peritoneal dialysis.
In the ITT population for the endpoint of clinically significant renal events, only the pairwise
comparison between celecoxib and ibuprofen was significant, HR 0.61 (0.44, 0.85), no
significant differences were observed between treatment regimens in the incidence of
hospitalisation for congestive heart failure, and a significantly lower incidence of
hospitalisation for hypertension was observed between celecoxib and ibuprofen, HR 0.59 (0.36,
0.99).
All-cause Mortality
In the mITT populations celecoxib, naproxen and ibuprofen were associated with 53 (0.7%),
79 (1.0%), and 73 (0.9%) deaths, respectively. Significant differences were observed in the
pairwise comparisons between celecoxib and either naproxen HR 0.65 (0.46, 0.92) or celecoxib
and ibuprofen HR 0.68 (0.48, 0.97). In the ITT population the celecoxib, naproxen and
ibuprofen were associated with 132 (1.6%), 163 (2.0%) and 142 (1.8%) deaths, respectively.
No significant differences were observed in pairwise comparisons between treatments.
ABPM Substudy
In the PRECISION-ABPM substudy, among the total of 444 analyzable patients, at Month 4,
celecoxib-treated patients had the smallest change in 24-hour ambulatory systolic blood
pressure (SBP) compared to ibuprofen and naproxen: celecoxib produced a slight reduction of
0.3 mmHg while ibuprofen and naproxen increased mean 24-hour SBP by 3.7 and 1.6 mmHg,
respectively. These changes resulted in a statistically significant and clinically meaningful
difference of -3.9 mmHg (p=0.0009) between celecoxib and ibuprofen; a non-significant
difference of -1.8 (p=0.119) mmHg between celecoxib and naproxen, and a non-significant
difference of -2.1 mmHg (p=0.0787) between naproxen and ibuprofen.
CELEBREX – data sheet Page 31 of 35
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 CV 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 CV death,
myocardial infarction, or stroke (adjudicated) were 3.4 (95% CI 1.4 - 8.5) with celecoxib 400
mg BD and 2.8 (95% CI 1.1 - 7.2) with celecoxib 200 mg BD. Cumulative rates for this
composite endpoint over 3 years were 3.0% (20/671) and 2.5% (17/685) for the 400 mg BD
and 200 mg BD celecoxib treatment groups, respectively, compared to 0.9% (6/679) for the
placebo group. 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 OD. Cumulative rate for this composite endpoint
over 3 years was 2.3% (21/933) compared to 1.9% (12/628) for the placebo group.
When data from the APC and PreSAP trials were considered together, risk for CV
thromboembolic events was greater in celecoxib-treated patients with a history of
atherosclerotic CV disease, than in celecoxib-treated patients without such history.
Cardiovascular Safety - Long-term Study of Alzheimer's Disease Anti-inflammatory Prevention
Trial (ADAPT)
Data from the ADAPT study did not show a significantly increased CV risk with celecoxib
200 mg BD 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 – 2.15) with celecoxib
200 mg BD. The incidence of myocardial infarction was 1.1% (8/717 patients) with celecoxib
200 mg BD and 1.2% (13/1070 patients) with placebo.
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
from 41 completed celecoxib clinical studies of up to 1 year duration has been conducted,
representing 44,308 patients (24,933 (56.3%) patients exposed to celecoxib, 13,990 (31.6%)
patients exposed to NSAIDs, 4057 (9.2%) patients exposed to placebo, and 1328 (3.0%)
patients exposed to rofecoxib).
In this analysis, the incidence of serious CV thromboembolic events (CV death, non-fatal
myocardial infarction and non-fatal stroke) was similar between Celebrex (N=19,773) and non-
selective NSAIDs (N=13,990) treatment (RR=0.84, 95% CI 0.63 - 1.13). This pattern of effect
was maintained with or without aspirin use (≤325 mg). The incidence of non-fatal myocardial
infarction trended higher (RR=1.49, 95% CI 0.82 - 2.70); however that of stroke was
significantly lower (RR=0.31, 95% CI 0.14 - 0.68), and that of CV death was comparable
(RR=0.72, 95% CI 0.37 - 1.39) for Celebrex compared to combined non-selective NSAIDs.
In this analysis, the incidence of serious CV thromboembolic events (CV death, non-fatal
myocardial infarction and non-fatal stroke) was 0.38% for celecoxib (N=7,462) and 0.27% for
CELEBREX – data sheet Page 32 of 35
placebo (N=4,057) treatment (RR=1.14, 95% CI 0.57 - 2.27). This pattern of effect was
maintained with or without aspirin use (≤325 mg). The incidence of non-fatal myocardial
infarction trended higher (RR=1.24, 95% CI 0.27 - 5.76), as did that of CV death (RR=1.74,
95% CI 0.49 - 6.17), and that of stroke was similar RR=0.96, 95% CI 0.29 - 3.17) for celecoxib
compared to placebo.
Cardiovascular Safety - CLASS Trial
CV safety outcomes were evaluated in the CLASS trial (see Celecoxib Long-term Arthritis
Safety Study (CLASS) for description of trial). Kaplan-Meier cumulative rates for
investigator-reported serious CV thromboembolic adverse events (including MI, pulmonary
embolism, deep venous thrombosis, unstable angina, transient ischaemic attacks, and
ischaemic cerebrovascular accidents) demonstrated no differences between the celecoxib,
diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months
for celecoxib, 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.
5.2 Pharmacokinetic Properties
Absorption
When celecoxib is given under fasting conditions, peak plasma concentrations are reached after
approximately 2-3 hours. Under fasting conditions, both peak plasma levels (C
max
) and area
under the curve (AUC) are roughly dose proportional up to 200 mg BD; at higher doses there
are less than proportional increases in C
max
and AUC, which is thought to be due to the low
solubility of the drug in aqueous media. Absolute bioavailability studies have not been
conducted because of celecoxib's low solubility in aqueous media. The relative oral solubility
of Celebrex capsules compared with a suspension is about 99%. With multiple dosing, steady-
state conditions are reached on or before day 5.
When Celebrex 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%.
Distribution
In healthy subjects, celecoxib is highly protein bound (~97%) within the therapeutic dose
range. In-vitro studies indicate that it binds primarily to albumin, and to a lesser extent, α
1
glycoprotein. The apparent volume of distribution at steady-state is about 400 L in healthy
young adults, suggesting extensive tissue distribution.
Biotransformation
Celecoxib is extensively metabolised in the liver. In-vitro and in-vivo studies indicate that
metabolism is mainly by cytochrome P450 2C9 (see section 4.5 Interaction with Other
Medcines and Other Forms of Interaction). Three metabolites have been identified in human
plasma: a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate.
Pharmacological activity resides in the parent drug. The main metabolites found in human
plasma have no detectable COX-1 or COX-2 inhibitory activity.
Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead
to reduced enzyme activity, such as those homozygous for the CYP 2C9*3 polymorphism. In
CELEBREX – data sheet Page 33 of 35
a pharmacokinetic study of celecoxib 200 mg administered OD in healthy volunteers,
genotyped as either CYP 2C9*1/*1, CYP 2C9*1/*3, or CYP 2C9*3/*3, the median C
max
and
AUC
0-24
of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects
genotyped as CYP 2C9*3/*3 compared to other genotypes. In three separate single dose
studies, involving a total of 5 subjects genotyped as CYP 2C9*3/*3, single-dose AUC
0-24
increased by approximately 3-fold compared to normal metabolisers. 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 poor P450 2C9 metabolisers based on previous
history should be administered Celebrex with caution as they may have abnormally high
plasma concentrations due to reduced metabolic clearance. Consider starting treatment at half
the lowest recommended dose (see section 4.2 Dose and Method of Administration 4.1
Therapeutic Indications, and section 4.5 Interaction with Other Medcines and Other Forms of
Interaction).
At steady-state, subjects older than 65 years of age had a 40% higher C
max
and a 50% higher
AUC than those of younger subjects. In elderly females, the C
max
and AUC were higher than
those for elderly males predominantly due to the lower body weight of the females.
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.
A pharmacokinetic study in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh
Class II) hepatic impairment has shown that steady-state celecoxib AUC is increased about
40% and 180%, respectively, above that seen in healthy control subjects. Therefore, Celebrex
capsules should be introduced at the lowest recommended dose in arthritis patients with
moderate hepatic impairment.
Patients with severe hepatic impairment have not been studied. Therefore, the use of Celebrex
in patients with severe hepatic impairment (Child-Pugh score ≥10) is contraindicated.
In elderly volunteers with age-related reductions in glomerular filtration rate (GFR) (mean
GFR >65 mL/min/1.73 m
2
) and in patients with chronic stable renal insufficiency
(GFR 35-60 mL/min/1.73 m
2
) celecoxib pharmacokinetics was comparable to those seen in
patients with normal renal function. No significant relationship was found between serum
creatinine (or creatinine clearance) and celecoxib clearance. In clinical studies comparing renal
function as measured by the GFR, BUN (Blood Urea Nitrogen) and creatinine, and platelet
function as measured by bleeding time and platelet aggregation, the results were not different
between elderly and young volunteers. Severe renal insufficiency would not be expected to
alter clearance of celecoxib since the main route of elimination is via hepatic metabolism to
inactive metabolites. There are no studies in patients with severe renal impairment.
Elimination
Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged
drug recovered in the urine and faeces. Following a single oral dose of radiolabelled drug,
approximately 57% of the dose was excreted in the faeces and 27% was excreted into the urine.
The primary metabolite in both the urine and faeces was the carboxylic acid metabolite (73%
of the dose) with low amounts of the glucuronide also appearing in the urine. At steady-state
the elimination half-life (t
½
) was 4-15 hours and the clearance is about 500 mL/min. It appears
that the low solubility of the drug prolongs absorption resulting in variable terminal half-life
(t
½
) determinations.
CELEBREX – data sheet Page 34 of 35
5.3 Preclinical Safety Data
Genotoxicity
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.
Carcinogenicity
Celecoxib was not carcinogenic in 2-year studies in rats given oral doses up to 200 mg/kg/day
for males and 10 mg/kg/day for females (approximately 2-4 fold the human exposure as
measured by the AUC
0-24 h
at 400 mg BD, which is twice the recommended maximum daily
dose), or in mice given dietary doses up to 25 mg/kg/day for males and 50 mg/kg/day for
females (slightly less than human exposure as measured by the AUC
0-24 h
at 400 mg BD).
6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Each capsule contain lactose, sodium lauryl sulfate, povidone, croscarmellose sodium, and
magnesium stearate. The capsule shells contain gelatin, titanium dioxide; and the inks contain:
iron oxide yellow CI 77492 (200 mg capsule); indigo carmine CI 73015 (100 mg capsule).
6.2 Incompatibilities
Incompatibilities with other medicines - None known.
6.3 Shelf Life
36 months.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
PVC/Aclar/Aluminium foil blisters or PVC/Aluminium foil blisters in an outer carton. Packs
of 10 capsules (100 mg and 200 mg), 60 capsules (100 mg), 30 capsules (200 mg).
Not all presentations are available in New Zealand.
6.6 Special Precautions for Disposal
No special requirements.
7. MEDICINE SCHEDULE
Prescription medicine.
8. SPONSOR
Pharmacy Retailing (NZ) Limited trading as Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Auckland
CELEBREX – data sheet Page 35 of 35
New Zealand
www.aspenpharma.co.nz
9. DATE OF FIRST APPROVAL
09 September 1999
10. DATE OF REVISION OF TEXT
20 July 2022
Summary table of changes
Section changed
Summary of new information
All
Updated product name, and removed 400 mg information.