Apo-Celecoxib

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Celecoxib 200 mg
Available from:
Apotex NZ Ltd
INN (International Name):
Celecoxib 200 mg
Dosage:
200 mg
Pharmaceutical form:
Capsule
Composition:
Active: Celecoxib 200 mg Excipient: Crospovidone Gelatin Magnesium stearate Povidone Purified water Sodium laurilsulfate Tekprint gold SB-3002 Titanium dioxide
Prescription type:
Prescription
Manufactured by:
Cadila Pharmaceuticals Ltd
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 COX-2 inhibitor should only be made: · if non-pharmaceutical 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 risks of the selective COX-2 inhibitors may increase with dose and duration of exposures, 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
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVDC/Al - 30 capsules - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-9523a
Authorization date:
2014-03-28

Read the complete document

New Zealand Data Sheet

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 1 of 30

Presentation

APO-CELECOXIB 100mg are hard gelatin capsules with white opaque body and white

opaque cap. Imprinted “APO/C100” in blue ink. Filled with white to off-white granular

powder.

APO-CELECOXIB 200mg are hard gelatin capsules with white opaque body and white

opaque cap. Imprinted “APO/C200” in yellow ink. Filled with white to off-white granular

powder.

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 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 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 on-going need for treatment.

Dosage and Administration

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.

Adults

The following doses can be given without regard to timing of meals.

Osteoarthritis

The recommended daily dose is 200mg taken once daily or in two divided doses. A dose of

200mg twice daily may be used if needed.

Rheumatoid Arthritis

The recommended daily dose is 200-400mg taken in two divided doses.

Ankylosing Spondylitis

The recommended daily dose is 200mg taken once daily or in two divided doses. Some

patients may benefit from a total daily dose of 400mg.

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 2 of 30

Management of Acute Pain and Treatment of Primary Dysmenorrhoea

The recommended dose is 400mg as a single dose on the first day followed by 200mg once

daily on subsequent days. Patients may be instructed to take an additional dose of 200mg on

any given day, if needed. The maximum recommended dose is 400mg per day. APO-

CELECOXIB can be administered up to 2 hours prior to surgery.

Elderly

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.

Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment. In arthritis

patients with moderate hepatic impairment, APO-CELECOXIB should be introduced at the

lowest recommended dose.

There is no clinical experience in patients with severe hepatic impairment. Therefore, the use

of APO-CELECOXIB in patients with severe hepatic impairment (Child-Pugh score

10) is

contraindicated (see USES, Pharmacokinetics and CONTRAINDICATIONS).

Renal Impairment

No dosage adjustment is necessary in patients with mild or moderate renal impairment.

There is

clinical

experience

patients

with

severe

renal

impairment (see

USES,

Pharmacokinetics and WARNINGS AND PRECAUTIONS).

Children and Adolescents

APO-CELECOXIB is not approved in patients under 18 years old.

CYP 2C9 Poor Metabolisers

Patients who are known, or suspected to be CYP 2C9 poor metabolisers based on previous

history/experience with other CYP 2C9 substrates should be administered celecoxib with

caution.

Consider

starting

treatment

half

lowest

recommended

dose

(see

INTERACTIONS and USES, Pharmacokinetics).

Maximum Tolerated Daily Dose

The maximum recommended dose is 400mg per day.

Patients on long-term treatment should be reviewed regularly, such as every three months,

with regards to efficacy, risk factors and on-going need for treatment.

Contraindications

Known

hypersensitivity

celecoxib or

excipients

contained

APO-

CELECOXIB capsules (see FURTHER INFORMATION).

Demonstrated allergic-type reactions to sulphonamides.

APO-CELECOXIB should not be given to patients who have experienced asthma, urticaria,

or allergic-type reactions after taking acetyl salicylic acid (ASA) or other non-steroidal

anti-

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 3 of 30

inflammatory drugs (NSAIDs), including other COX-2 specific inhibitors. Severe, rarely fatal,

anaphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS

AND PRECAUTIONS, Anaphylactoid Reactions).

APO-CELECOXIB should not be used with other NSAIDs because of the absence of any

evidence demonstrating synergistic benefits and the potential for additive adverse reactions.

APO-CELECOXIB is contraindicated for the peri-operative treatment of pain in patients

undergoing

coronary

artery

bypass

graft

(CABG)

surgery

(see

WARNINGS

AND

PRECAUTIONS).

CELECOXIB is contraindicated in:

Patients with unstable or significant established ischaemic heart disease, peripheral

arterial

disease

and/or

cerebrovascular

disease

(see

WARNINGS

AND

PRECAUTIONS).

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

USES,

Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Child-Pugh is a classification of the severity of liver disease.

Parameter

Points assigned

Ascites

Absent

Slight

Moderate

Bilirubin (mg/dL)

<2

>3

Albumin (g/dL)

>3.5

2.8-3.5

<2.8

Prothrombin time (seconds over control)

<4

>6

<1.7

1.7-2.3

>2.3

Encephalopathy

None

Grade 1-2

Grade 3-4

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);

grade

(significant

functional

compromise);

10-15

grade

(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.

Warnings and Precautions

Cardiovascular Adverse Effects

Cardiovascular Thrombotic Events

COX-2 inhibitors (of which celecoxib is one) have been associated with an increased risk of

cardiovascular and thrombotic adverse events (see USES, Clinical Trials, Cardiovascular

Safety).

All NSAIDs, both COX-2 selective and non-selective may cause an increased risk of serious

cardiovascular thrombotic events. This risk may increase with duration of use.

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 4 of 30

Patients with known cardiovascular disease, history of atherosclerotic cardiovascular disease

or risk factors for cardiovascular disease may be at greater risk.

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 cardiovascular 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 cardiovascular

event. Patients with significant risk factors for cardiovascular 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.

To minimize the potential risk for an adverse cardiovascular event in patients treated with

celecoxib, the lowest effective dose should be used for the shortest duration possible (see

DOSAGE AND ADMINISTRATION).

Prescribers

should

inform

individual

patient

possible

increased

risks

when

prescribing celecoxib for patients at high risk of cardiovascular adverse events. Physicians

patients

should

remain

alert

such

events,

even

absence

previous

cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of

serious cardiovascular toxicity and the steps to take if they occur. Celecoxib is not a

substitute for cardiovascular 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 cardiovascular adverse events associated

with COX-2 inhibitors, including celecoxib.

Gastrointestinal Effects

Infrequently, serious gastrointestinal toxicity such as bleeding, ulceration, and perforation of

the stomach or intestine has been observed in patients treated with celecoxib.

Physicians

and patients should remain alert for ulceration and bleeding, even in the absence of previous

GI tract symptoms.

Celecoxib exhibited a low incidence of gastroduodenal ulceration and serious clinically

significant GI events within clinical trials (see USES, 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. Most spontaneous reports of fatal GI

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 5 of 30

events are in elderly or debilitated patients and therefore special care should be taken in

treating this population.

NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer

disease or gastrointestinal bleeding. Upper gastrointestinal perforations, ulcers or bleeds

have occurred in patients treated with celecoxib.

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 APO-CELECOXIB 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

prior

history

peptic

ulcer

disease

and/or

gastrointestinal 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

APO-CELECOXIB.

addition

past

history

ulcer

disease,

pharmacoepidemiological studies have identified several other co-therapies or co-morbid

conditions

that

increase

risk

bleeding

such

treatment

with

oral

corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking,

alcoholism, older age, and poor general health status.

There is further increase in the risk of gastrointestinal adverse effects (gastrointestinal

ulceration or other gastrointestinal complications), when celecoxib is taken concomitantly

with aspirin (even at low doses).

In patients on concurrent therapy with warfarin or similar agents, serious bleeding events

have been reported. Because increases in prothrombin time (INR) have been reported, anti-

coagulant activity should be monitored after initiating treatment with celecoxib or

changing

the dose. If INR increases, it may be sufficient to reduce the dose of warfarin in order to

manage the interaction.

There is no definitive evidence that the concomitant administration of histamine H2-receptor

antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects

or allow the continuation of APO-CELECOXIB if these adverse reactions appear.

Anaphylactoid Reactions

As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known

prior exposure to celecoxib. In post-marketing experience, rare cases of anaphylactoid

reactions and angioedema have been reported in patients receiving celecoxib.

APO-

CELECOXIB 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 WARNINGS AND PRECAUTIONS, 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 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

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 6 of 30

treatment. APO-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

which

contribute

increased

incidence

cardiovascular 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.

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

NSAID

cause

dose-dependent

reduction

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

inhibitors

(see

WARNINGS

AND

PRECAUTIONS,

Concomitant

Use

of

ACE

Inhibitors

or

Angiotensin

Receptor

Antagonists and Anti-inflammatory Drugs and Thiazide Diuretics), and the elderly.

Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.

Reported cclinical

trials with celecoxib have shown renal effects similar to those observed

with comparator NSAIDs. At the present time the relative roles of COX-1 and COX-2 in renal

physiology is incompletely understood. Celecoxib reduces the urinary excretion of PGE2 and

6-keto-PGF1a (a prostacyclin metabolite) but leaves serum thromboxane B2 (TXB2) and

urinary excretion of 11-dehydro-TXB2, a thromboxane metabolite (both COX-1 products)

unaffected.

Caution should be used when initiating treatment with APO-CELECOXIB in patients with

considerable dehydration. It is advisable to rehydrate patients first and then start therapy with

APO-CELECOXIB.

No information is available regarding the use of

celecoxib in patients with advanced kidney

disease. Therefore, treatment with APO-CELECOXIB is not recommended in these patients.

If celecoxib therapy must be initiated, close monitoring of the patient's kidney function is

advisable.

Concomitant use of ACE Inhibitors or Angiotensin Receptor Antagonists and

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

accompanied

increased

monitoring

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.

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 7 of 30

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

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, hepatic failure (some with fatal outcome),

and liver

transplant have been reported with NSAIDs, including celecoxib (see ADVERSE EFFECTS).

In reported controlled clinical trials of celecoxib, the incidence of borderline elevations of liver

tests was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking

celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal

liver test has occurred, should be monitored carefully for evidence of the development of

more severe hepatic reaction while on therapy with APO-CELECOXIB. If clinical signs and

symptoms consistent with liver disease develop, or if systemic manifestations occur

(e.g.

eosinophilia, rash, etc.), APO-CELECOXIB should be discontinued.

The incidence of elevations in ALT and/or AST may be increased in patients treated with

celecoxib at doses greater than 400mg daily.

Haematological Effects

Anaemia is sometimes seen in patients receiving celecoxib. In reported controlled clinical

trials the incidence of anaemia was 0.6% with celecoxib and 0.4% with placebo. Patients on

long-term treatment with celecoxib should have their haemoglobin or haematocrit checked if

they exhibit any signs or symptoms of anaemia or blood loss. Celecoxib 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 USES, 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, APO-CELECOXIB 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 celecoxib (see

ADVERSE

EFFECTS).

with

NSAIDs,

celecoxib

exacerbate

pre-existing

hypertension, cardiac failure or oedema, and the treatment of these conditions may be

compromised. Therefore, APO-CELECOXIB 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.

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 8 of 30

Use in Patients being Treated with Corticosteroids

Abrupt

discontinuation

corticosteroids

lead

exacerbation

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.

Detecting Infections

By reducing inflammation, celecoxib may diminish the utility of diagnostic signs, such as

fever, in detecting infections.

Effects on Fertility

Celecoxib did not affect male or female fertility in rats at oral doses up to 600mg/kg/day

(approximately 7-fold human exposure based on AUC0-24h at 400mg 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.

Use in Pregnancy

Category B3

There is no information on the use of celecoxib in pregnant women. APO-CELECOXIB use is

not recommended in pregnancy unless it is considered clinically essential (see information

on animal studies below). 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 foetal lambs and to contribute to

maintenance of patency. Therefore, use of APO-CELECOXIB during the third trimester of

pregnancy should be avoided and APO-CELECOXIB 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 foetus. The effects of celecoxib on labour and delivery in pregnant

women are not known.

rats,

celecoxib

caused

early

embryonic

death

doses

greater

than

30mg/kg/day

administered

before

mating

during

early

gestation

(approximately

2-fold

human

exposure based on AUC0-24 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 100mg/kg/day, increased incidences of diaphragmatic hernias at 30

and 100mg/kg/day in another rat study; and increased incidences of rib and sternebral

abnormalities

rabbits

doses

mg/kg/day

greater

cardiovascular

abnormalities in rabbits at doses of 150mg/kg/day or greater. At

the no-effect dose in rats

(10mg/kg/day),

AUC0-24h was similar

to that in humans dosed at 400mg BD. At

threshold dose of

60mg/kg/day in rabbits, AUC0-24h was slightly below that in humans

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 9 of 30

dosed

400mg

Celecoxib

marginal

effect

parturition,

causing

slight

prolongation of gestation and parturition and increased incidence of still births at oral doses

of 10mg/kg/day or greater

(slightly greater than human exposure based on AUC0-24h at

400mg 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.

Use in 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.

Effects on ability to drive and use machines

Presumed to be safe or unlikely to produce an effect on the ability to drive or use machinery.

The effect of APO-CELECOXIB 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.

Other

Paediatric Use

APO-CELECOXIB is not approved for use in patients under 18 years of age.

Use in the Elderly

Of the total number of patients who received celecoxib 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. Other reported clinical experience including data from the Celecoxib

Long-term Arthritis Safety Study has not identified differences in response between the

elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled

out. 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.

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

carcinogenic

2-year

studies

rats

given

oral

doses

200mg/kg/day for males and 10mg/kg/day for females (approximately 2-4 fold the human

exposure as measured by the AUC0-24h at 400mg BD, which is twice the recommended

maximum daily dose), or in mice given dietary doses up to 25mg/kg/day for males and

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 10 of 30

50mg/kg/day for females (slightly less than human exposure as measured by the AUC0-24h

at 400mg BD).

Adverse Effects

Of the celecoxib treated patients reported in controlled trials, approximately 4,250 were

patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were

patients with post-surgical pain. More than 8,500 patients have received a total daily dose of

celecoxib of 200mg (100mg BD or 200mg once daily) or more, including more than 400

treated at 800mg (400mg BD). Approximately 3,900 patients have received celecoxib at

these doses for 6 months or more; approximately 2,300 of these have received it for 1 year

or more and 124 of these have received it for 2 years or more.

Adverse Events from Original Celecoxib Arthritis Trials

Table 1 lists all adverse events, regardless of causality, occurring in

2% of patients

receiving celecoxib from 12 reported 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

Celecoxib

Patients

from

Original

Celecoxib Arthritis Trials

Celecoxib

(100-200mg

BD or 200mg

once daily)

(N=4146)

Placebo

(N=1864)

Naproxen

500mg DB

(N=1366)

Diclofenac

75mg DB

(N=387)

Ibuprofen

800mg

TDS

(N=345)

Gastrointestinal

Abdominal pain

4.1%

2.8%

7.7%

9.0%

9.0%

Diarrhoea

5.6%

3.8%

5.3%

9.3%

5.8%

Dyspepsia

8.8%

6.2%

12.2%

10.9%

12.8%

Flatulence

2.2%

1.0%

3.6%

4.1%

3.5%

Nausea

3.5%

4.2%

6.0%

3.4%

6.7%

Body as a whole

Back pain

2.8%

3.6%

2.2%

2.6%

0.9%

Peripheral

oedema

2.1%

1.1%

2.1%

1.0%

3.5%

Injury-accidental

2.9%

2.3%

3.0%

2.6%

3.2%

Central and peripheral nervous system

Dizziness

2.0%

1.7%

2.6%

1.3%

2.3%

Headache

15.8%

20.2%

14.5%

15.5%

15.4%

Psychiatric

Insomnia

2.3%

2.3%

2.9%

1.3%

1.4%

Respiratory

Pharyngitis

2.3%

1.1%

1.7%

1.6%

2.6%

Rhinitis

2.0%

1.3%

2.4%

2.3%

0.6%

Sinusitis

5.0%

4.3%

4.0%

5.4%

5.8%

Upper respiratory

tract infection

6.7%

9.9%

9.8%

9.9%

Skin

Rash

2.2%

2.1%

2.1%

1.3%

1.2%

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In the reported placebo-

or active-controlled clinical trials, the discontinuation rate due to

adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving

placebo. Among the most common reasons for discontinuation due to adverse events in the

celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for

discontinuation in 0.8% and 0.7% of celecoxib 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 Celecoxib (100-

200mg BD or 200mg once daily) regardless of causality:

Gastrointestinal:

Constipation, diverticulitis, dysphagia, eructation, oesophagitis,

gastritis, gastroenteritis, gastroesophageal reflux, haemorrhoids,

hiatal

hernia, melaena, dry mouth, stomatitis, tenesmus, tooth

disorder, vomiting

Cardiovascular:

Aggravated

hypertension,

hypertension,

angina

pectoris,

coronary

artery

disorder,

myocardial

infarction*,

heart

failure,

palpitations, arrhythmia

General:

Allergy aggravated, allergic reaction, asthenia, chest pain, cyst

NOS,

oedema

generalized,

face

oedema,

fatigue,

fever,

flushes, influenza-like symptoms, pain, peripheral pain

Resistance mechanism

disorders:

Herpes

simplex,

herpes

zoster,

infection

bacterial,

infection

fungal,

infection soft tissue, infection viral, moniliasis, moniliasis

genital, otitis media

Central, peripheral

nervous system:

cramps,

hypertonia,

hypoaesthesia,

migraine,

neuralgia,

neuropathy, paraesthesia, vertigo

Female reproductive:

Breast

fibroadenosis,

breast

neoplasm,

breast

pain,

dysmenorrhoea,

menstrual

disorder,

vaginal

haemorrhage,

vaginitis

Male reproductive:

Prostatic disorder

Hearing and

vestibular:

Deafness, ear abnormality, earache, tinnitus

Heart rate and rhythm:

Palpitation, tachycardia

Liver and biliary

system:

Hepatic function abnormal, AST increased, ALT increased

Metabolic and

nutritional:

increased,

increased,

diabetes

mellitus,

hypercholesterolaemia,

hyperglycaemia,

hypokalaemia,

non-

protein

nitrogen

increase,

creatinine

increased,

alkaline

phosphatase increased, weight increase

Musculoskeletal:

Arthralgia, arthrosis, bone disorder, fracture accidental, myalgia,

neck stiffness, synovitis, tendonitis

Platelets

(bleeding

or

clotting):

Ecchymosis, epistaxis, thrombocythaemia

Psychiatric:

Anorexia, anxiety, appetite increased, depression, nervousness,

somnolence

Hemic:

Anaemia

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Respiratory:

Bronchitis, bronchospasm, bronchospasm aggravated, coughing,

dyspnoea, laryngitis, pneumonia

Skin and appendages:

Alopecia,

dermatitis,

nail

disorder,

photosensitivity

reaction,

pruritus,

rash erythematous, rash maculopapular, skin disorder,

skin dry, sweating increased, urticaria

Application site

disorders:

Cellulitis, dermatitis contact, injection site reaction, skin nodule

Special senses:

Taste perversion

Urinary system:

Albuminuria, cystitis, dysuria, haematuria, micturition frequency,

renal calculus, urinary incontinence, urinary tract infection

Vision:

Blurred vision, cataract, conjunctivitis, eye pain, glaucoma

Other Serious Adverse Events which Occur Rarely (<0.1%), Regardless of Causality

The following serious adverse events have occurred rarely in patients, taking celecoxib.

Cases reported only in the post-marketing experience are indicated in italics.

Cardiovascular:

Syncope,

congestive

heart

failure,

ventricular

fibrillation,

pulmonary

embolism,

cerebrovascular

accident,

peripheral

gangrene,

thrombophlebitis,

vasculitis,

ischaemic

stroke*,

cerebral haemorrhage

Gastrointestinal:

Intestinal

obstruction,

intestinal

perforation,

gastrointestinal

bleeding,

colitis

with

bleeding,

oesophageal

perforation,

pancreatitis, ileus, ulcers (oesophageal, gastric and duodenal)

Liver

and

biliary

system:

Cholelithiasis, hepatitis, fulminant hepatitis jaundice, liver failure,

liver

necrosis, cholestasis, cholestatic hepatitis, liver transplant,

elevation of hepatic enzymes.

Haemic and lymphatic:

Thrombocytopenia,

agranulocytosis,

aplastic

anaemia,

pancytopenia, leukopenia

Metabolic:

Hypoglycaemia

Psychiatric:

Hallucinations

Nervous system:

Ageusia, anosmia, aseptic meningitis, ataxia, suicide, aggravated

epilepsy, confusion

Reproductive

system

and breast disorders:

Menstrual disorders, female fertility decreased

Renal:

Acute

renal

failure,

interstitial

nephritis,

nephrotic

syndrome,

minimal change disease, hyponatraemia

Skin:

Erythema

multiforme,

exfoliative

dermatitis,

Stevens-Johnson

syndrome, toxic epidermal necrolysis, drug rash with eosinophilia

and systemic symptoms (DRESS, or hypersensitivity syndrome),

acute generalised exanthematous pustulosis (AGEP)

Ear:

Decreased hearing

Eye:

Conjunctivitis

General:

Sepsis,

sudden

death,

anaphylactoid

reaction,

angioedema,

bullous eruption

* 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 400mg daily over placebo was 0.7 events per 1000 patients (Rare) and there was no excess of

strokes.

In preliminary data from two studies in patients with colorectal polyps treated with celecoxib

400mg daily (see USES, Clinical Trials, Cardiovascular Safety) the excess rate over

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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 400mg

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 celecoxib 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 600mg/day were studied in primary dysmenorrhoea

and post-orthopaedic 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 celecoxib in the post-general and orthopaedic surgery pain studies,

the most commonly reported adverse events were nausea, vomiting, headache, dizziness

and fever.

Adverse Events from Polyp Prevention Trials

The following additional adverse events in Table 2 were reported at incidence rates greater

than placebo in long-term polyp prevention studies of duration up to 3 years at daily doses

from 400mg up to 80 mg (see USES, Clinical Trials, Cardiovascular Safety). Adverse

events are listed by system organ class are ranked by frequency. Frequencies are defined

as: very common (>10%), common (>1% and <10%), uncommon (>0.1% and <1%).

Table 2: Adverse Events Occurring in Celecoxib Patients from Long-term Studies

involving Patients with Sporadic Adenomatous Polyps

System Organ Class

Frequency

Adverse Drug Events

Infections and infestations

Common

Uncommon

infection,

fungal

infection

(primarily

nonsystemic)

Helicobacter

infection,

herpes

zoster,

erysipelas,

wound

infection,

gingival

infection, labyrinthitis, bacterial infection

Neoplasms benign, malignant,

and unspecified

Uncommon

Lipoma

Psychiatric disorders

Uncommon

Sleep disorder

Nervous system disorders

Uncommon

Cerebral infarction

Eye disorders

Uncommon

Vitreous floaters, conjunctival haemorrhage

Ear and labyrinth disorders

Uncommon

Hypoacusis

Cardiac disorders

Common

Uncommon

Angina pectoris, myocardial infarction

Angina unstable, aortic valve incompetence,

coronary

artery

atherosclerosis,

sinus

bradycardia, ventricular hypertrophy

Vascular disorders

Very Common

Hypertension*

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Uncommon

Deep vein thrombosis, haematoma

Respiratory, thoracic, and

mediastinal disorders

Common

Uncommon

Dyspnoea

Dysphonia

Gastrointestinal disorders

Very Common

Common

Uncommon

Diarrhoea*

Nausea, gastro-oesophageal reflux disease,

diverticulum,

vomiting*,

dysphagia,

irritable

bowel syndrome

Haemorrhoidal haemorrhage, frequent bowel

movements, mouth ulceration, stomatitis

Hepatobiliary disorders

Rare

Elevation of hepatic enzymes

Skin and subcutaneous tissue

disorders

Uncommon

Dermatitis allergic

Musculoskeletal and connective

tissue disorders

Common

Uncommon

Muscle spasms

Ganglion

Renal and urinary disorders

Common

Uncommon

Nephrolithiasis

Nocturia

Reproductive system and breast

disorders

Common

Uncommon

Benign prostatic hyperplasia, prostatitis

Vaginal

haemorrhage,

breast

tenderness,

dysmenorrhoea,

ovarian

cyst,

menopausal

symptoms

General disorders and

administration site conditions

Uncommon

Oedema

Investigations

Common

Uncommon

Blood creatinine increased, prostatic specific

antigen increased, weight increased

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 and diarrhoea are included in Table 5 because they were reported more

frequently in these studies, which were of 3-year duration, compared to Table 4, which includes

adverse events from studies of 12-week duration.

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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 100mg BD,

and two at 400mg BD.

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 reported controlled clinical trials, there was an increased incidence of hypochloraemia

in patients

receiving

celecoxib

compared

with

patients

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.

Post-marketing Experience

See Adverse Effects: Other Serious Adverse Events which Occur Rarely (<0.1%),

Regardless of Causality.

Interactions

Pharmacokinetics Interactions

General

Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver.

Patients who are known or suspected to be poor CYP 2C9 metabolisers based on previous

history/experience with other CYP 2C9 substrates should be administered celecoxib with

caution

they

have

abnormally

high

plasma

levels

reduced

metabolic

clearance. Co-administration of celecoxib with drugs that are known to inhibit 2C9 should be

done with caution. Consider starting treatment at half the lowest recommended dose (see

DOSAGE AND ADMINISTRATION).

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.

ACE Inhibitors and Angiotensin II Antagonists

Reports suggest that NSAIDs 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 celecoxib concomitantly with ACE inhibitors

and/or angiotensin II antagonists.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with

compromised

renal

function,

co-administration

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.

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Frusemide

Clinical studies, as well as post marketing observations, have shown that NSAIDs can

reduce the natriuretic effect of frusemide and thiazides in some patients. This response has

been attributed to inhibition of renal prostaglandin synthesis.

Aspirin

APO-CELECOXIB can be used with low dose aspirin. However, concomitant administration

aspirin

with

celecoxib may

result

increased

rate

ulceration

other

complications, compared to use of celecoxib alone (see USES, Special Studies, Upper

Gastrointestinal Complications). Because of its lack of platelet effects, celecoxib is not a

substitute for aspirin for cardiovascular prophylaxis.

Fluconazole

Concomitant administration of fluconazole at 200mg 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 USES, Pharmacokinetics, Metabolism).

APO-CELECOXIB should

introduced

at the

lowest

recommended

dose

patients

receiving fluconazole.

Lithium

In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased

approximately 17% in subjects receiving lithium 450mg BD with celecoxib 200mg BD as

compared to subjects receiving lithium alone. Patients on lithium treatment should be closely

monitored when APO-CELECOXIB is introduced or withdrawn.

Oral Hypoglycaemics

The effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glibenclamide

and tolbutamide have been studied and clinically important interactions have not been found.

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

Coadministration

celecoxib

with

aluminium-

magnesium-containing

antacid

resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax

and 10% in AUC.

Methotrexate

Celecoxib does not have a significant effect on the pharmacokinetics of methotrexate.

Ketoconazole

Celecoxib does not have a significant effect on the pharmacokinetics of ketoconazole.

Phenytoin

Celecoxib does not have a significant effect on the pharmacokinetics of phenytoin.

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Warfarin

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, anti-coagulant activity should be monitored after

initiating treatment with celecoxib or changing the dose. If INR increases, it may be sufficient

to reduce the dose of warfarin in order to manage the interaction (see WARNING AND

PRECAUTIONS, Gastrointestinal Effects).

Pharmacodynamic Interactions

In arthritis patients, celecoxib, at doses up to 200mg BD can be administered without regard

to the timing of meals (See FURTHER INFORMATION, Food Effects).

Overdosage

Clinical experience of overdose is limited. No overdoses of celecoxib were reported during

clinical trials. Doses up to 2400mg/day for up to 10 days in 12 patients did not result

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

NSAID

overdose.

Monitor

patients

signs

symptoms

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. Forced diuresis, alkalinisation of urine, haemodialysis, or haemoperfusion may not

be useful due to high protein binding.

Contact the National Poisons Centre on 0800 764 766 for advice on the management of an

overdose.

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Further Information

Actions

Pharmacotherapeutic group: M01AH Coxibs.

Celecoxib is a member of a class of agents which has a mechanism of action that inhibits

prostaglandin synthesis primarily by inhibition of cyclooxygenase 2 (COX-2). At therapeutic

concentrations in humans celecoxib does not inhibit cyclooxygenase 1 enzyme (COX-1).

COX-2 is induced in response to inflammatory stimuli. This leads to the synthesis and

accumulation

inflammatory

prostanoids,

particular

prostaglandin

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.

Pharmacokinetics

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 (Cmax) and

area under the curve (AUC) are roughly dose proportional up to 200mg BD; at higher doses

there are less than proportional increases in Cmax and AUC (see Pharmacokinetics, Food

Effects). Absolute bioavailability studies have not been conducted because of celecoxib's

low solubility in aqueous media. The relative oral solubility of celecoxib capsules compared

with a suspension is about 99%. With multiple dosing, steady state conditions are reached

on or before day 5.

Food Effects

When celecoxib 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 200mg, 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

celecoxib

with

aluminium-

magnesium-containing

antacid

resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax

and 10% in AUC. In arthritis patients, celecoxib, at doses up to 200mg BD can be

administered without regard to the timing of meals.

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,

glycoprotein. The apparent volume of distribution at steady state is about 400 L in healthy

young adults, suggesting extensive tissue distribution.

Metabolism

Celecoxib is extensively metabolised in the liver. In-vitro and in-vivo studies indicate that

metabolism is mainly by cytochrome P450 2C9 (see INTERACTIONS). Three metabolites

have been identified in human plasma, a primary alcohol, the corresponding carboxylic acid

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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

a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers,

genotyped as either CYP 2C9*1/*1, CYP 2C9*1/*3, or CYP 2C9*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 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 APO-CELCOXIB with caution as they may have abnormally

high plasma concentrations due to reduced metabolic clearance. Consider starting treatment

half

lowest

recommended

dose

(see

DOSAGE

AND

ADMINISTRATION

INTERACTIONS).

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 (t½) 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 (t½) determinations.

Special Populations

Hepatic Impairment

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,

APO-CELECOXIB 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 APO-

CELECOXIB in

patients

with

severe

hepatic

impairment

(Child-Pugh

score

=10)

contraindicated (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

Renal Impairment

In elderly volunteers with age related reductions in glomerular filtration rate (GFR) (mean

GFR >65 mL/min/1.73 m

) and in patients with chronic stable renal insufficiency (GFR 35-60

mL/min/1.73 m

) celecoxib pharmacokinetics were comparable to those seen in patients with

normal renal function. No significant relationship was found between serum creatinine (or

creatinine clearance) and celecoxib clearance. 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.

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Elderly (>65 years)

At steady state, subjects older than 65 years of age had a 40% higher Cmax and a 50%

higher AUC than those of younger subjects. In elderly females, the Cmax and AUC were

higher than those for elderly males predominantly due to the lower body weight of the

females. No dosage adjustment in the elderly is generally necessary. However, for elderly

patients with a body weight of less than 50kg treatment should be initiated at the lowest

recommended dose.

Children and Adolescents

APO-CELECOXIB is not approved for use in patients under 18 years of age.

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.

Other

Clinical Trials

Osteoarthritis (OA)

Celecoxib

demonstrated

significant

reduction

joint

pain

compared

placebo.

Celecoxib 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 celecoxib 100mg BD or

200mg once

daily 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, celecoxib doses of 100mg BD and 200mg

BD provided significant reduction of pain within 24-48 hours of initiation of

dosing. At doses

of 100mg BD or 200mg BD the effectiveness of celecoxib was shown to be similar to that of

naproxen 500mg BD. Doses of 200mg BD provided no additional

benefit above that seen

with 100mg BD. A total daily dose of 200mg has been shown to be equally effective whether

administered as 100mg BD or 200mg once daily.

Rheumatoid Arthritis (RA)

Celecoxib has demonstrated significant reduction in joint tenderness/pain and joint

swelling

compared to placebo. Celecoxib 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. Celecoxib 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.

Celecoxib doses of 100mg BD and 200mg BD were similar in effectiveness and both were

comparable to naproxen 500mg BD.

Although celecoxib 100mg BD and 200mg BD provided similar overall effectiveness,

some

patients derived additional benefit from the 200mg BD dose. Doses of 400mg BD provided

no additional benefit above that seen with 100-200mg BD.

Ankylosing Spondylitis (AS)

Celecoxib has been investigated in 896 patients in placebo and active (diclofenac, naproxen

or ketoprofen) controlled clinical trials of 6 weeks (one trial) and 12 weeks (three trials)

duration for the symptomatic treatment of ankylosing spondylitis. At doses of 100mg twice

daily (BD), 200mg once daily (OD), and 400mg once daily (OD), celecoxib was statistically

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Page 21 of 30

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

200mg total daily

dose and 400mg total daily dose, non-

inferiority was demonstrated relative to diclofenac

150mg total daily dose for global pain intensity. Results for global pain intensity are

presented below.

Table 3: Global pain intensity

a

in Celecoxib ankylosing spondylitis clinical trials

Study

Placebo

Celecoxib

Celecoxib

Ketoprofen

Naproxen

Diclofenac

200mg

b

TDD

400mg

b

TDD

100mg BD

500mg BD

150mg

b

TDD

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 200mg TDD

and celecoxib 400 mg TDD were not statistically significant.



Differences

compared

diclofenac

were

statistically

significant

>0.50),

based

Analysis

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.

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.

TDD = Total daily dose: celecoxib 200mg TDD was administered as 100mg twice daily (Study 137) or 200mg

once daily (Studies 193, 243, and 247); celecoxib 400mg TDD was administered as 200mg twice daily (Study

243 and 247) or 400mg once daily (study 193); diclofenac 150mg TDD was administered as Sustained

Release 75 mg twice daily in Study 243, or 50mg three times daily in Study 247.

Analgesia, including Dysmenorrhoea

In acute analgesic models of post-oral surgery pain, post-orthopaedic surgery pain, and

primary dysmenorrhoea, celecoxib relieved pain that was rated by patients as moderate to

severe. Single doses of celecoxib provided pain relief within 30-60 minutes. In replicate

multiple dose studies of post-orthopaedic surgery pain, celecoxib was effective in reducing

pain without additional analgesic medication.

Special Studies

Celecoxib Long-term Arthritis 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 celecoxib treated

patients compared to each comparator. Patients received celecoxib 400mg BD (4-fold and 2-

fold greater than the recommended OA and RA doses, respectively), ibuprofen 800mg TDS

(approved

maintenance

dose

1600mg

daily)

diclofenac

75mg

BD (approved

maintenance dose is 75-100mg daily) for a median exposure of 9 months for celecoxib and

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diclofenac, and 6 months for ibuprofen. Patients were allowed to take concomitant low-dose

aspirin

≤325

mg mostly for cardiovascular 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

patients

celecoxib vs.

those

diclofenac,

although

incidence

significantly lower for celecoxib 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 celecoxib, diclofenac and ibuprofen (see Special Studies, Use with Aspirin).

incidence rates for diclofenac may be underestimated because of a higher incidence of early

withdrawals due to GI adverse events than celecoxib and ibuprofen.

Figure 1: Incidence of symptomatic ulcers and ulcer complications

Celecoxib (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 celecoxib

patients taking aspirin was lower than in ibuprofen and diclofenac patients taking aspirin.

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Figure 2: Incidence of clinically relevant decreases in haemoglobin and/or haematocrit

Upper Gastrointestinal Complications

original

registration

studies,

incidence

serious

upper

gastrointestinal

complications

(bleeding,

perforation,

gastric

outlet

obstruction)

with

celecoxib was

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 celecoxib at doses ranging from 50-400mg BD. In all three reported

studies that

included naproxen 500mg BD, and in the study that included ibuprofen 800mg

TDS, celecoxib was associated with a statistically significantly lower incidence of endoscopic

ulcers over the study period. Two studies compared celecoxib with diclofenac 75mg 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 celecoxib groups after 1, 2, and 3 months of treatment. There was no

consistent relationship between the incidence of gastroduodenal ulcers and the dose of

celecoxib over the range studied.

Figure 3 and Table 4 summarise the incidence of endoscopic ulcers in two 12-week studies

Celecoxib

*p<0.05 Celecoxib vs. ibuprofen and diclofenac

that enrolled patients in whom baseline endoscopies revealed no ulcers.

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Figure 3

Celecoxib 100mg BD, 200mg once daily or 200mg BD are the recommended doses.

These studies were not powered to compare the endoscopic ulcer rates of celecoxib 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 Months Studies

Study 1 (n=1108)

Study 2 (n=1049)

Placebo

2.3% (5/217)

2.0% (4/200)

Celecoxib 50mg BD

3.4% (8/233)

Celecoxib 100mg BD

3.1% (7/227)

4.0% (9/223)

Celecoxib 200mg BD

5.9% (13/221)

2.7% (6/219)

Celecoxib 400mg BD

4.1% (8/197)

Naproxen 500mg BD

16.2% (34/210)*

17.6% (37/210)*

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.

Celecoxib (mg BID)

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Page 25 of 30

Figure

4:

Cumulative

incidence

of

gastroduodenal

ulcers

based

on

4

serial

endoscopies over 12 weeks

C = Celecoxib 200mg BD D = Diclofenac 75mg BD

N = Naproxen 500mg BD I = Ibuprofen 800mg TDS

Table 5: Incidence of gastroduodenal ulcers from 3-months serial endoscopy studies

in OA and RA patients

Week 4

Week 8

Week 12

Final

Study 3 (n=523)

Celecoxib

200mg BD

4.0%

(10/252)*

2.2%

(5/227)*

1.5%

(3/196)*

7.5%

(20/266)*

Naproxen

500mg BD

19.0%

(47/247)

14.2%

(26/182)

9.9%

(14/141)

34.6%

(89/257)

Study 4 (n=1062)

Celecoxib

200mg BD

3.9%

(12/337)**

2.4%

(7/296)**

1.8%

(5/274)**

7.0%

(25/356)**

Diclofenac

75mg BD

5.1%

(18/350)

3.3%

(10/306)

2.9%

(8/278)

9.7%

(36/372)

Ibuprofen

800mg TDS

13.0%

(42/323)

6.2%

(15/241)

9.6%

(21/219)

23.3%

(78/334)

0.05 Celecoxib vs. naproxen based on interval and cumulative analyses

**p=0.05 Celecoxib 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.

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Celecoxib USP 100mg & 200mg Capsules

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Page 26 of 30

Figure 5

Significantly different from Celecoxib; p<0.001

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

celecoxib in controlled and open-labelled trials, albeit infrequently. Among 5,285 patients

who received celecoxib in the original arthritis controlled clinical trials of 1 to 6 months

duration (most were 3 month studies) at a daily dose of 200mg or more, 2 patients (0.04%)

experienced

significant

bleeding.

Patients

most

risk

developing

ulcer

complication were the elderly (

75 years), patients in poor health or with cardiovascular

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 celecoxib 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 total daily doses of 1200mg (three times the highest recommended therapeutic dose) for

Celecoxib

up to 7 days duration, celecoxib had no effect on platelet aggregation and bleeding time

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Page 27 of 30

compared to placebo. Active controls (non-specific COX inhibitors i.e. naproxen, diclofenac,

ibuprofen) all significantly reduced platelet aggregation and prolonged bleeding time.

Figure 6: Effect of high dose celecoxib (600 mg BD) on platelet aggregation and

bleeding time in healthy individuals

* Significantly different from placebo; p<0.05

** Significantly different from celecoxib; p<0.05

Gastrointestinal Safety - Meta-Analysis from Osteoarthritis and Rheumatoid Arthritis

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 with placebo or NSAIDs (including naproxen, diclofenac

and ibuprofen). The incidence of clinical ulcers and ulcer bleeds with celecoxib 200-400mg

total daily dose was 0.2% compared with an incidence of 0.6% with NSAIDs (RR = 0.35; 95%

CI 0.22-0.56).

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 400mg twice daily and 2.8 (95% CI 1.1-7.2) with celecoxib 200mg twice daily

(cumulative rates for this composite endpoint over 3 years were 20/671 subjects, 3.0%,

Celecoxib

Celecoxib

17/685 subjects, 2.5%, respectively, compared to 6/679 subjects, 0.9%, for placebo). The

APO-CELECOXIB

Celecoxib USP 100mg & 200mg Capsules

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Page 28 of 30

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).

When data from the APC and PreSAP trials were considered together, risk for cardiovascular

thromboembolic

events

greater

celecoxib-treated

patients

with

history

atherosclerotic

cardiovascular

disease,

than

celecoxib-treated

patients

without

such

history.

Cardiovascular Safety -

Long-term Study of Alzheimer's Disease Anti-inflammatory

Prevention Trial (ADAPT)

Data from a third long-term study, ADAPT (The Alzheimer’s Disease Anti-inflammatory

Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib

200mg 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 – 2.12) with celecoxib

200mg twice daily. The incidence of myocardial infarction was 1.1% (8/717 patients) with

celecoxib 200mg twice daily 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 in 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 cardiovascular thromboembolic events (CV death,

non-fatal

myocardial

infarction

non-fatal

stroke)

similar

between

celecoxib

(N=19,773) and non-selective NSAID (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 cardiovascular death

was comparable (RR=0.72, 95% CI 0.37-1.39) for celecoxib compared to combined non-

selective NSAIDs.

In this analysis, the incidence of serious cardiovascular thromboembolic events (CV death,

non-fatal myocardial infarction and non-fatal stroke) was 0.38% for celecoxib (N=7462) and

0.27% for 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 cardiovascular 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

Cardiovascular safety outcomes were evaluated in the CLASS trial (see Special Studies,

Celecoxib Long-term Arthritis Safety Study (CLASS) for description of trial). Kaplan-Meier

cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse

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Page 29 of 30

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.

Chemical Structure

Chemical name:

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]

benzenesulfonamide

Molecular formula:

Molecular weight:

381.38

CAS Registry Number:

169590-42-5

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.

List of excipients

APO-CELCOXIB 100mg and 200mg capsules contain the following excipients:

Povidone, Sodium lauryl sulfate, Crospovidone and Magnesium stearate

APO-CELECOXIB capsules are lactose free and gluten free.

The capsule shells contain gelatin, and titanium dioxide.

Pharmaceutical Precautions

Instructions for Handling

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Incompatibilities

See INTERACTIONS;

ACE Inhibitors and Angiotensin II Antagonists; Frusemide; Aspirin;

Fluconazole; Lithium; Glucocorticoids; Antacids and Warfarin).

Shelf-Life

Shelf life: 2 years from the date of manufacture.

Special Precautions for Storage

Store at or below 25

Package Quantities

APO-CELECOXIB 100mg: Blisters containing 60 capsules.

APO-CELECOXIB 200mg: Blisters containing 30 capsules

Medicine Schedule

Prescription Medicine

Sponsor Details

Apotex NZ Ltd

32 Hillside Road

Glenfield

Private Bag 102-995

North Shore Mail Centre

Auckland

Telephone: (09) 444 2073

Fax: (09) 444 2951

Date of Preparation

26 September 2014

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