OxibinTM is indicated in adults for the symptomatic relief in the treatment of
osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing spondylitis (AS).
The decision to prescribe a selective cyclooxygenase-2 (COX-2) inhibitor should be
based on an assessment of the individual patient's overall risks (see sections 4.3 and
4.4).

Posology
As the cardiovascular risks of celecoxib may increase with dose and duration of
exposure, the shortest duration possible and the lowest effective daily dose should be
used. The patient's need for symptomatic relief and response to therapy should be reevaluated
periodically, especially in patients with osteoarthritis (see sections 4.3, 4.4,
4.8 and 5.1).

Osteoarthritis
The usual recommended daily dose is 200 mg taken once daily or in two divided
doses. In some patients, with insufficient relief from symptoms, an increased dose of
200 mg twice daily may increase efficacy. In the absence of an increase in therapeutic
benefit after two weeks, other therapeutic options should be considered.
Rheumatoid arthritis
The initial recommended daily dose is 200 mg taken in two divided doses. The dose
may, if needed, later be increased to 200 mg twice daily. In the absence of an increase
in therapeutic benefit after two weeks, other therapeutic options should be considered.
Ankylosing spondylitis
The recommended daily dose is 200 mg taken once daily or in two divided doses. In a
few patients, with insufficient relief from symptoms, an increased dose of 400 mg
once daily or in two divided doses may increase efficacy. In the absence of an
increase in therapeutic benefit after two weeks, other therapeutic options should be
considered.
The maximum recommended daily dose is 400 mg for all indications.
Special populations
Older people (>65 years)
As in younger adults, 200 mg per day should be used initially. The dose may, if
needed, later be increased to 200 mg twice daily. Particular caution should be
exercised in elderly with a body weight less than 50 kg. (see sections 4.4 and 5.2).
Paediatric populations
Celecoxib is not indicated for use in children.
CYP2C9 poor metabolisers
Patients who are known, or suspected to be CYP2C9 poor metabolisers based
on genotyping or previous history/experience with other CYP2C9 substrates
should be administered celecoxib with caution as the risk of dose-dependent
adverse effects is increased. Consider reducing the dose to half the lowest
recommended dose (see section 5.2).
Hepatic impairment
Treatment should be initiated at half the recommended dose in patients with
established moderate liver impairment with a serum albumin of 25-35 g/l. Experience
in such patients is limited to cirrhotic patients (see sections 4.3, 4.4 and 5.2).
Renal impairment

Experience with celecoxib in patients with mild or moderate renal impairment is
limited, therefore such patients should be treated with caution. (see sections 4.3, 4.4
and 5.2).
Method of administration
Oral use
OxibinTM may be taken with or without food. For patients who have difficulty
swallowing capsules, the contents of a celecoxib capsule can be added to applesauce,
rice gruel, yogurt or mashed banana. To do so, the entire capsule contents must be
carefully emptied onto a level teaspoon of cool or room temperature applesauce, rice
gruel, yogurt or mashed banana and should be ingested immediately with 240 ml of
water. The sprinkled capsule contents on applesauce, rice gruel or yogurt are stable
for up to 6 hours under refrigerated conditions (2-8°C). The sprinkled capsule
contents on mashed banana should not be stored under refrigerated conditions and
should be ingested immediately.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Known hypersensitivity to sulphonamides. Active peptic ulceration or gastrointestinal (GI) bleeding. Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or other NSAIDs including COX-2 inhibitors. In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6). Celecoxib has been shown to cause malformations in the two animal species studied (see sections 4.6 and 5.3). The potential for human risk in pregnancy is unknown, but cannot be excluded. Breast feeding (see sections 4.6 and 5.3). Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score 10). Patients with estimated creatinine clearance <30 ml/min. Inflammatory bowel disease. Congestive heart failure (NYHA II-IV). Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

Gastrointestinal (GI) effects
Upper and lower gastrointestinal complications [perforations, ulcers or bleedings
(PUBs)], some of them resulting in fatal outcome, have occurred in patients treated
with celecoxib. Caution is advised with treatment of patients most at risk of
developing a gastrointestinal complication with NSAIDs; the elderly, patients using
any other NSAID or acetylsalicylic acid concomitantly, glucocorticoids, patients
using alcohol, or patients with a prior history of gastrointestinal disease, such as
ulceration and GI bleeding.
There is further increase in the risk of gastrointestinal adverse effects for celecoxib
(gastrointestinal ulceration or other gastrointestinal complications), when celecoxib is
taken concomitantly with acetylsalicylic acid (even at low doses).
A significant difference in GI safety between selective COX-2 inhibitors +
acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in
long-term clinical trials (see section 5.1).
Concomitant NSAID use
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
Cardiovascular effects
Increased number of serious cardiovascular (CV) events, mainly myocardial
infarction (MI), has been found in a long-term placebo-controlled study in subjects
with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg BID and
400 mg BID compared to placebo (see section 5.1).
As the cardiovascular risks of celecoxib may increase with dose and duration of
exposure, the shortest duration possible and the lowest effective daily dose should be
used. The patient's need for symptomatic relief and response to therapy should be reevaluated
periodically, especially in patients with osteoarthritis (see sections 4.2, 4.3,
4.8 and 5.1).
Patients with significant risk factors for cardiovascular events (e.g. hypertension,
hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib
after careful consideration (see section 5.1).
COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis
of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet
effects. Therefore, antiplatelet therapies should not be discontinued (see section 5.1).

Fluid retention and oedema
As with other drugs known to inhibit prostaglandin synthesis fluid retention and
oedema have been observed in patients taking celecoxib. Therefore, celecoxib should
be used with caution in patients with history of cardiac failure, left ventricular
dysfunction or hypertension, and in patients with pre-existing oedema from any other
reason, since prostaglandin inhibition may result in deterioration of renal function and
fluid retention. Caution is also required in patients taking diuretic treatment or
otherwise at risk of hypovolaemia.
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 cardiovascular events. Therefore, blood pressure should be
monitored closely during the initiation of therapy with celecoxib and throughout the
course of therapy.
Hepatic and renal effects
Compromised renal or hepatic function and especially cardiac dysfunction are more
likely in the elderly and therefore medically appropriate supervision should be
maintained.
NSAIDs, including celecoxib, may cause renal toxicity. Clinical trials with celecoxib
have shown renal effects similar to those observed with comparator NSAIDs. Patients
at greatest risk for renal toxicity are those with impaired renal function, heart failure,
liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor
antagonists, and the elderly (see section 4.5). Such patients should be carefully
monitored while receiving treatment with celecoxib.
Some cases of severe hepatic reactions, including fulminant hepatitis (some with fatal
outcome), liver necrosis and, hepatic failure (some with fatal outcome or requiring
liver transplant), have been reported with celecoxib. Among the cases that reported
time to onset, most of the severe adverse hepatic events developed within one month
after initiation of celecoxib treatment (see section 4.8).
If during treatment, patients deteriorate in any of the organ system functions described
above, appropriate measures should be taken and discontinuation of celecoxib therapy
should be considered.
CYP2D6 inhibition
Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a
dose reduction may be necessary for individually dose-titrated drugs that are
metabolised by CYP2D6 (see section 4.5).

CYP2C9 poor metabolisers
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see
section 5.2).
Skin and systemic hypersensitivity 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 (see section 4.8). Patients appear to be at highest
risk for these reactions early in the course of therapy: the onset of the reaction
occurring in the majority of cases within the first month of treatment. Serious
hypersensitivity reactions (including anaphylaxis, angioedema and drug rash with
eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome) have
been reported in patients receiving celecoxib (see section 4.8). Patients with a history
of sulphonamide allergy or any drug allergy may be at greater risk of serious skin
reactions or hypersensitivity reactions (see section 4.3). Celecoxib should be
discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of
hypersensitivity.
General
Celecoxib may mask fever and other signs of inflammation.
Use with oral anticoagulants
In patients on concurrent therapy with warfarin, serious bleeding events, some of
them fatal, have been reported. Increased prothrombin time (INR) with concurrent
therapy has been reported. Therefore, this should be closely monitored in patients
receiving warfarin/coumarin-type oral anticoagulants, particularly when therapy with
celecoxib is initiated or celecoxib dose is changed (see section 4.5). Concomitant use
of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should be
exercised when combining celecoxib with warfarin or other oral anticoagulants,
including novel anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban).
Excipients
OxibinTM contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should
not take this medicine.

Pharmacodynamic interactions
Anticoagulants
Anticoagulant activity should be monitored particularly in the first few days after
initiating or changing the dose of celecoxib in patients receiving warfarin or other

anticoagulants since these patients have an increased risk of bleeding complications.
Therefore, patients receiving oral anticoagulants should be closely monitored for their
prothrombin time INR, particularly in the first few days when therapy with celecoxib
is initiated or the dose of celecoxib is changed (see section 4.4). Bleeding events in
association with increases in prothrombin time have been reported, predominantly in
the elderly, in patients receiving celecoxib concurrently with warfarin, some of them
fatal.
Anti-hypertensives
NSAIDs may reduce the effect of anti-hypertensive medicinal products including
ACE-inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers. As
for NSAIDs, the risk of acute renal insufficiency, which is usually reversible, may be
increased in some patients with compromised renal function (e.g. dehydrated patients,
patients on diuretics, or elderly patients) when ACE inhibitors, angiotensin II receptor
antagonists, and/or diuretics are combined with NSAIDs, including celecoxib (see
section 4.4). Therefore, the combination should be administered with caution,
especially in the elderly. Patients should be adequately hydrated and consideration
should be given to monitoring of renal function after initiation of concomitant
therapy, and periodically thereafter.
In a 28-day clinical study in patients with lisinopril-controlled Stage I and II
hypertension, administration of celecoxib 200 mg BID resulted in no clinically
significant increases, when compared to placebo treatment, in mean daily systolic or
diastolic blood pressure as determined using 24-hour ambulatory blood pressure
monitoring. Among patients treated with celecoxib 200 mg BID, 48 % were
considered unresponsive to lisinopril at the final clinic visit (defined as either cuff
diastolic blood pressure >90 mmHg or cuff diastolic blood pressure increased >10 %
compared to baseline), compared to 27 % of patients treated with placebo; this
difference was statistically significant.
Ciclosporin and Tacrolimus
Coadministration of NSAIDs and ciclosporin or tacrolimus may increase the
nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be
monitored when celecoxib and any of these drugs are combined.
Acetylsalicylic acid
Celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for
acetylsalicylic acid for cardiovascular prophylaxis. In the submitted studies, as with
other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal
complications compared to use of celecoxib alone was shown for concomitant
administration of low-dose acetylsalicylic acid (see section 5.1).
Pharmacokinetic interactions

Effects of celecoxib on other drugs
CYP2D6 Inhibition
Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of drugs that are
substrates of this enzyme may be increased when celecoxib is used concomitantly.
Examples of drugs which are metabolised by CYP2D6 are antidepressants (tricyclics
and SSRIs), neuroleptics, anti-arrhythmic drugs, etc. The dose of individually dosetitrated
CYP2D6 substrates may need to be reduced when treatment with celecoxib is
initiated or increased if treatment with celecoxib is terminated.
Concomitant administration of celecoxib 200 mg twice daily resulted in 2.6-fold and
1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol
(CYP2D6 substrates), respectively. These increases are due to celecoxib CYP2D6
inhibition of the CYP2D6 substrate metabolism.
CYP2C19 Inhibition
In vitro studies have shown some potential for celecoxib to inhibit CYP2C19
catalysed metabolism. The clinical significance of this in vitro finding is unknown.
Examples of drugs which are metabolised by CYP2C19 are diazepam, citalopram and
imipramine.
Methotrexate
In patients with rheumatoid arthritis celecoxib had no statistically significant effect on
the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic
doses). However, adequate monitoring for methotrexate-related toxicity should be
considered when combining these two drugs.
Lithium
In healthy subjects, co-administration of celecoxib 200 mg twice daily with 450 mg
twice daily of lithium resulted in a mean increase in Cmax of 16 % and in AUC of
18 % of lithium. Therefore, patients on lithium treatment should be closely monitored
when celecoxib is introduced or withdrawn.
Oral contraceptives
In an interaction study, celecoxib had no clinically relevant effects on the
pharmacokinetics of oral contraceptives (1 mg norethisterone /35 micrograms
ethinylestradiol).
Glibenclamide/tolbutamide
Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate),
or glibenclamide to a clinically relevant extent.
Effects of other drugs on celecoxib

CYP2C9 Poor Metabolisers
In individuals who are CYP2C9 poor metabolisers and demonstrate increased
systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors such
as fluconazole could result in further increases in celecoxib exposure. Such
combinations should be avoided in known CYP2C9 poor metabolisers (see sections
4.2 and 5.2).
CYP2C9 Inhibitors and Inducers
Since celecoxib is predominantly metabolised by CYP2C9 it should be used at half
the recommended dose in patients receiving fluconazole. Concomitant use of 200 mg
single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9
inhibitor, resulted in a mean increase in celecoxib Cmax of 60 % and in AUC of
130 %. Concomitant use of inducers of CYP2C9 such as rifampicin, carbamazepine
and barbiturates may reduce plasma concentrations of celecoxib.
Ketoconazole and Antacids
Ketoconazole or antacids have not been observed to affect the pharmacokinetics of
celecoxib.
Paediatric populations
Interaction studies have only been performed in adults.

Pregnancy
Studies in animals (rats and rabbits) have shown reproductive toxicity, including
malformations (see sections 4.3 and 5.3). Inhibition of prostaglandin synthesis might
adversely affect pregnancy. Data from epidemiological studies suggest an increased
risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early
pregnancy. The potential for human risk in pregnancy is unknown, but cannot be
excluded. Celecoxib, as with other drugs inhibiting prostaglandin synthesis, may
cause uterine inertia and premature closure of the ductus arteriosus during the last
trimester. Celecoxib is contraindicated in pregnancy and in women who can become
pregnant (see sections 4.3 and 4.4). If a woman becomes pregnant during treatment,
celecoxib should be discontinued.
Breast-feeding
Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in
plasma. Administration of celecoxib to a limited number of lactating women has
shown a very low transfer of celecoxib into breast milk. Women who take celecoxib
should not breastfeed.

Fertility
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.

Patients who experience dizziness, vertigo or somnolence while taking celecoxib
should refrain from driving or operating machinery.

Adverse reactions are listed by system organ class and ranked by frequency in
Table 1, reflecting data from the following sources:
 Adverse reactions reported in osteoarthritis patients and rheumatoid arthritis
patients at incidence rates greater than 0.01 % and greater than those
reported for placebo during 12 placebo- and/or active-controlled clinical
trials of duration up to 12 weeks at celecoxib daily doses from 100 mg up to
800 mg. In additional studies using non-selective NSAID comparators,
approximately 7400 arthritis patients have been treated with celecoxib at
daily doses up to 800 mg, including approximately 2300 patients treated for
1 year or longer. The adverse reactions observed with celecoxib in these
additional studies were consistent with those for osteoarthritis and
rheumatoid arthritis patients listed in Table 1.
 Adverse reactions reported at incidence rates greater than placebo for
subjects treated with celecoxib 400 mg daily in long-term polyp prevention
trials of duration up to 3 years (the Adenoma Prevention with Celecoxib
(APC) and Prevention of Colorectal Sporadic Adenomatous Polyps
(PreSAP) trials; see section 5.1, Pharmacodynamic properties:
Cardiovascular safety – long-term studies involving patients with sporadic
adenomatous polyps).
 Adverse drug reactions from post-marketing surveillance as spontaneously
reported during a period in which an estimated >70 million patients were
treated with celecoxib (various doses, durations, and indications). Even
though these were identified as reactions from post-marketing reports, trial
data were consulted to estimate frequency. Frequencies are based on a
cumulative meta-analysis with pooling of trials representing exposure in
38102 patients.

In final data (adjudicated) from the APC and PreSAP trials in patients treated with
celecoxib 400 mg daily for up to 3 years (pooled data from both trials; see section 5.1
for results from individual trials), the excess rate over placebo for myocardial
infarction was 7.6 events per 1,000 patients (uncommon) and there was no excess rate
for stroke (types not differentiated) over placebo.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product.
To report any side effects:
The National Pharmacovigilance and Drug Safety Centre (NPC)
 Fax: +966-11-205-7662
 Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
 Toll free phone: 8002490000
 E-mail: npc.drug@sfda.gov.sa
 Website: www.sfda.gov.sa/npc

There is no clinical experience of overdose. Single doses up to 1200 mg and multiple
doses up to 1200 mg twice daily have been administered to healthy subjects for nine
days without clinically significant adverse effects. In the event of suspected overdose,
appropriate supportive medical care should be provided e.g. by eliminating the gastric
contents, clinical supervision and, if necessary, the institution of symptomatic
treatment. Dialysis is unlikely to be an efficient method of drug removal due to high
protein binding.

Pharmacotherapeutic group: Non-steroidal antiinflammatory and antirheumatic drugs,
NSAIDs, Coxibs.
ATC code: M01AH01.
Mechanism of action
Celecoxib is an oral, selective, cyclooxygenase-2 (COX-2) inhibitor within the
clinical dose range (200-400 mg daily). No statistically significant inhibition of COX-
1 (assessed as ex vivo inhibition of thromboxane B2 [TxB2] formation) was observed
in this dose range in healthy volunteers.
Pharmacodynamic effects
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-
1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been
shown to be induced by pro-inflammatory stimuli and has been postulated to be
primarily responsible for the synthesis of prostanoid mediators of pain, inflammation,
and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus
arteriosus, regulation of renal function, and central nervous system functions (fever
induction, pain perception and cognitive function). It may also play a role in ulcer

healing. COX-2 has been identified in tissue around gastric ulcers in human but its
relevance to ulcer healing has not been established.
The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and
COX-2 selective inhibitors may be of clinical significance in patients at risk of
thrombo-embolic reactions. COX-2 selective inhibitors reduce the formation of
systemic (and therefore possibly endothelial) prostacyclin without affecting platelet
thromboxane.
Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine
sulfonamides (e.g. thiazides, furosemide) but differs from arylamine sulfonamides
(e.g. sulfamethoxizole and other sulfonamide antibiotics).
A dose dependent effect on TxB2 formation has been observed after high doses of
celecoxib. However, in healthy subjects, in small multiple dose studies with 600 mg
BID (three times the highest recommended dose) celecoxib had no effect on platelet
aggregation and bleeding time compared to placebo.
Clinical efficacy and safety
Several clinical studies have been performed confirming efficacy and safety in
osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Celecoxib was
evaluated for the treatment of the inflammation and pain of OA of the knee and hip in
approximately 4200 patients in placebo and active controlled trials of up to 12 weeks
duration. It was also evaluated for treatment of the inflammation and pain of RA in
approximately 2100 patients in placebo and active controlled trials of up to 24 weeks
duration. Celecoxib at daily doses of 200 mg – 400 mg provided pain relief within 24
hours of dosing.
Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in
896 patients in placebo and active controlled trials of up to 12 weeks duration.
Celecoxib at doses of 100 mg BID, 200 mg QD, 200 mg BID and 400 mg QD in these
studies demonstrated significant improvement in pain, global disease activity and
function in ankylosing spondylitis.
Five randomised double-blind controlled studies have been conducted including
scheduled upper gastrointestinal endoscopy in approximately 4500 patients free from
initial ulceration (celecoxib doses from 50 mg-400 mg BID). In twelve week
endoscopy studies celecoxib (100-800 mg per day) was associated with a significantly
lower risk of gastroduodenal ulcers compared with naproxen (1000 mg per day) and
ibuprofen (2400 mg per day). The data were inconsistent in comparison with
diclofenac (150 mg per day). In two of the 12-week studies the percentage of patients
with endoscopic gastroduodenal ulceration was not significantly different between
placebo and celecoxib 200 mg BID and 400 mg BID.

In a prospective long-term safety outcome study (6 to 15 month duration, CLASS
study), 5,800 OA and 2,200 RA patients received celecoxib 400 mg BID (4-fold and
2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg TID or
diclofenac 75 mg BID (both at therapeutic doses). Twenty-two percent of enrolled
patients took concomitant low-dose acetylsalicylic acid (325 mg/day), primarily for
cardiovascular prophylaxis. For the primary endpoint complicated ulcers (defined as
gastrointestinal bleeding, perforation or obstruction) celecoxib was not significantly
different than either ibuprofen or diclofenac individually. Also for the combined
NSAID group there was no statically significant difference for complicated ulcers
(relative risk 0,77, 95 % CI 0.41-1.46, based on entire study duration). For the
combined endpoint, complicated and symptomatic ulcers, the incidence was
significantly lower in the celecoxib group compared to the NSAID group, relative risk
0.66, 95 % CI 0.45-0.97 but not between celecoxib and diclofenac. Those patients on
celecoxib and concomitant low-dose acetylsalicylic acid experienced 4 fold higher
rates of complicated ulcers as compared to those on celecoxib alone. The incidence of
clinically significant decreases in haemoglobin (>2 g/dL), confirmed by repeat
testing, was significantly lower in patients on celecoxib compared to the NSAID
group, relative risk 0.29, 95 % CI 0.17- 0.48. The significantly lower incidence of this
event with celecoxib was maintained with or without acetylsalicylic acid use.
In a prospective randomised 24 week safety study in patients who were aged ≥60
years or had a history of gastroduodenal ulcers (users of ASA excluded), the
percentages of patients with decreases in haemoglobin (≥2 g/dL)and/or haematocrit
(≥10 %) of defined or presumed GI origin were lower in patients treated with
celecoxib 200 mg twice daily (N=2238) compared to patients treated with diclofenac
SR 75 mg twice daily plus omeprazole 20 mg once daily (N=2246) (0.2 % vs. 1.1 %
for defined GI origin, p= 0.004; 0.4 % vs. 2.4 % for presumed GI origin, p = 0.0001).
The rates of clinically manifest GI complications such as perforation, obstruction or
haemorrhage were very low with no differences between the treatment groups (4-5
per group).
Cardiovascular safety – long-term studies involving subjects with sporadic
adenomatous polyps
Two studies involving subjects 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 relative risks compared to placebo for a composite endpoint
(adjudicated) of cardiovascular death, myocardial infarction, or stroke were
3.4 (95 % CI 1.4 - 8.5) with celecoxib 400 mg twice daily and 2.8 (95 % CI 1.1 - 7.2)
with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over
3 years were 3.0 % (20/671 subjects) and 2.5 % (17/685 subjects), respectively,
compared to 0.9 % (6/679 subjects) for placebo. The increases for both celecoxib dose
groups versus placebo were mainly due to an increased incidence of myocardial
infarction.
In the PreSAP trial, the relative risk compared to placebo for this same composite
endpoint (adjudicated) was 1.2 (95 % CI 0.6 - 2.4) with celecoxib 400 mg once daily
compared to placebo. Cumulative rates for this composite endpoint over 3 years were
2.3 % (21/933 subjects) and 1.9 % (12/628 subjects), respectively. The incidence of
myocardial infarction (adjudicated) was 1.0 % with (9/933 subjects) with celecoxib
400 mg once daily and 0.6 % (4/628 subjects) with placebo.
Data from a third long-term study, ADAPT (The Alzheimer's Disease Antiinflammatory
Prevention Trial), did not show a significantly increased cardiovascular
risk with celecoxib 200 mg BID compared to placebo. The relative risk compared to
placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95 % CI
0.61 - 2.12) with celecoxib 200 mg twice daily. The incidence of myocardial
infarction was 1.1 % (8/717 patients) with celecoxib 200 mg twice daily and 1.2 %
(13/1070 patients) with placebo.

Absorption
Celecoxib is well absorbed reaching peak plasma concentrations after approximately
2-3 hours. Dosing with food (high fat meal) delays absorption of celecoxib by about
1 hour resulting in a Tmax of about 4 hours and increases bioavailability by about
20 %.
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was
equivalent when celecoxib was administered as intact capsule or capsule contents
sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or T1/2
after administration of capsule contents on applesauce.
Distribution
Plasma protein binding is about 97 % at therapeutic plasma concentrations and the
drug is not preferentially bound to erythrocytes.
Metabolism
Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three
metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human
plasma i.e., a primary alcohol, the corresponding carboxylic acid and its glucuronide
conjugate.

Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms
that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3
polymorphism.
In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy
volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the
median Cmax and AUC0-24 of celecoxib on day 7 were approximately 4-fold and 7-
fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other
genotypes. In three separate single dose studies, involving a total of 5 subjects
genotyped as CYP2C9*3/*3, single-dose AUC 0-24 increased by approximately 3-
fold compared to normal 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 CYP2C9 poor metabolisers based on
previous history/experience with other CYP2C9 substrates should be administered
celecoxib with caution (see section 4.2).
No clinically significant differences were found in PK parameters of celecoxib
between elderly African-Americans and Caucasians.
The plasma concentration of celecoxib is approximately 100 % increased in elderly
women (>65 years).
Compared to subjects with normal hepatic function, patients with mild hepatic
impairment had a mean increase in Cmax of 53 % and in AUC of 26 % of celecoxib.
The corresponding values in patients with moderate hepatic impairment were 41 %
and 146 % respectively. The metabolic capacity in patients with mild to moderate
impairment was best correlated to their albumin values. Treatment should be initiated
at half the recommended dose in patients with moderate liver impairment (with serum
albumin 25-35 g/l). Patients with severe hepatic impairment (serum albumin <25 g/l)
have not been studied and celecoxib is contraindicated in this patient group.
There is little experience of celecoxib in renal impairment. The pharmacokinetics of
celecoxib has not been studied in patients with renal impairment but is unlikely to be
markedly changed in these patients. Thus caution is advised when treating patients
with renal impairment. Severe renal impairment is contraindicated.
Elimination
Celecoxib is mainly eliminated by metabolism. Less than 1 % of the dose is excreted
unchanged in urine. The inter-subject variability in the exposure of celecoxib is about
10-fold. Celecoxib exhibits dose- and time-independent pharmacokinetics in the
therapeutic dose range. Elimination half-life is 8-12 hours. Steady state plasma
concentrations are reached within 5 days of treatment.

 

Non-clinical safety data revealed no special hazard for humans based on
conventional studies of repeated dose toxicity, mutagenicity or
carcinogenicity beyond those addressed in section 4.4., 4.6. and 5.1 of the
SmPC.
Celecoxib at oral doses >150 mg/kg/day (approximately 2-fold human exposure at
200 mg twice daily as measured by AUC0-24), caused an increased incidence of
ventricular septal defects, a rare event, and fetal alterations, such as ribs fused,
sternebrae fused and sternebrae misshapen when rabbits were treated throughout
organogenesis.A dose-dependent increase in 30 mg/kg/day (approximately 6-fold
human exposure based on the AUC0-24 at 200 mg twice daily) throughout
organogenesis. These effects are expected following inhibition of prostaglandin
synthesis. In rats, exposure to celecoxib during early embryonic development resulted
in pre-implantation and post-implantation losses, and reduced embryo/fetal survival.
Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was
observed.
In a two-year toxicity study an increase in nonadrenal thrombosis was observed in
male rat at high doses.

Capsule contents:
lactose monohydrate
sodium lauryl sulphate
povidone K- 29/32
croscarmellose sodium
magnesium stearate.
Capsule shell:
gelatin
sodium lauryl sulphate
titanium dioxide E171
indigotine E132 (only capsules 100 mg)
yellow iron oxide E172 (only capsules 200 mg)
printing ink contains:
black iron oxid

Not applicable.

Capsules 200 mg: 30 months.

Do not store above 30oC.

PVC-PVDC/Aluminium blister.
Capsules 200 mg:
Packs of 6, 10, 20, 30, 50, 100.
Not all pack sizes may be marketed.

No special requirements.