Cebatix is indicated in adults for the symptomatic relief in the treatment of osteoarthritis, rheumatoid
arthritis and ankylosing spondylitis.
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 (CV) 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 re-evaluated 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
Elderly
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 population
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

Cebatix 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 sulfonamides. 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 non-steroidal antiinflammatory drugs (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 antiplatelet drugs (such as acetylsalicylic acid), or
glucocorticoids concomitantly, 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 longterm 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, has been found
in a long-term placebo-controlled study in subjects with sporadic adenomatous polyps treated with
celecoxib at doses of 200 mg bis in die (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. NSAIDs, including COX-2
selective inhibitors, have been associated with increased risk of cardiovascular and thrombotic adverse
events when taken long-term. The exact magnitude of the risk associated with a single-dose has not
been determined, nor has the exact duration of therapy associated with increased risk. The patient's
need for symptomatic relief and response to therapy should be re-evaluated 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 medicinal products 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,
angiotensin converting enzyme (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 medicinal products 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 sulfonamide 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
Cebatix 200 mg capsules contain lactose (49.75 mg, respectively). Patients with rare hereditary
problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should
not take this medicine.

Cebatix 200 mg contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially
'sodium-free'.

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
Co-administration 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 medicinal products are combined.

Acetylsalicylic acid
Celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid
for CV 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 medicinal products

CYP2D6 inhibition
Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of medicinal products that are
substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of
medicinal products which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs),
neuroleptics, anti-arrhythmic medicinal products, etc. The dose of individually dose-titrated 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 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 medicinal products 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
medicinal products.
 

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 area under the curve (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 medicinal products 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 population
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 medicinal products inhibiting
prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus
during the last trimester.

During the second or third trimester of pregnancy, NSAIDs including celecoxib may cause fetal renal
dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe
cases. Such effects may occur shortly after treatment initiation and are usually reversible upon
discontinuation.
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 Cebatix 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.
 

Cebatix may have minor influence on the ability to drive and use machines.
Patients who experience dizziness, vertigo or somnolence while taking Cebatix 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 activecontrolled 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 7 400 arthritis
patients have been treated with celecoxib at daily doses up to 800 mg, including approximately 2 300
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, 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 was
consulted to estimate frequency. Frequencies are based on a cumulative meta-analysis with pooling of
trials representing exposure in 38102 patients.
Table 1. Adverse drug reactions in celecoxib clinical trials and surveillance experience
(MedDRA preferred terms)1,2

Adverse Drug Reaction Frequency
System organ class	Very common (≥ 1/10)	Common (≥ 1/100 to < 1/10)	Uncommon (≥ 1/1,000 to < 1/100)	Rare (≥ 1/10,000 to < 1/1,000)	Very rare (< 1/10,000)	Not known (cannot be estimated from available data)
Infections and infestations	Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection

 

Blood and lymphatic system disorders	Anaemia	Leukopenia, thrombo cytopenia	Pancytopenia4
Immune system disorders	Hypersensitivity	Anaphylactic shock4, anaphylactic reaction4
Metabolism and nutrition disorders	Hyperkalaemia
Psychiatric disorders	Insomnia	Anxiety, depression, fatigue	Confusional state, hallucinations4
Nervous system disorders	Dizziness, hypertonia, headache4	Cerebral infarction1, paraesthesia, somnolence	Ataxia, dysgeusia	Haemorrhage intracranial (including fatal intracranial haemorrhage)4, meningitis aseptic4, epilepsy (including aggravated epilepsy)4, ageusia4, anosmia4
Eye disorders	Vision blurred, conjunctivitis4	Eye haemorrhage4	Retinal artery occlusion4, retinal vein occlusion4
Ear and labyrinth disorders	Tinnitus, hypoacusis1
Cardiac disorders	Myocardial infarction1	Cardiac failure, palpitations, tachycardia	Arrhythmia4
Vascular disorders	Hyper tension1 (including aggravated hyper tension)	Pulmonary embolism4, flushing4	Vasculitis4
Respiratory, thoracic, and mediastinal disorders	Rhinitis, cough, dyspnoea1	Bronchospasm4	Pneumonitis4
Gastrointestinal disorders	Nausea4, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting1, dysphagia1	Constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation	Gastro intestinal haemorrhage4, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation,

 

oesophagitis, melaena, pancreatitis, colitis4
Hepatobiliary disorders	Hepatic function abnormal, hepatic enzyme increased (including increased SGOT and SGPT)	Hepatitis4	Hepatic failure4 (sometimes fatal or requiring liver transplant), hepatitis fulminant4 (some with fatal outcome), hepatic necrosis4, cholestasis4, hepatitis cholestatic4, jaundice4
Skin and subcutaneous tissue disorders	Rash, pruritus (includes pruritus generalised)	Urticaria, ecchymosis4	Angioedema4, alopecia, photo sensitivity	Dermatitis exfoliative4, erythema multiforme4, Stevens-Johnson syndrome4, toxic epidermal necrolysis4, drug reaction with eosinophilia and systemic symptoms (DRESS) 4, acute generalised exanthematous pustulosis (AGEP)4, dermatitis bullous4
Musculoskeletal and connective tissue disorders	Arthralgia4	Muscle spasms (leg cramps)	Myositis4
Renal and urinary disorders	Blood creatinine increased, blood urea increased	Renal failure acute4, hypo natraemia4	Tubulointerstitial nephritis4, nephrotic syndrome4, glomerulonephritis minimal lesion4
Reproductive system and breast disorders	Menstrual disorder4	Infertility female (female fertility decreased)3
General disorders and administrative site conditions	Influenza-like illness, oedema peripheral/ fluid retention	Face oedema, chest pain4

 

Injury, poisoning and procedural complications

Injury (accidental injury)

SGOT - serum glutamic oxaloacetic transaminase SGPT - serum glutamic pyruvic transaminase 1 Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials). The adverse drug reactions listed above for the polyp prevention trials are only those that have been previously recognised in the post-marketing surveillance experience, or have occurred more frequently than in the arthritis trials. 2 Furthermore, the following previously unknown adverse reactions occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials): Common: angina pectoris, irritable bowel syndrome, nephrolithiasis, blood creatinine increased, benign prostatic hyperplasia, weight increased. Uncommon: helicobacter infection, herpes zoster, erysipelas, bronchopneumonia, labyrinthitis, gingival infection, lipoma, vitreous floaters, conjunctival haemorrhage, deep vein thrombosis, dysphonia, haemorrhoidal haemorrhage, frequent bowel movements, mouth ulceration, allergic dermatitis, ganglion, nocturia, vaginal haemorrhage, breast tenderness, lower limb fracture, blood sodium increased. 3 Women intending to become pregnant are excluded from all trials, thus consultation of the trial database for the frequency of this event was not reasonable. 4 Frequencies are based on 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.

To report any side effect(s):
• Saudi Arabia:

- The National Pharmacovigilance and Drug Safety Centre (NPC)
- SFDA Call Center: 19999
- E-mail: npc.drug@sfda.gov.sa
- Website: https://ade.sfda.gov.sa/

• United Arab Emirates

- Pharmacovigilance & Medical Device section
- P.O.Box: 1853
- Tel: 80011111
- Email : pv@mohap.gov.ae
- Drug Department Ministry of Health & Prevention Dubai, UAE

• Other GCC states
- Please contact the relevant competent authority

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 medicinal product removal
due to high protein binding
 

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs, NSAIDs,
Coxibs, ATC code: M01AH01.
 

Mechanism of action
Celecoxib is an oral, selective, 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 proinflammatory 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 humans 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 osteoarthritis 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 rheumatoid arthritis in approximately 2100 patients in placebo and activecontrolled 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
osteoarthritis and 2,200 rheumatoid arthritis patients received celecoxib 400 mg BID (4-fold and 2-
fold the recommended osteoarthritis and rheumatoid arthritis doses, respectively), ibuprofen 800 mg
ter in die (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 CV 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 statistically 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 acetylsalicylic acid (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 and the PreSAP trial. In the APC trial, there was a dose-related increase in the composite
endpoint of CV death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to
placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant
increased risk for the same composite endpoint.

In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of CV
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 with 1.0 %
(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 Anti-inflammatory Prevention
Trial), did not show a significantly increased CV risk with celecoxib 200 mg BID compared to
placebo. The relative risk compared to placebo for a similar composite endpoint (CV death,
myocardial infarction, stroke) was 1.14 (95 % CI 0.61 - 2.15) 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.

Prospective randomised evaluation of celecoxib integrated safety vs. ibuprofen or naproxen
(PRECISION)
The PRECISION study was a double-blind study of cardiovascular safety in Osteo arthritis (OA) or
Rheumatoid arthritis (RA) patients with or at high risk for cardiovascular disease comparing
Celecoxib (200-400 mg daily) with Naproxen (750-1 000 mg daily) and Ibuprofen (1 800-2 400 mg
daily). The primary endpoint, Antiplatelet Trialists Collaboration (APTC), was an independently
adjudicated composite of cardiovascular death (including haemorrhagic death), non-fatal myocardial
infarction or non-fatal stroke. The study was planned with 80% power to evaluate non-inferiority. All
patients were prescribed open-label esomeprazole (20-40 mg) for gastro protection. Patients who were
taking low-dose aspirin were permitted to continue therapy, at baseline nearly half of the subjects were
on aspirin. Secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal
outcomes. The Average Dose dispensed was 209±37 mg/day for Celecoxib, 2045±246 for Ibuprofen
and 852±103 for Naproxen.

Regarding the primary endpoint, Celecoxib, as compared with either naproxen or ibuprofen, met all
four pre-specified non-inferiority requirements, see Table 2.
Other independently adjudicated secondary and tertiary endpoints included cardiovascular,
gastrointestinal and renal outcomes. Additionally, there was a 4-month substudy focusing on the
effects of the three medicinal products on blood pressure as measured by ambulatory monitoring
(ABPM).
Table 2. Primary analysis of the adjudicated APTC composite endpoint

Intent-To-Treat Analysis (ITT, through month 30)
Celecoxib 100-200 mg bid	Ibuprofen 600-800 mg tid	Naproxen 375-500 mg bid
N	8,072	8,040	7,969
Subjects with Events	188 (2.3%)	218 (2.7%)	201 (2.5%)
Pairwise Comparison	Celecoxib vs. Naproxen	Celecoxib vs. Ibuprofen	Ibuprofen vs. Naproxen
HR (95% CI)	0.93 (0.76, 1.13)	0.86 (0.70, 1.04)	1.08 (0.89, 1.31)
Modified Intent-To-Treat Analysis (mITT, on treatment through month 43)
Celecoxib 100-200 mg bid	Ibuprofen 600-800 mg tid	Naproxen 375-500 mg bid
N	8,030	7,990	7,933
Subjects with Events	134 (1.7%)	155 (1.9%)	144 (1.8%)
Pairwise Comparison	Celecoxib vs. Naproxen	Celecoxib vs. Ibuprofen	Ibuprofen vs. Naproxen
HR (95% CI)	0.90 (0.72, 1.14)	0.81 (0.64, 1.02)	1.12 (0.889, 1.40)

HR - hazard Ratio
BID - bis in die
TID - ter in die
The results were overall numerically similar in the celecoxib and comparator groups for the secondary
and tertiary endpoints and there were overall no unexpected safety findings.
Taken together the PRECISION study indicates that celecoxib at the lowest approved dose of 100 mg
twice daily is non-inferior to ibuprofen dosed in the range of 600 mg-800 mg three times daily or
naproxen dosed in the range of 375 mg-500 mg twice daily with respect to cardiovascular adverse
effects. The cardiovascular risks of the NSAID class, including coxibs, are dose-dependent, therefore,
the results for celecoxib 200 mg daily on the composite cardiovascular endpoint cannot be
extrapolated to dosing regimens using the higher doses of celecoxib.

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 medicinal product
is not preferentially bound to erythrocytes.
Biotransformation
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 AUC0-24 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 Pharmacokinetic 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 diaphragmatic hernias was observed
when rats were given celecoxib at oral doses ≥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 2 year toxicity study an increase in nonadrenal thrombosis was observed in male rat at high doses.
 

Capsules content
Lactose monohydrate
Sodium lauryl sulphate
Povidone K-30
Croscarmellose sodium
Magnesium stearate
 

Not applicable.
 

2 years

Do not store above 30 °C.
 

Cebatix Capsules are available in a pack size of 30 hard gelatin capsules
Cebatix capsules are provided in a white opaque HDPE bottle containing 30 units of Cebatix 200 mg capsule,
packed into a carton box with an insert leaflet.
 

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.