Onsenal

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 200 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains 200 mg of celecoxib.  
Excipients: Lactose Monohydrate 49.8 mg For a full list of excipients, see section 6.1. 

 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule. 
White, opaque capsules with two gold bands marked 7767 and 200. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Onsenal is indicated for the reduction of the number of adenomatous intestinal polyps in familial 
adenomatous polyposis (FAP), as an adjunct to surgery and further endoscopic surveillance (see 
section 4.4). 
 
The effect of Onsenal-induced reduction of polyp burden on the risk of intestinal cancer has not been 
demonstrated (see sections 4.4 and 5.1) 
 
4.2 Posology and method of administration 
 
The recommended oral dose is two 200 mg capsules twice per day, taken with food (see section 5.2). 
 
Usual medical care for FAP patients should be continued while on celecoxib. The maximum 
recommended daily dose is 800 mg. 
 
Hepatic impairment: In patients with moderate hepatic impairment (serum albumin of 25-35 g/l), the 
daily recommended dose of celecoxib should be reduced by 50% (see sections 4.3 and 5.2). Caution 
should be used as there is no experience in such patients at doses higher than 200 mg. 
 
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). 
 
Paediatric patients: Experience with celecoxib in FAP patients below the age of 18 years is limited to 
a single pilot study in a very small population, in which patients were treated with celecoxib at doses 
up to 16 mg/kg daily, which corresponds to the recommended adult FAP dose of 800 mg daily (see 
section 5.1).   
 
CYP2C9 Poor Metabolizers:  Patients who are known or suspected to be CYP2C9 poor 
metabolizers 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.  
Patients with the CYP2C9*3 allele, and, in particular those with  CYP2C9*3*3 homozygous 
genotype, may be exposed to celecoxib levels that are higher than those for which safety has 
been studied in clinical trials. Therefore, the risk for high celecoxib exposure in poor 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



3 

metabolizers should be considered carefully when treating FAP patients. Consider starting 
treatment at a reduced dose (see section 5.2). 
 
Elderly: The dose for elderly FAP patients has not been established. Special care should be used in 
such patients (see section 5.2).  
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance or to any of the excipients (see 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 or non steroidal anti-
inflammatory drugs (NSAIDs) including COX-2 (cyclooxigenase-2) selective inhibitors. 

• In pregnancy and in women who can become pregnant unless using an effective method of 
contraception (see sections 4.5, 4.6 and 5.3)  

• Breast feeding (see sections 4.6 and 5.3) 
• Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score >10) (Class C). 
• Patients with renal insufficiency 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 
 
4.4 Special warnings and precautions for use 
 
Treatment with celecoxib in FAP has been studied for up to 6 months and has not been shown to 
reduce the risk of gastrointestinal or other form of cancer or the need for surgery. Therefore, the usual 
care of FAP patients should not be altered because of the concurrent administration of celecoxib. In 
particular, the frequency of routine endoscopic surveillance should not be decreased and FAP-related 
surgery should not be delayed. 
 
Gastro-intestinal disorder 
Upper gastrointestinal complications [perforations, ulcers or bleeds (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 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 (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 5.1).The concomitant use of celecoxib and a non-aspirin NSAID should be avoided. 
 
FAP patients carrying an ileorectal anastomosis or ileo pouch-anal anastomosis can develop 
anastomotic ulcerations. If an anastomotic ulcer is present, patients should not receive concomitant 
treatment with anticoagulants or acetyl salicylic acid. 
 
Blood and lymphatic system disorder / Cardio-vascular disorder 
Increased number of serious cardiovascular 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 BID and 400 mg BID compared to placebo (see section 5.1).  
 
As the cardiovascular risks of celecoxib were increased with the 400 mg twice daily dose in the APC 
trial (section 5.1), the response of the FAP patient to celecoxib should be re-examined periodically in 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



4 

order to avoid unnecessary exposure in FAP patients for whom celecoxib is not effective (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 effect. Therefore, 
antiplatelet therapies should not be discontinued (see section 5.1). 
 
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. 
 
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.   
 
In the event of elderly patients with mild to moderate cardiac dysfunction requiring therapy, special 
care and follow up is warranted.  Compromised renal or hepatic function and especially cardiac 
dysfunction are more likely in the elderly and therefore medically appropriate supervision should be 
maintained. 
 
Renal and hepatic disorders 
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, and the elderly. Such 
patients should be carefully monitored while receiving treatment with celecoxib.  
Experience with celecoxib in patients with mild or moderate renal or hepatic impairment is limited, 
therefore such patients should be treated with caution (see sections 4.2 and 5.2). 
 
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. 
 
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 (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 (anaphylaxis and angioedema) 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. 
 
Other 
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2). 
 
Celecoxib may mask fever and other signs of inflammation. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



5 

In patients on concurrent therapy with warfarin, serious bleeding events have been reported. Caution 
should be exercised when combining celecoxib with warfarin and other oral anticoagulants (see 
section 4.5). 
 
Onsenal 200 mg capsules contain lactose (49.8 mg). Patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take 
this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacodynamic interactions 
The majority of the interaction studies have been performed with celecoxib doses of 200 mg BID (i.e. 
those used for osteoarthritis/rheumatoid arthritis). A more pronounced effect at 400 mg BID therefore 
cannot be excluded. 
 
Anticoagulant activity should be monitored in patients taking warfarin or other anticoagulants, 
particularly in the first few days after initiating or changing the dose of celecoxib, since these patients 
have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants 
should be closely monitored for their prothrombin time INR. Bleeding events in association with 
increases in prothrombin time have been reported in arthritis patients (mainly elderly) receiving 
celecoxib concurrently with warfarin, some of them fatal (see section 4.4). 
 
NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. 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 or elderly patients) when ACE inhibitors or 
angiotensin II receptor antagonists are combined with NSAIDs, including celecoxib. 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. 
 
Co-administration of NSAIDs and ciclosporin D derivatives or tacrolimus have been suggested to 
increase the nephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored 
when celecoxib and any of these medicinal products are combined. 
 
Celecoxib can be used with low dose acetylsalicylic acid, however it cannot be considered a substitute 
for acetylsalicylic acid for cardiovascular prophylaxis. 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 
Celecoxib is a weak inhibitor of CYP2D6. During celecoxib treatment, the mean plasma 
concentrations of the CYP2D6 substrate dextromethorphan were increased by 136%. The plasma 
concentrations of medicinal products that are substrates of this enzyme may be increased when 
celecoxib is used concomitantly. Examples of medicines which are metabolised by CYP2D6 are 
antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmics, etc. The dose of individually 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



6 

dose-titrated CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or 
increased if treatment with celecoxib is terminated. 
 
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. 
 
In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral 
contraceptives (1 mg norethistherone /35 microg ethinylestradiol). 
 
Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide 
to a clinically relevant extent. 
 
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. 
 
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. 
 
Effects of other medicinal products on celecoxib 
 
In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to 
celecoxib, concomitant treatment with CYP2C9 inhibitors (eg. fluconazole, amiodarone) 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). 
 
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% (analogous studies have not been performed with amiodarone or 
other known CYP2C9 inhibitors). Concomitant use of inducers of CYP2C9 such as rifampicin, 
carbamazepine and barbiturates may reduce plasma concentrations of celecoxib. 
 
4.6 Pregnancy and lactation 
 
For celecoxib no clinical data on exposed pregnancies are available. Studies in animals (rats and 
rabbits) have shown reproductive toxicity (see sections 4.3 and 5.3). The potential risk for humans is 
unknown. Celecoxib, as with other medicinal products 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 unless using an effective 
method of contraception (see section 4.3). If a woman becomes pregnant during treatment, celecoxib 
should be discontinued. 
 
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. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effect on the ability to drive and use machines have been performed. However, 
patients who experience dizziness, vertigo or somnolence while taking celecoxib should refrain from 
driving or operating machinery. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



7 

4.8 Undesirable effects 
 
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 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).  Because not all adverse drug reactions are reported to the MAH and included in 
the safety database, the frequencies of these reactions cannot be reliably determined. 

 

TABLE 1 Common (≥1/100 to <1/10) 
Uncommon 

(≥1/1000 to <1/100) 
Rare 

(≥1/10,000 to 
<1/1000) 

Frequency Not 
Known 

(Post-marketing 
experience)1 

Infections and 
infestations 

Sinusitis, upper 
respiratory tract 
infection, urinary 
tract infection 

   

Blood and 
lymphatic 
system 
disorders 

 Anemia Leucopenia, 
thrombocytopenia 

Pancytopenia 

Immune system 
disorders 

Allergy 
aggravated 

  Serious allergic 
reactions, 
anaphylactic 
shock, 
anaphylaxis 

Psychiatric 
disorders 

Insomnia Anxiety, depression, 
tiredness 

Confusion Hallucinations 

Metabolism and 
nutrition 

 Hyperkaelemia  

Nervous system 
disorders 

Dizziness, 
hypertonia 

Paraesthesia, 
somnolence 

Ataxia, taste 
alteration 

Headache, 
aggravated 
epilepsy, 
meningitis 
aseptic, ageusia , 
anosmia, fatal 
intracranial 
haemorrhage 

Eye disorders  Blurred vision  Conjunctivitis, 
ocular 
haemorrhage, 
retinal artery or 
vein occlusion 

Ear and 
labyrinth 
disorders 

 Tinnitus  Decreased 
hearing 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



8 

Cardiac 
disorders 

 Heart failure, 
palpitations, 
tachycardia 

Myocardial 
infarction2 

Arrhythmia 

Vascular 
disorders  

 Hypertension, 
hypertension aggravated

 Flushing, 
vasculitis, 
pulmonary 
embolism 

Respiratory, 
thoracic, 
and mediastinal 
disorders 

Pharyngitis, 
rhinitis, cough 

Dyspnoea  Bronchospasm 

Gastrointestinal 
disorders 

Abdominal pain, 
diarrhoea, 
dyspepsia, 
flatulence 

Constipation, 
eructation, gastritis, 
stomatitis, vomiting, 
aggravation of 
gastrointestinal 
inflammation 

Duodenal, gastric, 
oesophageal, 
intestinal, and 
colonic ulceration; 
dysphagia, 
intestinal 
perforation; 
oesophagitis, 
melaena; 
pancreatitis 

Nausea, acute 
pancreatitis, 
gastrointestinal 
haemorrhage, 
colitis/colitis 
aggravated 

Hepatobiliary 
disorders 

 Abnormal hepatic 
function, increased 
SGOT and SGPT  

Elevation of 
hepatic enzymes 

Hepatitis, 
hepatic failure 
jaundice 

Skin and 
subcutaneous 
tissue disorders 

Rash, pruritus Urticaria Alopecia, 
photosensitivity 

Ecchymosis, 
bullous eruption, 
exfoliative 
dermatitis, 
erythema 
multiforme, 
Stevens-Johnson 
syndrome, toxic 
epidermal 
necrolysis, 
angioedema 

Musculoskeletal 
and connective 
tissue disorders 

 Leg cramps  Arthralgia, 
myositis 

Renal and 
urinary 
disorders 

 Increased creatinine, 
BUN increased 

 Acute renal 
failure, 
interstitial 
nephritis, 
hyponatraemia 

Reproductive 
system 
and breast 
disorders 

   Menstrual 
disorder 

General 
disorders and 
administration 
site conditions 

Flu-like 
symptoms, 
peripheral oedema/ 
fluid retention 

  Chest pain 

 1  Adverse drug reactions spontaneously reported to the safety surveillance database over a period in which an 
estimated >70 million patients were treated with celecoxib (various doses, durations, and indications).  As a 
result, the frequencies of these adverse drug reactions cannot be reliably determined.  Adverse drug reactions 
listed for the post-marketing population are only those that are not already listed for the arthritis trials (Table 1) 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



9 

or the polyp prevention trials (Table 2). 
2  In a pooled analysis of 20 placebo-controlled studies with duration greater than 2 weeks up to 1 year in patients 

with OA and RA, the excess rate of myocardial infarction in patients treated with celecoxib 200 or 400 mg daily 
over placebo was 0.7 events per 1000 patients (Rare) and there was no excess of strokes. 

 
The additional adverse reactions listed by system organ class and ranked by frequency in Table 2 were 
reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg to 800 mg 
daily in long-term polyp prevention trials of duration up to 3 years (the APC and PreSAP trials; 
see Section 5.1, Pharmacodynamic properties: Cardiovascular Safety – Long-Term Studies Involving 
Patients With Sporadic Adenomatous Polyps). 
 

TABLE 2 Very Common (≥1/10) 
Common 

(≥1/100 to <1/10) 
Uncommon 

(≥1/1000 to <1/100) 
Infections and 
infestations 

 Ear infection, fungal 
infection (fungal infections 
were primarily nonsystemic) 

Helicobacter infection, herpes 
zoster, erysipelas, wound 
infection, gingival infection, 
labrynthitis, bacterial infection 

Neoplasms    Lipoma 
Psychiatric    Sleep disorder 
Nervous system 
disorders 

  Cerebral infarction 

Eye disorders   Vitreous floaters; 
conjunctival hemorrhage 

Ear and labyrinth 
disorders 

  Hypoacusis 

Cardiac disorders  Angina pectoris; 
myocardial infarction 

Angina unstable, aortic valve 
incompetence, coronary artery 
atherosclerosis, sinus 
bradycardia, ventricular 
hypertropy 

Vascular 
disorders                  

Hypertension*  Deep vein thrombosis; 
hematoma 

Respiratory, 
thoracic, 
and mediastinal 
disorders 

 Dyspnoea Dysphonia 

Gastrointestinal 
disorders  

Diarrhoea* Nausea, gastroesophageal 
reflux disease, diverticulum, 
vomiting,* dysphagia, 
irritable bowel syndrome 

Haemorrhoidal haemorrhage, 
frequent bowel movements, 
mouth ulceration, stomatitis 

Skin and 
subcutaneous 
tissue disorders 

  Dermatitis allergic 

Musculoskeletal 
and connective 
tissue disorders 

 Muscle spasms Ganglion 

Renal and urinary 
disorders 

 Nephrolithiasis, 
blood creatinine increased 

Nocturia 

Reproductive 
and breast 
disorders 

 Benign prostatic 
hyperplasia, prostatitis, 
prostatic specific antigen 
increased 

Vaginal haemorrhage, breast 
tenderness, dysmenorrhea, 
ovarian cyst, menopausal 
symptoms 

General disorders 
and 
administration 

 Edema  

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



10 

site conditions 
Investigations  Weight increased Blood levels increased:  

potassium, sodium, hemoglobin 
Blood levels decreased:  
hematocrit, testosterone 

Injury, poisoning,  
and procedural 
complications 

  Foot fracture, lower limb 
fracture, epicondylitis, tendon 
rupture, fracture 

*  Hypertension, vomiting and diarrhoea are included in Table 2 because they were reported more frequently in 
these studies, which were of 3-year duration, compared to Table 1, which includes adverse reactions from 
studies of 12-week duration. 

 
In final data (adjudicated) from the APC trial in patients treated with celecoxib 800 mg daily for up to 
3 years, the excess rates over placebo were 11 events per 1000 patients for myocardial infarction 
(common); and 5 events per 1000 patients for stroke (uncommon; types of stroke not differentiated).  
 
4.9 Overdose 
 
There is no clinical experience of overdose in clinical trials. 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 events. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic, ATC code: L01XX33 
 
Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides 
(e.g. thiazides, furosemide) but differing from arylamine sulfonamides (e.g. sulfamethoxizole and 
other sulfonamide antibiotics). 
 
Celecoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor. No statistically significant 
inhibition of COX-1 (assessed as ex vivo inhibition of thromboxane B2 [TxB2] formation) was 
observed in healthy volunteers at the FAP therapeutic dose of 400 mg BID. 
 
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. Elevated levels of COX-2 are found in many 
pre-malignant lesions (such as adenomatous colorectal polyps) and epithelial cancers. Familial 
Adenomatous Polyposis (FAP) is a genetic disease resulting from an autosomal dominant genetic 
alteration of a tumor suppressor gene, the adenomatous polyposis coli (APC) gene. Polyps with the 
APC mutation overexpress COX-2 and left untreated, these polyps continue to form and enlarge in the 
colon or rectum resulting in essentially a 100% chance of developing colorectal cancer. 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 man 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 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



11 

inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without 
affecting platelet thromboxane. 
 
A dose-dependent effect on TxB2 formation has been observed after high doses of celecoxib. 
However, in small multiple dose studies in healthy subjects with 600 mg BID celecoxib had no effect 
on platelet aggregation and bleeding time compared to placebo. 
 
Experimental evidence shows that the mechanism(s) of action by which celecoxib leads to tumour 
death may be related to induction of apoptosis and inhibition of angiogenesis. Inhibition of COX-2 
may have consequences on tumour viability that are unrelated to inflammation. 
 
Celecoxib inhibits tumour formation in preclinical models of colon cancer, which overexpress COX-2, 
whether induced by chemical (rat AOM model) or genetic (MIN mouse model) mutation.  
 
Celecoxib has been shown to reduce the number and size of adenomatous colorectal polyps. A 
randomized double-blind placebo controlled study was conducted in 83 patients with FAP. The study 
population included 58 patients with a prior subtotal or total colectomy and 25 patients with an intact 
colon. Thirteen patients had the attenuated FAP phenotype. The mean reduction in the number of 
colorectal polyps following six months of treatment was 28% (SD + 24%) for celecoxib 400 mg BID 
which was statistically superior to placebo (mean 5%, SD +16%). A meaningful reduction in duodenal 
adenoma area was also observed compared with placebo (14.5% celecoxib 400 mg BID versus 1.4% 
placebo), which however was not statistically significant. 
 
Pilot Study in Juvenile FAP Patients: A total of 18 children 10 to 14 years of age who had genotype or 
phenotype positive FAP were treated with celecoxib 4 mg/kg/day (4 patients, compared to 2 patients 
treated with placebo), celecoxib 8 mg/kg/day (4 patients, compared to 2 patients treated with placebo), 
or celecoxib 16 mg/kg/day (4 patients, compared to 2 patients treated with placebo).  Results 
demonstrated a statistically significant reduction in polyp burden in all celecoxib treatment groups 
compared to the corresponding placebo treatment groups.  The greatest reduction was observed in 
patients treated with celecoxib 16 mg/kg/day, which corresponds to the recommended adult FAP dose 
of 800 mg daily.  Safety data were reviewed in detail by a Data Safety Monitoring Committee, which 
concluded that celecoxib 16 mg/kg/day was a safe dose to recommend for further studies in juvenile 
FAP patients. 
 
The long-term cardiovascular toxicity in children exposed to celecoxib has not been evaluated and it is 
unknown if the long-term risk may be similar to that seen in adults exposed to celecoxib or other 
COX-2 selective and non-selective NSAIDs (see section 4.4; cardiovascular effects.). 

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 theAPC 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% 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



12 

(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 Anti-inflammatory Prevention 
Trial), did not show a significantly increased cardiovascular risk with celecoxib 200mg 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. 
 
Data from pooled analysis of controlled randomized trials also suggest that cardiovascular risk may be 
associated with the use of celecoxib compared to placebo, with evidence for differences in risk based 
on celecoxib dose. 
 
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due 
to the rarity of the disease it has not been possible to obtain complete information on this medicinal 
product. 
The European Medicines Agency (EMA) will review any new information which may become 
available every year and this SPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. 
Dosing with food (high fat meal) delays absorption by about 1 hour with an increase in total 
absorption (AUC) of 10 to 20%. 
 
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. Plasma protein binding is 
about 97% at therapeutic plasma concentrations and celecoxib is not preferentially bound to 
erythrocytes. Elimination half-life is 8-12 hours. Steady state plasma concentrations are reached within 
5 days of treatment. Pharmacological activity resides in the parent substance. The main metabolites 
found in the circulation have no detectable COX-1 or COX-2 activity. 
 
Celecoxib metabolism is primarily mediated via cytochrome P450 CYP2C9. 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 CYP2C9 activity 
is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as 
those homozygous for the CYP2C9*3 polymorphism. 
  
In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, 
genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median Cmax and AUC 0-
24 of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as 
CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 
5 subjects genotyped as CYP2C9*3/*3, single-dose AUC 0-24 increased by approximately 3-fold 
compared to normal metabolizers.  It is estimated that the frequency of the homozygous *3/*3 
genotype is 0.3-1.0% among different ethnic groups.   

 
Patients who are known or suspected to be CYP2C9 poor metabolizers based on previous 
history/experience with other CYP2C9 substrates should be administered celecoxib with caution (see 
Section 4.2). 
 
No clinically significant differences were found in pharmacokinetic parameters of celecoxib between 
African-Americans and Caucasians. The plasma concentration of celecoxib is approximately 100% 
increased in elderly women (>65 years). 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



13 

 
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. When dosed at 200 mg per day 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. In FAP patients with moderate hepatic impairment (serum albumin of 25-35 g/l), the 
daily recommended dose of celecoxib should be reduced by 50%. Patients with severe hepatic 
impairment (serum albumin <25 g/l) have not been studied and celecoxib is contraindicated in this 
patient group.  
 
The pharmacokinetics of celecoxib has not been studied in patients with renal impairment but is 
unlikely to be markedly changed in these patients since it is mainly eliminated by hepatic metabolism. 
There is little experience of celecoxib in renal impairment and therefore caution is advised when 
treating patients with renal impairment. Severe renal impairment is a contraindication to use.  
 
5.3 Preclinical safety data 
 
Conventional embryo-foetal toxicity studies resulted in dose dependent occurrences of diaphragmatic 
hernia in rat foetuses and of cardiovascular malformations in rabbit foetuses at systemic exposures to 
free celecoxib approximately 3 times (rat) and 2 times (rabbit) higher than those achieved at the 
recommended daily human dose (800 mg). Diaphragmatic hernia was also seen in a peri-post natal 
toxicity study in rats, which included exposure during the organogenetic period. In the latter study, at 
the lowest systemic exposure where this anomaly occurred in a single animal, the estimated margin 
relative to the recommended daily human dose was 2 times more than the recommended daily human 
dose (800 mg). 
 
In animals, exposure to celecoxib during early embryonic development resulted in pre-implantation 
and post-implantation losses. These effects are expected following inhibition of prostaglandin 
synthesis. 
 
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.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsules contain: 
lactose monohydrate 
sodium lauryl sulphate 
povidone K30 
croscarmellose sodium  
magnesium stearate  
 
Capsule shells contain: 
gelatin 
titanium dioxide (E171) 
 
Printing ink contains: 
shellac  
propylene glycol 
iron oxide (E172)  
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



14 

6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30oC. 
 
6.5 Nature and contents of container 
 
Clear or opaque PVC/Aclar/Aluminium foil blisters.  
Packs of 10 or 60 capsules. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/259/001-004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
17 October 2003/17 October 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



15 

1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 400 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains 400 mg of celecoxib.  
Excipients: Lactose Monohydrate 99.6 mg For a full list of excipients, see section 6.1. 

 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule. 
White, opaque capsules with two green bands marked 7767 and 400. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Onsenal is indicated for the reduction of the number of adenomatous intestinal polyps in familial 
adenomatous polyposis (FAP), as an adjunct to surgery and further endoscopic surveillance (see 
section 4.4).   
 
The effect of Onsenal-induced reduction of polyp burden on the risk of intestinal cancer has not been 
demonstrated (see sections 4.4 and 5.1) 
 
4.2  Posology and method of administration 
 
The recommended oral dose is one 400 mg capsule twice per day, taken with food (see section 5.2). 
 
Usual medical care for FAP patients should be continued while on celecoxib. The maximum 
recommended daily dose is 800 mg. 
 
Hepatic impairment: In patients with moderate hepatic impairment (serum albumin of 25-35 g/l), the 
daily recommended dose of celecoxib should be reduced by 50% (see sections 4.3 and 5.2). Caution 
should be used as there is no experience in such patients at doses higher than 400 mg. 
 
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). 
 
Paediatric patients: Experience with celecoxib in FAP patients below the age of 18 years is limited to 
a single pilot study in a very small population, in which patients were treated with celecoxib at doses 
up to 16 mg/kg daily, which corresponds to the recommended adult FAP dose of 800 mg daily (see 
section 5.1).  
 
CYP2C9 Poor Metabolizers:  Patients who are known or suspected to be CYP2C9 poor 
metabolizers 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.   
 
Patients with the CYP2C9*3 allele, and, in particular those with  CYP2C9*3*3 homozygous 
genotype, may be exposed to celecoxib levels that are higher than those for which safety has 
been studied in clinical trials. Therefore, the risk for high celecoxib exposure in poor 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



16 

metabolizers should be considered carefully when treating FAP patients. Consider starting 
treatment at a reduced dose (see section 5.2). 
 
 
Elderly: The dose for elderly FAP patients has not been established. Special care should be used in 
such patients (see section 5.2).  
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance or to any of the excipients (see 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 or non steroidal anti-
inflammatory drugs (NSAIDs) including COX-2 (cyclooxigenase-2) selective inhibitors. 

• In pregnancy and in women who can become pregnant unless using an effective method of 
contraception (see sections 4.5, 4.6 and 5.3)  

• Breast feeding (see sections 4.6 and 5.3) 
• Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score >10) (Class C). 
• Patients with renal insufficiency 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 
 
4.4 Special warnings and precautions for use 
 
Treatment with celecoxib in FAP has been studied for up to 6 months and has not been shown to 
reduce the risk of gastrointestinal or other form of cancer or the need for surgery. Therefore, the usual 
care of FAP patients should not be altered because of the concurrent administration of celecoxib. In 
particular, the frequency of routine endoscopic surveillance should not be decreased and FAP-related 
surgery should not be delayed. 
 
Gastro-intestinal disorder 
Upper gastrointestinal complications [perforations, ulcers or bleeds (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 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 (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 5.1). 
 
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided. 
 
FAP patients carrying an ileorectal anastomosis or ileo pouch-anal anastomosis can develop 
anastomotic ulcerations. If an anastomotic ulcer is present, patients should not receive concomitant 
treatment with anticoagulants or acetyl salicylic acid. 
 
Blood and lymphatic system disorder / Cardio-vascular disorder 
Increased number of serious cardiovascular 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 BID and 400 mg BID compared to placebo (see section 5.1).  
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



17 

As the cardiovascular risks of celecoxib were increased with the 400 mg twice daily dose in the APC 
trial (section 5.1), the response of the FAP patient to celecoxib should be re-examined periodically in 
order to avoid unnecessary exposure in FAP patients for whom celecoxib is not effective (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 effect. Therefore, 
antiplatelet therapies should not be discontinued (see section 5.1). 
 
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. 
 
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. 
 
In the event of elderly patients with mild to moderate cardiac dysfunction requiring therapy, special 
care and follow up is warranted. Compromised renal or hepatic function and especially cardiac 
dysfunction are more likely in the elderly and therefore medically appropriate supervision should be 
maintained. 
 
Renal and hepatic disorders 
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, and the elderly. Such 
patients should be carefully monitored while receiving treatment with celecoxib.  
 
Experience with celecoxib in patients with mild or moderate renal or hepatic impairment is limited, 
therefore such patients should be treated with caution (see sections 4.2 and 5.2). 
 
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. 
 
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 (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 (anaphylaxis and angioedema) 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. 
 
Other 
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2). 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



18 

Celecoxib may mask fever and other signs of inflammation. 
 
In patients on concurrent therapy with warfarin, serious bleeding events have been reported. Caution 
should be exercised when combining celecoxib with warfarin and other oral anticoagulants (see 
section 4.5). 
 
Onsenal 400 mg capsules contain lactose (99.6 mg). Patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take 
this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacodynamic interactions 
The majority of the interaction studies have been performed with celecoxib doses of 200 mg BID (i.e. 
those used for osteoarthritis/rheumatoid arthritis). A more pronounced effect at 400 mg BID therefore 
cannot be excluded. 
 
Anticoagulant activity should be monitored in patients taking warfarin or other anticoagulants, 
particularly in the first few days after initiating or changing the dose of celecoxib, since these patients 
have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants 
should be closely monitored for their prothrombin time INR. Bleeding events in association with 
increases in prothrombin time have been reported in arthritis patients (mainly elderly) receiving 
celecoxib concurrently with warfarin, some of them fatal (see section 4.4). 
 
NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. 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 or elderly patients) when ACE inhibitors or 
angiotensin II receptor antagonists are combined with NSAIDs, including celecoxib. 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. 
 
Co-administration of NSAIDs and cyclosporine D derivatives or tacrolimus have been suggested to 
increase the nephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored 
when celecoxib and any of these medicinal products are combined. 
 
Celecoxib can be used with low dose acetylsalicylic acid, however it cannot be considered a substitute 
for acetylsalicylic acid for cardiovascular prophylaxis. 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 
Celecoxib is a weak inhibitor of CYP2D6. During celecoxib treatment, the mean plasma 
concentrations of the CYP2D6 substrate dextromethorphan were increased by 136%. The plasma 
concentrations of medicinal products that are substrates of this enzyme may be increased when 
celecoxib is used concomitantly. Examples of medicines which are metabolised by CYP2D6 are 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



19 

antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmics, 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. 
 
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. 
 
In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral 
contraceptives (1 mg norethistherone /35 microg ethinylestradiol). 
 
Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide 
to a clinically relevant extent. 
 
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. 
 
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. 
 
Effects of other medicinal products on celecoxib 
 
In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to 
celecoxib, concomitant treatment with CYP2C9 inhibitors (eg. fluconazole, amiodarone) 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). 
 
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% (analogous studies have not been performed with amiodarone or 
other known CYP2C9 inhibitors). Concomitant use of inducers of CYP2C9 such as rifampicin, 
carbamazepine and barbiturates may reduce plasma concentrations of celecoxib. 
 
4.6 Pregnancy and lactation 
 
For celecoxib no clinical data on exposed pregnancies are available. Studies in animals (rats and 
rabbits) have shown reproductive toxicity (see sections 4.3 and 5.3). The potential risk for humans is 
unknown. Celecoxib, as with other medicinal products 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 unless using an effective 
method of contraception (see section 4.3). If a woman becomes pregnant during treatment, celecoxib 
should be discontinued. 
 
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. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effect on the ability to drive and use machines have been performed. However, 
patients who experience dizziness, vertigo or somnolence while taking celecoxib should refrain from 
driving or operating machinery. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



20 

 
4.8 Undesirable effects 
 
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 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).  Because not all adverse drug reactions are reported to the MAH and included in 
the safety database, the frequencies of these reactions cannot be reliably determined.  

 

TABLE 1 Common (≥1/100 to 
<1/10) 

Uncommon 
(≥1/1000 to <1/100) 

Rare 
(≥1/10,000 to 

<1/1000) 

Frequency Not 
Known 

(Post-marketing 
experience)1 

Infections and 
infestations 

Sinusitis, 
upper 
respiratory 
tract infection, 
urinary 
tract infection 

   

Blood and 
lymphatic 
system 
disorders 

 Anemia Leucopenia, 
thrombocytopenia 

Pancytopenia 

Immune system 
disorders 

Allergy 
aggravated 

  Serious allergic 
reactions, anaphylactic 
shock, anaphylaxis 

Psychiatric 
disorders 

Insomnia Anxiety, depression, 
tiredness 

Confusion Hallucinations 

Metabolism and 
nutrition 
disorders 

 Hyperkaelemia  

Nervous system 
disorders 

Dizziness, 
hypertonia 

Paraesthesia, 
somnolence 

Ataxia, taste 
alteration 

Headache, aggravated 
epilepsy, meningitis 
aseptic, ageusia , 
anosmia, fatal 
intracranial 
haemorrhage 

Eye disorders  Blurred vision  Conjunctivitis, ocular 
haemorrhage, retinal 
artery or vein 
occlusion 

Ear and 
labyrinth 
disorders 

 Tinnitus  Decreased hearing 

Cardiac 
disorders 

 Heart failure, 
palpitations, 

Myocardial 
infarction2 

Arrhythmia 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



21 

tachycardia 
Vascular 
disorders 

 Hypertension, 
hypertension aggravated

 Flushing, vasculitis, 
pulmonary embolism 

Respiratory, 
thoracic, 
and mediastinal 
disorders 

Pharyngitis, 
rhinitis, cough 

Dyspnoea  Bronchospasm 

Gastrointestinal 
disorders 

Abdominal 
pain, 
diarrhoea, 
dyspepsia, 
flatulence 

Constipation, 
eructation, gastritis, 
stomatitis, vomiting, 
aggravation of 
gastrointestinal 
inflammation 

Duodenal, gastric, 
oesophageal, 
intestinal, and 
colonic ulceration; 
dysphagia, 
intestinal 
perforation; 
oesophagitis, 
melaena; 
pancreatitis 

Nausea, acute 
pancreatitis, 
gastrointestinal 
haemorrhage, 
colitis/colitis 
aggravated 

Hepatobiliary 
disorders 

 Abnormal hepatic 
function, increased 
SGOT and SGPT  

Elevation of 
hepatic enzymes 

Hepatitis, hepatic 
failure jaundice 

Skin and 
subcutaneous 
tissue disorders 

Rash, pruritus Urticaria Alopecia, 
photosensitivity 

Ecchymosis, 
bullous eruption, 
exfoliative dermatitis, 
erythema multiforme, 
Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis, 
angioedema 

Musculoskeletal 
and connective 
tissue disorders 

 Leg cramps  Arthralgia, myositis 

Renal and 
urinary 
disorders 

 Increased creatinine, 
BUN increased 

 Acute renal failure, 
interstitial nephritis, 
hyponatraemia 

Reproductive 
system 
and breast 
disorders 

   Menstrual disorder 

General 
disorders and 
administration 
site conditions 

Flu-like 
symptoms, 
peripheral 
oedema/ 
fluid retention 

  Chest pain 

 1  Adverse drug reactions spontaneously reported to the safety surveillance database over a period in which an 
estimated >70 million patients were treated with celecoxib (various doses, durations, and indications).  As a result, 
the frequencies of these adverse drug reactions cannot be reliably determined.  Adverse drug reactions listed for the 
post-marketing population are only those that are not already listed for the arthritis trials (Table 1) or the polyp 
prevention trials (Table 2). 

2  In a pooled analysis of 20 placebo-controlled studies with duration greater than 2 weeks up to 1 year in patients 
with OA and RA, the excess rate of myocardial infarction in patients treated with celecoxib 200 or 400 mg daily 
over placebo was 0.7 events per 1000 patients (Rare) and there was no excess of strokes. 

 
The additional adverse reactions listed by system organ class and ranked by frequency in Table 2 were 
reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg to 800 mg 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



22 

daily in long-term polyp prevention trials of duration up to 3 years (the APC and PreSAP trials; 
see Section 5.1, Pharmacodynamic properties: Cardiovascular Safety – Long-Term Studies Involving 
Patients With Sporadic Adenomatous Polyps). 
 

TABLE 2 Very Common (≥1/10) 
Common 

(≥1/100 to <1/10) 
Uncommon 

(≥1/1000 to <1/100) 
Infections and 
infestations 

 Ear infection, fungal 
infection (fungal infections 
were primarily 
nonsystemic) 

Helicobacter infection, herpes 
zoster, erysipelas, wound 
infection, gingival infection, 
labrynthitis, bacterial infection 

Neoplasms    Lipoma 
Psychiatric    Sleep disorder 
Nervous system 
disorders 

  Cerebral infarction 

Eye disorders   Vitreous floaters; 
conjunctival hemorrhage 

Ear and labyrinth 
disorders 

  Hypoacusis 

Cardiac disorders  Angina pectoris; 
myocardial infarction 

Angina unstable, aortic valve 
incompetence, coronary artery 
atherosclerosis, sinus 
bradycardia, ventricular 
hypertropy 

Vascular 
disorders                 

Hypertension*  Deep vein thrombosis; hematoma

Respiratory, 
thoracic, 
and mediastinal 
disorders 

 Dyspnoea Dysphonia 

Gastrointestinal 
disorders 

Diarrhoea* Nausea, gastroesophageal 
reflux disease, diverticulum, 
vomiting,* dysphagia, 
irritable bowel syndrome 

Haemorrhoidal haemorrhage, 
frequent bowel movements, 
mouth ulceration, stomatitis 

Skin and 
subcutaneous 
tissue disorders 

  Dermatitis allergic 

Musculoskeletal 
and connective 
tissue disorders 

 Muscle spasms Ganglion 

Renal and 
urinary disorders 

 Nephrolithiasis, 
blood creatinine increased 

Nocturia 

Reproductive 
and breast 
disorders 

 Benign prostatic 
hyperplasia, prostatitis, 
prostatic specific antigen 
increased 

Vaginal haemorrhage, breast 
tenderness, dysmenorrhea, 
ovarian cyst, menopausal 
symptoms 

General disorders 
and 
administration 
site conditions 

 Edema  

Investigations  Weight increased Blood levels increased:  
potassium, sodium, hemoglobin 
Blood levels decreased:  
hematocrit, testosterone 

Injury, poisoning,  
and procedural 

  Foot fracture, lower limb fracture, 
epicondylitis, tendon rupture, 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



23 

complications fracture 
*  Hypertension, vomiting and diarrhoea are included in Table 2 because they were reported more frequently in 

these studies, which were of 3-year duration, compared to Table 1, which includes adverse reactions from 
studies of 12-week duration. 

 
In final data (adjudicated) from the APC trial in patients treated with celecoxib 800 mg daily for up to 
3 years, the excess rates over placebo were 11 events per 1000 patients for myocardial infarction 
(common); and 5 events per 1000 patients for stroke (uncommon; types of stroke not differentiated).  
 
4.9 Overdose 
 
There is no clinical experience of overdose in clinical trials. Single doses up to 1400 mg and multiple 
doses up to 1400 mg twice daily have been administered to healthy subjects for nine days without 
clinically significant adverse events. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic, ATC code: L01XX33 
 
Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides 
(e.g. thiazides, furosemide) but differing from arylamine sulfonamides (e.g. sulfamethoxizole and 
other sulfonamide antibiotics). 
 
Celecoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor. No statistically significant 
inhibition of COX-1 (assessed as ex vivo inhibition of thromboxane B2 [TxB2] formation) was 
observed in healthy volunteers at the FAP therapeutic dose of 400 mg BID. 
 
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. Elevated levels of COX-2 are found in many 
pre-malignant lesions (such as adenomatous colorectal polyps) and epithelial cancers. Familial 
Adenomatous Polyposis (FAP) is a genetic disease resulting from an autosomal dominant genetic 
alteration of a tumor suppressor gene, the adenomatous polyposis coli (APC) gene. Polyps with the 
APC mutation overexpress COX-2 and left untreated, these polyps continue to form and enlarge in the 
colon or rectum resulting in essentially a 100% chance of developing colorectal cancer. 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 man 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 
inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without 
affecting platelet thromboxane. 
 
A dose-dependent effect on TxB2 formation has been observed after high doses of celecoxib. 
However, in small multiple dose studies in healthy subjects with 600 mg BID celecoxib had no effect 
on platelet aggregation and bleeding time compared to placebo. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



24 

Experimental evidence shows that the mechanism(s) of action by which celecoxib leads to tumour 
death may be related to induction of apoptosis and inhibition of angiogenesis. Inhibition of COX-2 
may have consequences on tumour viability that are unrelated to inflammation. 
 
Celecoxib inhibits tumour formation in preclinical models of colon cancer, which overexpress COX-2, 
whether induced by chemical (rat AOM model) or genetic (MIN mouse model) mutation.  
 
Celecoxib has been shown to reduce the number and size of adenomatous colorectal polyps. A 
randomized double-blind placebo controlled study was conducted in 83 patients with FAP. The study 
population included 58 patients with a prior subtotal or total colectomy and 25 patients with an intact 
colon. Thirteen patients had the attenuated FAP phenotype. The mean reduction in the number of 
colorectal polyps following six months of treatment was 28% (SD + 24%) for celecoxib 400 mg BID 
which was statistically superior to placebo (mean 5%, SD +16%). A meaningful reduction in duodenal 
adenoma area was also observed compared with placebo (14.5% celecoxib 400 mg BID versus 1.4% 
placebo), which however was not statistically significant. 
 
Pilot Study in Juvenile FAP Patients: A total of 18 children 10 to 14 years of age who had genotype or 
phenotype positive FAP were treated with celecoxib 4 mg/kg/day (4 patients, compared to 2 patients 
treated with placebo), celecoxib 8 mg/kg/day (4 patients, compared to 2 patients treated with placebo), 
or celecoxib 16 mg/kg/day (4 patients, compared to 2 patients treated with placebo).  Results 
demonstrated a statistically significant reduction in polyp burden in all celecoxib treatment groups 
compared to the corresponding placebo treatment groups.  The greatest reduction was observed in 
patients treated with celecoxib 16 mg/kg/day, which corresponds to the recommended adult FAP dose 
of 800 mg daily.  Safety data were reviewed in detail by a Data Safety Monitoring Committee, which 
concluded that celecoxib 16 mg/kg/day was a safe dose to recommend for further studies in juvenile 
FAP patients. 
 
The long-term cardiovascular toxicity in children exposed to celecoxib has not been evaluated and it is 
unknown if the long-term risk may be similar to that seen in adults exposed to celecoxib or other 
COX-2 selective and non-selective NSAIDs (see section 4.4; cardiovascular effects). 

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 Anti-inflammatory Prevention 
Trial), did not show a significantly increased cardiovascular risk with celecoxib 200mg 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 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



25 

myocardial infarction was 1.1% (8/717 patients) with celecoxib 200 mg twice daily and 1.2% 
(13/1070 patients) with placebo. 
 
Data from pooled analysis of controlled randomized trials also suggest that cardiovascular risk may be 
associated with the use of celecoxib compared to placebo, with evidence for differences in risk based 
on celecoxib dose. 
 
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due 
to the rarity of the disease it has not been possible to obtain complete information on this medicinal 
product. The European Medicines Agency (EMA) will review any new information which may 
become available every year and this SPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. 
Dosing with food (high fat meal) delays absorption by about 1 hour with an increase in total 
absorption (AUC) of 10 to 20%. 
 
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. Plasma protein binding is 
about 97% at therapeutic plasma concentrations and celecoxib is not preferentially bound to 
erythrocytes. Elimination half-life is 8-12 hours. Steady state plasma concentrations are reached within 
5 days of treatment. Pharmacological activity resides in the parent substance. The main metabolites 
found in the circulation have no detectable COX-1 or COX-2 activity. 
 
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 400 mg administered once daily in healthy volunteers, 
genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median Cmax and AUC 0-
24 of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as 
CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 
5 subjects genotyped as CYP2C9*3/*3, single-dose AUC 0-24 increased by approximately 3-fold 
compared to normal metabolizers.  It is estimated that the frequency of the homozygous *3/*3 
genotype is 0.3-1.0% among different ethnic groups.   

 
Patients who are known or suspected to be CYP2C9 poor metabolizers based on previous 
history/experience with other CYP2C9 substrates should be administered celecoxib with caution (see 
Section 4.2). 
 
No clinically significant differences were found in pharmacokinetic parameters of celecoxib between 
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. When dosed at 200 mg per day 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. In FAP patients with moderate hepatic impairment (serum albumin of 25-35 g/l), the 
daily recommended dose of celecoxib should be reduced by 50%. Patients with severe hepatic 
impairment (serum albumin <25 g/l) have not been studied and celecoxib is contraindicated in this 
patient group.  

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



26 

 
The pharmacokinetics of celecoxib has not been studied in patients with renal impairment but is 
unlikely to be markedly changed in these patients since it is mainly eliminated by hepatic metabolism. 
There is little experience of celecoxib in renal impairment and therefore caution is advised when 
treating patients with renal impairment. Severe renal impairment is a contraindication to use.  
 
5.3 Preclinical safety data 
 
Conventional embryo-foetal toxicity studies resulted in dose dependent occurrences of diaphragmatic 
hernia in rat foetuses and of cardiovascular malformations in rabbit foetuses at systemic exposures to 
free celecoxib approximately 3 times (rat) and 2 times (rabbit) higher than those achieved at the 
recommended daily human dose (800 mg). Diaphragmatic hernia was also seen in a peri-post natal 
toxicity study in rats, which included exposure during the organogenetic period. In the latter study, at 
the lowest systemic exposure where this anomaly occurred in a single animal, the estimated margin 
relative to the recommended daily human dose was 2 times more than the recommended daily human 
dose (800 mg). 
 
In animals, exposure to celecoxib during early embryonic development resulted in pre-implantation 
and post-implantation losses. These effects are expected following inhibition of prostaglandin 
synthesis. 
 
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.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsules contain: 
lactose monohydrate 
sodium lauryl sulphate 
povidone K30 
croscarmellose sodium  
magnesium stearate  
 
Capsule shells contain: 
gelatin 
titanium dioxide (E171) 
 
Printing ink contains: 
shellac  
propylene glycol  
iron oxide (E172)  
Brilliant Blue FCF E133  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



27 

6.4 Special precautions for storage 
 
Do not store above 30oC. 
 
6.5  Nature and contents of container 
 
Opaque PVC/Aclar/Aluminium foil blisters.  
Packs of 10 or 60 capsules. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/259/005-006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
17 October 2003/17 October 2008 
 
 
10. DATE OF REVISION OF THE TEXT 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURING AUTHORISATION HOLDER(S) 

RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OF THE MARKETING AUTHORISATION 
 

C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE 
MARKETING AUTHORISATION HOLDER 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



29 

A.  MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
Name and address of the manufacturer(s) responsible for batch release 
 
• Pfizer Manufacturing Deutschland GmbH, Heinrich-Mack-Strasse 35, 89257 Illertissen, 

Germany 
 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to medical prescription. 
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
• OTHER CONDITIONS 
 
Pharmacovigilance system  
The MAH must ensure that the system of pharmacovigilance, as described in version 2.0 presented in 
Module 1.8.1. of the Marketing Authorisation, is in place and functioning before and whilst the 
product is on the market.  
 
Risk Management Plan 
The MAH commits to performing the studies and additional pharmacovigilance activities 
detailed in the Pharmacovigilance Plan, as agreed in the version dated 28 February 2005 of the 
Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation and 
any subsequent updates of the RMP agreed by the CHMP. 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any 
updated RMP should be submitted at the same time as the following Periodic Safety Update Report 
(PSUR).  
In addition, an updated RMP should be submitted:  

• When new information is received that may impact on the current Safety Specification, 
Pharmacovigilance Plan or risk minimisation activities  

• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 
reached  

• At the request of the EMA  
 
PSUR 
The MAH shall continue to submit Periodic Safety Update Reports (PSURs) on a yearly basis. 
 
 
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING 

AUTHORISATION HOLDER 
 
The Marketing Authorisation Holder shall complete the following programme of studies within the 
specified time frame, the results of which shall form the basis of the annual reassessment of the 
benefit/risk profile. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



30 

Clinical aspects 
 
The MAH has previously committed to undertake a “Phase III placebo-controlled trial with celecoxib 
in genotype positive subjects with Familial Adenomatous Polyposis” (CHIP trial, Protocol A3191193) 
to generate further efficacy and safety data. 
 
The MAH will submit a progress report for the CHIP trial, including an update on safety data, in the 
8th annual reassessment and will submit a full study report for the completed study when available. 
The progress report will include full documentation of efforts to achieve the target for yearly 
recruitment:  an increased number of 30 patients/year is expected. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



33 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Outer carton - 200 mg hard capsules (clear, opaque blister) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 200 mg hard capsules 
Celecoxib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 200 mg celecoxib 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose 
See leaflet for further information. 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 hard capsules  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



34 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/259/001, 002 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription.  
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Onsenal 200 mg 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Outer carton - 200 mg hard capsules (clear, opaque blister) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 200 mg hard capsules 
Celecoxib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 200 mg celecoxib 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 hard capsules  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



36 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/259/003,004 
 
 
13. BATCH NUMBER 
 
Batch {number} 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription.  
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Onsenal 200 mg 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



37 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 200 mg capsules 
Celecoxib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



38 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Outer carton - 400 mg hard capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 400 mg hard capsules 
Celecoxib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 400 mg celecoxib 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 hard capsules  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



39 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/259/005 
 
 
13. BATCH NUMBER 
Batch {number} 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Onsenal 400 mg 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



40 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Outer carton - 400 mg hard capsules 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 400 mg hard capsules 
Celecoxib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 400 mg celecoxib 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 hard capsules  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



41 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/259/006 
 
 
13. BATCH NUMBER 
Batch {number} 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Onsenal 400 mg 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



42 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Onsenal 400 mg capsules 
Celecoxib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Limited 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



43 

 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



44 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Onsenal 200 mg hard capsules 
celecoxib 

 
Read all of this leaflet carefully before you start taking this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
- If  any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet:  
1. What Onsenal is and what it is used for 
2. Before you take Onsenal 
3. How to take  Onsenal 
4. Possible side effects 
5. How to store Onsenal 
6. Further information 
 
 
1. WHAT ONSENAL IS AND WHAT IT IS USED FOR 
 
Onsenal belongs to a group of medicines called cyclo-oxygenase-2 (COX-2) inhibitors.  
Cyclo-oxygenase-2 is an enzyme that increases at inflammatory sites and in abnormally growing cells. 
Onsenal works by inhibiting COX-2, to which such dividing cells are sensitive. As a consequence the 
cells die. 
 
Onsenal is used to reduce the number of gastrointestinal polyps in patients with Familial Adenomatous 
Polyposis (FAP). FAP is an inherited disorder in which the rectum and colon are covered with many 
polyps that might develop colorectal cancer. Onsenal should be used along with the usual care for FAP 
patients such as surgery and endoscopic surveillance. 
 
 
2. BEFORE YOU TAKE ONSENAL 
 
Do not take ONSENAL 
- if you have had an allergic reaction to any of the ingredients of Onsenal 
- if you have had an allergic reaction to a group of medicines called “sulphfonamides”. These 

include some antibiotics (Bactrim and Septra used in combination of sulfamethoxazole and 
trimethoprim), which can be used to treat infections 

- if you have a stomach or duodenal ulcer, or bleeding in the stomach or intestines 
- if after taking aspirin or another anti-inflammatory medicine you have had nasal polyps or 

severe nasal congestion, or any allergic reaction such as an itchy skin rash, swelling, breathing 
difficulties or wheezing  

- women of childbearing potential unless using an effective method of contraception 
- if you are breast feeding 
- if you have inflammation of the colon (ulcerative colitis) or intestinal tract (Crohn’s disease) 
- if you have severe liver disease 
- if you have severe kidney disease 
- if you have heart failure, established heart disease and /or cerebrovascular disease, e.g. if you 

have had a heart attack, stroke, mini-stroke (TIA) or blockages of blood vessels to the heart 
or brain 

- if you have had  an operation to clear or bypass blockages 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



45 

- or if you have or have had problems with blood circulation (peripheral arterial disease) or if 
you have had surgery on the arteries of your legs 

 
Take special care with ONSENAL 
Some people will need special care from their doctors when they are taking Onsenal. Make sure that 
 your doctor knows before you start taking Onsenal: 
- if you have conditions which increase your risk of heart disease such as high blood pressure, 

diabetes, high cholesterol or if you smoke you should discuss with your doctor whether Onsenal 
is suitable for you 

- if you have had a stomach or duodenal (intestinal) ulcer or bleeding in the stomach or intestines 
- if your heart, liver, or kidneys are not working well, your doctor may want to keep a regular 

check on you 
- if you have fluid retention (such as swollen ankles or feet) 
- if you are dehydrated, for example by sickness or diarrhoea or if you are taking diuretic 

treatment (water tablets) 
- if you have had a serious allergic reaction or a serious skin reaction to any medicines 
- if you are taking acetylsalicylic acid 
- if you are taking anticoagulants 
- if you have intolerance to some sugars 
- if you are being treated for an infection, because Onsenal may mask a fever which is a sign of 

an infection 
if you are over 65 years of age your doctor may want to keep a regular check on you 

 
As with other non-steroidal, anti-inflammatory drugs (NSAIDs; eg, ibuprofen or diclofenac), this 
medicine may lead to an increase in blood pressure, and so your doctor may ask to monitor your blood 
pressure on a regular basis. 
 
Taking other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including those obtained without a prescription. 
 
Before you start taking Onsenal make sure your doctor knows if you are taking: 
- ACE inhibitors or Angiotensin II receptor antagonists (used for high blood pressure and heart 

failure) 
- Acetylsalcylic acid or other anti-inflammatory medicines 
- Cyclosporin and tacrolimus (used for immune system suppression e.g. after transplants) 
- Dextromethorphan (used as an antitussive in cough mixtures) 
- Diuretics (used to treat fluid retention) 
- Fluconazole (used to treat fungal infections) 
- Lithium (used to treat depression) 
- Rifampicin (used to treat bacterial infections) 
- Warfarin (used to prevent blood from clotting) or other anticoagulants 
- Other medicines to treat depression, sleep disorders, high blood pressure or an irregular 

heartbeat 
- Neuroleptics (used to treat some mental disorders) 
- Methotrexate (used to treat rheumatoid arthritis, psoriasis and leukaemia) 
- Carbamazepine (used to treat epilepsy/seizures and some forms of pain or depression) 
- Barbiturates ( used to treat epilepsy/seizures and some sleep disorders) 
 
Onsenal can be taken with low dose acetylsalicylic acid (aspirin). Ask your doctor for advice before 
taking both of these medicines together. 
 
Taking ONSENAL with food and drink 
You can take Onsenal with or without food. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



46 

Pregnancy and breast-feeding 
You must not take Onsenal if you are pregnant or if it is possible that you become pregnant. 
You must not take Onsenal if you are breast feeding. 
 
Driving and using machines 
If you feel dizzy or tired after taking Onsenal, do not drive or use machinery until you are feeling 
normal again. 
 
Important information about some of the ingredients of Onsenal: 
Onsenal contains lactose (a type of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3. HOW TO TAKE ONSENAL 
 
Always take Onsenal exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are unsure. The usual dose is 400 mg twice a day. You will usually take two 200 mg 
capsules twice a day. 
 
The maximum recommended daily dose is 800 mg. 
 
If you take more ONSENAL than you should 
If you accidentally take too many capsules, tell your doctor or pharmacist as soon as possible. 
 
If you forget to take ONSENAL 
Do not take a double dose to make up for forgotten individual doses. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, ONSENAL can cause side effects, although not everybody gets them. 
 
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, tell your 
doctor or pharmacist. 
 
The side effects listed below were observed in arthritis patients who took medicines with the 
same active ingredient as Onsenal: 
 
Stop taking the capsules and tell your doctor immediately 
− If you have an allergic reaction such as skin rash, swelling of the face, wheezing or difficulty 

breathing 
− If you have heart problems such as pain in the chest 
− If you have liver failure (symptoms may include nausea (feeling sick), diarrhoea, jaundice (your 

skin or the whites of your eyes look yellow)) 
− If you have blistering or peeling of the skin 
− If you have severe stomach pain or any sign of bleeding in the stomach or intestines, such as 

passing black or bloodstained bowel movements, or vomiting blood 
 
Common side effects which may affect more than 1 person in 100, are listed below 
- Fluid build up with swollen ankles, legs and/or hands 
- Urinary infections 
- Sinusitis (sinus inflammation, sinus infection, blocked or painful sinuses), blocked or runny 

nose, sore throat, coughs, colds, flu-like symptoms 
- Dizziness, difficulty sleeping   
- stomach ache, diarrhoea, indigestion, wind 
- Rash, itching  

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



47 

- Muscle stiffness  
- Worsening of existing allergies  
 
Uncommon side effects which may affect more than 1 person in a 1000, are listed below: 
− Heart failure, palpitations (awareness of heart beat), fast heart rate 
− Worsening of existing high blood pressure 
− Abnormalities in liver-related blood tests  
− Abnormalities in kidney-related blood tests  
− Anaemia (changes in red blood cells that can cause fatigue and breathlessness)  
− Anxiety, depression, tiredness, drowsiness, tingling sensations (pins and needles) 
− High levels of potassium in blood test results (can cause nausea (feeling sick), fatigue, muscle 

weakness or palpitations) 
− Impaired or blurred vision, ringing in the ears, mouth pain and soresConstipation, burping, 

stomach inflammation (indigestion, stomach ache or vomiting), worsening of inflammation of 
the stomach or intestine. 

− Leg cramps 
− Raised itchy rash (hives) 
 
Rare side effects which may affect more than 1 person in a 10,000, are listed below 
− Ulcers (bleeding) in the stomach,  gullet or intestines; or rupture of the intestine (can cause 

stomach ache, fever, nausea, vomiting, intestinal blockage), dark or black stools, inflammation 
of the gullet (can cause difficulty in swallowing), inflammation of the pancreas (can lead to 
stomach pain) 

− Reduced number of white blood cells (which help protect the body from infection) and blood 
platelets (increased chance of bleeding or bruising) 

− Difficulty coordinating muscular movements 
− Feeling confused, changes in the way things taste 
− Increased sensitivity to light 
− Loss of hair 
 
Additional reactions have been reported from actual use of the active ingredient of Onsenal (in 
post-marketing experience).  The frequencies of these reactions are difficult to determine but are 
generally considered to be very rare (affecting less than 1 person in every 10,000) 
− Bleeding within the brain causing death  
− Serious allergic reactions (including potentially fatal anaphylactic shock) which can cause skin 

rash, swelling of the face, lips, mouth, tongue or throat, wheezing or difficulty breathing; 
difficulty swallowing 

− Bleeding of the stomach or intestines (can lead to bloody stools or vomiting), inflammation of 
the intestine or colon, nausea (feeling sick)  

− Serious skin conditions such as Stevens-Johnson syndrome, exfoliative dermatitis and toxic 
epidermal necrolysis (can cause rash, blistering or peeling of the skin) 

− Liver failure, liver damage and severe liver inflammation (sometimes fatal or requiring liver 
transplant). Symptoms may include nausea (feeling sick), diarrhoea, jaundice, yellow 
discolouration of the skin or eyes, dark urine, pale stools, bleeding easily, itching or chills 

− Kidney problems (possible kidney failure, inflammation of the kidneys) 
− Blood clot in the blood vessels in the lungs. Symptoms may include sudden breathlessness, 

sharp pains when you breathe or collapse 
− Irregular heartbeat 
− Meningitis (inflammation of the membrane around the brain and spinal cord) 
− Hallucinations 
− Worsening of epilepsy (possible more frequent and/or severe seizures) 
− Inflamed blood vessels (can cause fever, aches, purple blotches on the skin) 
− Blockage of an artery or vein in the eye leading to partial or complete loss of vision, 

conjunctivitis, eye infection (pink eye), bleeding in the eye  
− A reduction in the number of red and white blood cells and platelets (may cause tiredness, easy 

bruising, frequent nose bleeds and increased risk of infections) 
− Chest pain 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



48 

− Impaired sense of smell  
− Skin discolouration (bruising), muscle pain and weakness, painful joints 
− Menstrual disturbances 
− Headache, flushing  
− Low levels of sodium in blood test results (can cause loss of appetite, headache, nausea (feeling 

sick), muscle cramps and weakness) 
 
In clinical studies where Onsenal was taken for up to 3 years to prevent spontaneous colon 
polyps, the following additional side effects have been observed (side effects marked with an 
asterisk were more common in these studies than in arthritis studies): 
 
Very Common side-effects (affecting more than 1 person in every 10): 
− High blood pressure*, diarrhoea* 
 
Common 
− Heart problems: heart attack*, angina (chest pain) 
− Stomach problems: nausea, heartburn, diverticulum (a problem with the stomach or intestine 

that can become painful or infected), vomiting*, irritable bowel syndrome (can include stomach 
ache, diarrhoea, indigestion, wind) 

− Kidney stones (which may lead to stomach or back pain, blood in urine), difficulty passing 
urine, increased creatinine (blood test result related to kidney function) 

− Difficulty breathing 
− Muscle spasms 
− Oedema (water retention that can cause swelling) 
− Enlarged or inflamed prostate, prostate specific antigen increased (lab test) 
− Infections of various types 
− Weight gain 
 
Uncommon 
− Stroke 
− Unstable angina (chest pain), troubles with heart valves, rhythm, or coronary arteries, or 

enlarged heart 
− Deep vein thrombosis (blood clot usually in the leg, which may cause pain, swelling or redness 

of the calf or breathing problems), bruising 
− Stomach infection(which can cause irritation and ulcers of the stomach and intestines), bleeding 

from piles/haemorrhoids, frequent bowel movements, inflamed or bleeding gums/mouth sores 
− Lower limb fracture, tendon rupture or inflammation 
− Shingles, skin infection, allergic dermatitis (dry itchy rash)  
− Floaters or haemorrhage in the eye causing blurred or impaired vision, vertigo due to inner ear 

troubles, difficulty speaking 
− Difficulty sleeping, excessive urination at night  
− Fatty lumps in skin or elsewhere, ganglion cyst (harmless swellings on or around joints and 

tendons in the hand or foot) 
− Abnormal or heavy bleeding from the vagina, painful menstruation, breast pain, ovarian cyst, 

menopausal symptoms 
− High levels of sodium or haemoglobin and low levels of hematocrit or testosterone in blood test 

results 
− Decreased hearing 
− Changes in blood counts  
 
 
5. HOW TO STORE ONSENAL 
 
Keep out of the reach and sight of children. 
 
Do not store your capsules above 30°C. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



49 

 
Do not take the capsule after the ‘expiry date’ shown on the blister and carton. If your capsules are out 
of date, take them to your pharmacist who will get rid of them safely. 
 
 
6. FURTHER INFORMATION 
 
What ONSENAL contains 
 
− The active substance is celecoxib 
− The other ingredients are gelatin, lactose monohydrate, sodium lauryl sulphate, povidone K30, 

croscarmellose sodium, magnesium stearate and the colouring agent titanium dioxide E171. 
− The printing ink contains also shellac, propylene glycol and iron oxide E172. 
 
What ONSENAL looks like and contents of the pack 
 
The capsules are white with ‘7767‘ and ‘200‘ marked in gold ink. 
Onsenal is packed in blisters and supplied in boxes of 10 or 60 capsules. 
 
Marketing Authrisation Holder 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
Manufacturer 
 
Pfizer Manufacturing Deutschland GmbH 
Heinrich-Mack-Strasse 35 
89257 Illertissen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
Belgique / België  /Belgien 
Pfizer S.A. / N.V. 
Tél/Tel: +32 (0)2 554 62 11 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: +32 (0)2 554 62 11 
 

България  
Pfizer HCP Corporation 
Тел.: +359 2 970 4333 
 

Magyarország 
Pfizer Kft. 
Tel.: +36-1-488-37-00 

Česká republika 
Pfizer s.r.o. 
Tel.: +420-283-004-111 

Malta 
V.J. Salomone Pharma Ltd. 
Tel. +356 212201 74 

Danmark 
Pfizer ApS 
Tlf: +45 44 20 11 00 
 

Nederland 
Pfizer BV 
Tel: +31 (0)10 406 4301 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



50 

Deutschland 
Pfizer Pharma GmbH 
Tel:  +49 30 550055-51000. 
  

Norge 
Pfizer AS 
Tlf: +47 67 52 61 00 
 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal  
Tel.: +372 6 405 328 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 
 

Ελλάδα 
Pfizer Hellas A.E. 
Τηλ:   +30 210 6785 800. 

Polska 
Pfizer Polska Sp. z o.o 
Tel.:+48 22 335 61 00 
 

España 
Pfizer S.A. 
Tel: +34 91 490 99 00 

Portugal 
Laboratórios Pfizer, Lda. 
Tel: +351 21 423 5500 
 

France 
Pfizer  
Tél: +33 (0)1 58 07 34 40 

România 
Pfizer România S.R.L. 
Tel: +40 21 207 28 00 
 

Ireland 
Pfizer Healthcare Ireland 
 
Tel: +1800 633 363  (toll free) 
+44 (0)1304 616161 

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel.: + 386 1 52 11 400 
 

Ísland 
Vistor hf 
Sími: +354 535 7000 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel.:+ 421-2-3355 5500 
 

Italia 
Pfizer Italia S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland 
Pfizer Oy 
Puh./Tel: +358 (0)9 43 00 40 

Kύπρος 
Geo. Pavlides & Araouzos Ltd. 
Tηλ.:+ 357 22 818087 
 

Sverige  
Pfizer AB 
Tel: +46 (0)8 550-52000  
 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā  
Tel.: + 371 670 35 775 

United Kingdom 
Pfizer Limited, 
Tel: +44 (0)1304 616161 
 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje Tel. 
+ 370 52 51 4000 
 

 

 
This leaflet was last approved in. 
 
This medicine has been authorised under “exceptional circumstances”. 
This means that because of the rarity of this disease it has been impossible to get complete information 
on  this medicine. 
The European Medicines Agency (EMA) will review any new information on the medicine  every year 
and this leaflet will be updated as necessary. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



51 

 
Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.ema.europa.eu/. There are also links to other websites about rare diseases and 
treatments. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



52 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Onsenal 400 mg hard capsules 
celecoxib 

 
Read all of this leaflet carefully before you start taking this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
- If  any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet:  
1. What Onsenal is and what it is used for 
2. Before you take Onsenal 
3. How to take  Onsenal 
4. Possible side effects 
5  How to store Onsenal 
6. Further information 
 
 
1. WHAT ONSENAL IS AND WHAT IT IS USED FOR 
 
Onsenal belongs to a group of medicines called cyclo-oxygenase-2 (COX-2) inhibitors.  
Cyclo-oxygenase-2 is an enzyme that increases at inflammatory sites and in abnormally growing cells. 
Onsenal works by inhibiting COX-2, to which such dividing cells are sensitive. As a consequence the 
cells die. 
 
Onsenal is used to reduce the number of gastrointestinal polyps in patients with Familial Adenomatous 
Polyposis (FAP). FAP is an inherited disorder in which the rectum and colon are covered with many 
polyps that might develop colorectal cancer. Onsenal should be used along with the usual care for FAP 
patients such as surgery and endoscopic surveillance. 
 
 
2. BEFORE YOU TAKE ONSENAL 
 
Do not take ONSENAL 
− if you have had an allergic reaction to any of the ingredients of Onsenal 
− if you have had an allergic reaction to a group of medicines called “sulphonamides”. These 

include some antibiotics (Bactrim and Septra used in combination with sulfamethoxole and 
trimethoprim), which can be used to treat infections 

− if you have a stomach or duodenal ulcer, or bleeding in the stomach or intestines 
− if after taking aspirin or another anti-inflammatory medicine you have had nasal polyps or 

severe nasal congestion, or any allergic reaction such as an itchy skin rash, swelling, breathing 
difficulties or wheezing  

− women of childbearing potential unless using an effective method of contraception 
− if you are breast feeding 
− if you have inflammation of the colon (ulcerative colitis) or intestinal tract (Crohn’s disease) 
− if you have severe liver disease 
− if you have severe kidney disease 
− if you have heart failure, established heart disease and /or cerebrovascular disease, e.g. if you 

have had a heart attack, stroke, mini-stroke (TIA) or blockages of blood vessels to the heart 
or brain 

− if you have had  an operation to clear or bypass blockages 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



53 

− or if you have or have had problems with blood circulation (peripheral arterial disease) or if 
you have had surgery on the arteries of your legs 

 
Take special care with ONSENAL 
− Some people will need special care from their doctors when they are taking Onsenal. Make sure 

that your doctor knows before you start taking Onsenal: 
− if you have conditions which increase your risk of heart disease such as high blood pressure, 

diabetes, high cholesterol or if you smoke you should discuss with your doctor whether Onsenal 
is suitable for you 

− if you have had a stomach or duodenal (intestinal) ulcer or bleeding in the stomach or intestines 
− if your heart, liver, or kidneys are not working well, your doctor may want to keep a regular 

check on you 
− if you have fluid retention (such as swollen ankles or feet) 
− if you are dehydrated, for example by sickness or diarrhoea or if you are taking diuretic 

treatment (water tablets) 
− if you have had a serious allergic reaction or a serious skin reaction to any medicines 
− if you are taking acetylsalicylic acid 
− if you are taking anticoagulants 
− if you have intolerance to some sugars 
− if you are being treated for an infection, because Onsenal may mask a fever which is a sign of 

an infection 
− if you are over 65 years of age your doctor may want to keep a regular check on you 
 
As with other non-steroidal, anti-inflammatory drugs (NSAIDs; eg, ibuprofen or diclofenac), this 
medicine may lead to an increase in blood pressure, and so your doctor may ask to monitor your blood 
pressure on a regular basis. 
 
Taking other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including those obtained without a prescription. 
 
Before you start taking Onsenal make sure your doctor knows if you are taking: 
− ACE inhibitors or Angiotensin II receptor antagonists (used for high blood pressure and heart 

failure) 
− Acetylsalcylic acid or other anti-inflammatory medicines 
− Cyclosporin and tacrolimus (used for immune system suppression e.g. after transplants) 
− Dextromethorphan (used as an antitussive in cough mixtures) 
− Diuretics (used to treat fluid retention) 
− Fluconazole (used to treat fungal infections) 
− Lithium (used to treat depression) 
− Rifampicin (used to treat bacterial infections) 
− Warfarin (used to prevent blood from clotting) or other anticoagulants 
− Other medicines to treat depression, sleep disorders, high blood pressure or an irregular 

heartbeat 
− Neuroleptics (used to treat some mental disorders) 
− Methotrexate (used to treat rheumatoid arthritis, psoriasis and leukaemia) 
− Carbamazepine (used to treat epilepsy/seizures and some forms of pain or depression) 
− Barbiturates ( used to treat epilepsy/seizures and some sleep disorders) 
 
Onsenal can be taken with low dose acetylsalicylic acid (aspirin). Ask your doctor for advice before 
taking both of these medicines together. 
 
Taking ONSENAL with food and drink 
You can take Onsenal with or without food. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



54 

Pregnancy and breast-feeding 
You must not take Onsenal if you are pregnant or if it is possible that you become pregnant. 
You must not take Onsenal if you are breast feeding. 
 
Driving and using machines 
If you feel dizzy or tired after taking Onsenal, do not drive or use machinery until you are feeling 
normal again. 
 
Important information about some of the ingredients of Onsenal: 
Onsenal contains lactose (a type of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3. HOW TO TAKE ONSENAL 
 
Always take Onsenal exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are unsure. The usual dose is 400 mg twice a day. You will usually take one 400 mg 
capsule twice a day. 
 
The maximum recommended daily dose is 800 mg.  
 
If you take more ONSENAL than you should 
If you accidentally take too many capsules, tell your doctor or pharmacist as soon as possible. 
 
If you forget to take ONSENAL 
Do not take a double dose to make up for forgotten individual doses. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, ONSENAL can cause side effects, although not everybody gets them. 
 
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, tell your 
doctor or pharmacist. 
 
The side effects listed below were observed in arthritis patients who took medicines with the same 
active ingredient as Onsenal: 
 
Stop taking the capsules and tell your doctor immediately… 
If you have an allergic reaction such as skin rash, swelling of the face, wheezing or difficulty breathing 

If you have heart problems such as pain in the chest 
If you have liver failure (symptoms may include nausea (feeling sick), diarrhoea, jaundice (your skin 
or the whites of your eyes look yellow) 
If you have blistering or peeling of the skin 
If you have severe stomach pain or any sign of bleeding in the stomach or intestines, such as passing 
black or bloodstained bowel movements, or vomiting blood 
 
Common side effects which may affect more than 1 person in 100, are listed below 
− Fluid build up with swollen ankles, legs and/or hands 
− Urinary infections 
− Sinusitis (sinus inflammation, sinus infection, blocked or painful sinuses), blocked or runny 

nose, sore throat, coughs, colds, flu-like symptoms 
− Dizziness, difficulty sleeping   
− stomach ache, diarrhoea, indigestion, wind 
− Rash, itching  

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



55 

− Muscle stiffness  
− Worsening of existing allergies  
 
Uncommon side effects which may affect more than 1 person in a 1000, are listed below 
− Heart failure, palpitations (awareness of heart beat), fast heart rate 
− Worsening of existing high blood pressure 
− Abnormalities in liver-related blood tests  
− Abnormalities in kidney-related blood tests  
− Anaemia (changes in red blood cells that can cause fatigue and breathlessness)  
− Anxiety, depression, tiredness, drowsiness, tingling sensations (pins and needles) 
− High levels of potassium in blood test results (can cause nausea (feeling sick), fatigue, muscle 

weakness or palpitations) 
− Impaired or blurred vision, ringing in the ears, mouth pain and sores 
− Constipation, burping, stomach inflammation (indigestion, stomach ache or vomiting), 

worsening of inflammation of the stomach or intestine. 
− Leg cramps 
− Raised itchy rash (hives) 
 
Rare side effects which may affect more than 1 person in a 10,000, are listed below 
− Ulcers (bleeding) in the stomach,  gullet or intestines; or rupture of the intestine (can cause 

stomach ache, fever, nausea, vomiting, intestinal blockage), dark or black stools, inflammation 
of the gullet (can cause difficulty in swallowing), inflammation of the pancreas (can lead to 
stomach pain) 

− Reduced number of white blood cells (which help protect the body from infection) and blood 
platelets (increased chance of bleeding or bruising) 

− Difficulty coordinating muscular movements 
− Feeling confused, changes in the way things taste 
− Increased sensitivity to light 
− Loss of hair 
 
Additional reactions have been reported from actual use of the active ingredient of Onsenal (in 
post-marketing experience). The frequencies of these reactions are difficult to determine but are 
generally considered to be very rare (affecting less than 1 person in every 10,000) 
− Bleeding within the brain causing death  
− Serious allergic reactions (including potentially fatal anaphylactic shock) which can cause skin 

rash, swelling of the face, lips, mouth, tongue or throat, wheezing or difficulty breathing; 
difficulty swallowing 

− Bleeding of the stomach or intestines (can lead to bloody stools or vomiting), inflammation of 
the intestine or colon, inflammation of the pancreas, nausea (feeling sick)  

− Serious skin conditions such as Stevens-Johnson syndrome, exfoliative dermatitis and toxic 
epidermal necrolysis (can cause rash, blistering or peeling of the skin) 

− Liver failure, liver damage and severe liver inflammation (sometimes fatal or requiring liver 
transplant). Symptoms may include nausea (feeling sick), diarrhoea, jaundice, yellow 
discolouration of the skin or eyes, dark urine, pale stools, bleeding easily, itching or chills 

− Kidney problems (possible kidney failure, inflammation of the kidneys) 
− Blood clot in the blood vessels in the lungs. Symptoms may include sudden breathlessness, 

sharp pains when you breathe or collapse 
− Irregular heartbeat 
− Meningitis (inflammation of the membrane around the brain and spinal cord) 
− Hallucinations 
− Worsening of epilepsy (possible more frequent and/or severe seizures) 
− Inflamed blood vessels (can cause fever, aches, purple blotches on the skin) 
− Blockage of an artery or vein in the eye leading to partial or complete loss of vision, 

conjunctivitis, eye infection (pink eye), bleeding in the eye 
− A reduction in the number of red and white blood cells and platelets (may cause tiredness, easy 

bruising, frequent nose bleeds and increased risk of infections) 
− Chest pain 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



56 

− Impaired sense of smell  
− Skin discolouration (bruising), muscle pain and weakness, painful joints 
− Menstrual disturbances 
− Headache, flushing 
− Low levels of sodium in blood test results (can cause loss of appetite, headache, nausea (feeling 

sick), muscle cramps and weakness) 
 
In clinical studies where Onsenal was taken for up to 3 years to prevent spontaneous colon 
polyps, the following additional side effects have been observed (side effects marked with an 
asterisk were more common in these studies than in arthritis studies): 
 
Very Common side-effects (affecting more than 1 person in every 10): 
− High blood pressure*, diarrhoea* 
 
Common 
− Heart problems: heart attack*, angina (chest pain) 
− Stomach problems: nausea, heartburn, diverticulum (a problem with the stomach or intestine 

that can become painful or infected), vomiting*, irritable bowel syndrome (can include stomach 
ache, diarrhoea, indigestion, wind) 

− Kidney stones (which may lead to stomach or back pain, blood in urine), difficulty passing 
urine, increased creatinine (blood test result related to kidney function) 

− Difficulty breathing 
− Muscle spasms 
− Oedema (water retention that can cause swelling) 
− Enlarged or inflamed prostate, prostate specific antigen increased (lab test) 
− Infections of various types 
− Weight gain 
 
Uncommon 
− Stroke 
− Unstable angina (chest pain), troubles with heart valves, rhythm, or coronary arteries, or 

enlarged heart 
− Deep vein thrombosis (blood clot usually in the leg, which may cause pain, swelling or redness 

of the calf or breathing problems), bruising 
− Stomach infection (which can cause irritation and ulcers of the stomach and intestines), bleeding 

from piles/haemorrhoids, frequent bowel movements, inflamed or bleeding gums/mouth sores 
− Lower limb fracture, tendon rupture or inflammation 
− Shingles, skin infection, allergic dermatitis (dry itchy rash)  
− Floaters or haemorrhage in the eye causing blurred or impaired vision, vertigo due to inner ear 

troubles, difficulty speaking 
− Difficulty sleeping, excessive urination at night  
− Fatty lumps in skin or elsewhere, ganglion cyst (harmless swellings on or around joints and 

tendons in the hand or foot) 
− Abnormal or heavy bleeding from the vagina, painful menstruation, breast pain, ovarian cyst, 

menopausal symptoms 
− High levels of sodium or haemoglobin and low levels of hematocrit or testosterone in blood test 

results 
− Decreased hearing 
− Changes in blood counts 
 
 
5. HOW TO STORE ONSENAL 
 
Keep out of the reach and sight of children. 
 
Do not store your capsules above 30°C. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



57 

 
Do not take the capsule after the ‘expiry date’ shown on the blister and carton. If your capsules are out 
of date, take them to your pharmacist who will get rid of them safely. 
 
 
6. FURTHER INFORMATION 
 
What ONSENAL contains 
 
− The active substance is celecoxib 
− The other ingredients are gelatin, lactose monohydrate, sodium lauryl sulphate, povidone K30, 

croscarmellose sodium, magnesium stearate and the colouring agent titanium dioxide E171. 
− The printing ink contains also shellac, propylene glycol and iron oxide E172, Brilliant Blue FCF 

E 133. 
 
What ONSENAL looks like and contents of the pack 
 
The capsules are white with ‘7767‘ and ‘400‘ marked in green ink. Onsenal is packed in blisters and 
supplied in boxes of 10 or 60 capsules. 
 
Marketing Authrisation Holder 
 
Pfizer Limited 
Ramsgate Road 
Sandwich 
Kent CT13 9NJ 
United Kingdom 
 
Manufacturer 
 
Pfizer Manufacturing Deutschland GmbH 
Heinrich-Mack-Strasse 35 
89257 Illertissen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique / België  /Belgien 
Pfizer S.A. / N.V. 
Tél/Tel: +32 (0)2 554 62 11 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: +32 (0)2 554 62 11 
 

България  
Pfizer HCP Corporation 
Тел.: +359 2 970 4333 
 

Magyarország 
Pfizer Kft. 
Tel.: +36-1-488-37-00 

Česká republika 
Pfizer s.r.o. 
Tel.: +420-283-004-111 

Malta 
V.J. Salomone Pharma Ltd. 
Tel. +356 212201 74 

Danmark 
Pfizer ApS 
Tlf: +45 44 20 11 00 
 

Nederland 
Pfizer BV 
Tel: +31 (0)10 406 4301 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



58 

Deutschland 
Pfizer Pharma GmbH 
Tel:  +49 30 550055-51000.  

Norge 
Pfizer AS 
Tlf: +47 67 52 61 00 
 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal  
Tel.: +372 6 405 328 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 
 

Ελλάδα 
Pfizer Hellas A.E. 
Τηλ:   +30 210 6785 800. 

Polska 
Pfizer Polska Sp. z o.o 
Tel.:+48 22 335 61 00 
 

España 
Pfizer S.A. 
Tel: +34 91 490 99 00 

Portugal 
Laboratórios Pfizer, Lda. 
Tel: +351 21 423 5500 
 

France 
Pfizer  
Tél: +33 (0)1 58 07 34 40 

România 
Pfizer România S.R.L. 
Tel: +40 21 207 28 00 
 

Ireland 
Pfizer Healthcare Ireland 
Tel: +1800 633 363 (toll free) 
+44 (0)1304 616161 

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel.: + 386 1 52 11 400 
 

Ísland 
Vistor hf 
Sími: +354 535 7000 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel.:+ 421-2-3355 5500 
 

Italia 
Pfizer Italia S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland 
Pfizer Oy 
Puh./Tel: +358 (0)9 43 00 40 

Kύπρος 
Geo. Pavlides & Araouzos Ltd. 
Tηλ.:+ 357 22 818087 
 

Sverige  
Pfizer AB 
Tel: +46 (0)8  550-52000 
 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā  
Tel.: + 371 670 35 775 

United Kingdom 
Pfizer Limited, 
Tel: +44 (0)1304 616161 
 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje Tel. 
+ 370 52 51 4000 

 

This leaflet was last approved in {MM/YYYY}. 
 
This medicine has been authorised under “exceptional circumstances”. 
This means that because of the rarity of this disease it has  been impossible to get complete 
information on  this medicine. 
 
The European Medicines Agency (EMA) will review any new information on the medicine  every year 
and this leaflet will be updated as necessary. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



59 

Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.ema.europa.eu/. There are also links to other websites about rare diseases and 
treatments. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCHRELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETINGAUTHORISATION HOLDER
	A. LABELLING
	B. PACKAGE LEAFLET