Adverse reactions : תופעות לוואי

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 reactions reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg daily in long-term polyp prevention trials of duration up to 3 years (the Adenoma Prevention with Celecoxib (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials; see section 5.1, Cardiovascular safety – long- term studies involving patients with sporadic adenomatous polyps).

•           Adverse drug reactions from post-marketing surveillance as spontaneously reported during a period in which an         estimated >70 million patients were treated with celecoxib (various doses, durations, and indications). Even though these were identified as reactions from post-marketing reports, trial data was consulted to estimate frequency. Frequencies are based on a cumulative meta-analysis with pooling of trials representing exposure in 38102 patients.

Table 1. Adverse drug reactions in celecoxib clinical trials and surveillance experience (MedDRA preferred terms)1,2

Adverse Drug Reaction Frequency
System organ        Very         Common (≥ 1/100           Uncommon (≥        Rare (≥          Very rare (<                  Not known class               common (≥    to < 1/10)                1/1,000 to         1/10,000 to <    1/10,000)                     (cannot be 1/10)                                  <1/100)            1/1,000)                                       estimated from available data)
Infections and                   Sinusitis, upper infestations                     respiratory tract infection,
pharyngitis, urinary tract infection
Blood and                                                  Anaemia            Leukopenia,      Pancytopenia4 lymphatic                                                                     thrombo- system                                                                        cytopenia disorders
Immune system                    Hyper-sensitivity                                             Anaphylactic shock4, disorders                                                                                      anaphylactic reaction4 
Metabolism and                                             Hyperkalaemia nutrition disorders
Psychiatric                      Insomnia                  Anxiety,           Confusional disorders                                                  depression,        state, fatigue            hallucinations
4

Nervous system                   Dizziness,                Cerebral           Ataxia,          Haemorrhage disorders                        hypertonia,               infarction1,       dysgeusia        intracranial (including headache4                 paraesthesia,                       fatal intracranial somnolence                          haemorrhage)4,
meningitis aseptic4,
epilepsy (including aggravated epilepsy)4, ageusia4,
anosmia4

Eye disorders                                              Vision blurred,    Eye              Retinal artery conjunctivitis4    haemorrhage4     occlusion4, retinal vein occlusion4
Ear and labyrinth                                          Tinnitus,
disorders                                                  hypoacusis1 
Cardiac                          Myocardial                Cardiac failure,   Arrhythmia4 disorders                        infarction1               palpitations, tachycardia

Vascular            Hyper-                                                    Pulmonary        Vasculitis4 disorders           tension1                                                  embolism4, (including                                                flushing4 aggravated hyper- tension)
Respiratory,                     Rhinitis, cough,          Bronchospasm       Pneumonitis4 thoracic, and                    dyspnoea1                 4
 mediastinal disorders

Gastrointestinal    Nausea4, abdominal        Constipation,      Gastro- disorders           pain, diarrhoea,          gastritis,         intestinal dyspepsia,                stomatitis,        haemorrhage4 flatulence, vomiting1,    gastrointestinal   , duodenal dysphagia1                inflammation       ulcer, gastric
(including         ulcer,
aggravation of     oesophageal gastrointestinal   ulcer,
inflammation),     intestinal eructation         ulcer, large intestinal ulcer,
intestinal perforation,
oesophagitis,
melaena,
pancreatitis,
colitis4
Hepatobiliary                                 Hepatic            Hepatitis4       Hepatic failure4 disorders                                     function                            (sometimes fatal or abnormal,                           requiring liver hepatic enzyme                      transplant), hepatitis increased                           fulminant4 (some with
(including                          fatal outcome),
increased                           hepatic necrosis4,
SGOT and                            cholestasis4, hepatitis,
SGPT)                               cholestatic4, jaundice4
Skin and            Rash, pruritus            Urticaria,         Angioedema4,     Dermatitis exfoliative4, subcutaneous        (includes pruritus        ecchymosis4        alopecia,        erythema multiforme4, tissue disorders    generalized)                                 photo-           Stevens-Johnson sensitivity      syndrome4, toxic epidermal,
necrolysis4, drug reaction with eosinophilia and systemic symptoms
(DRESS)4, acute generalized exanthematous pustulosis (AGEP)4,
dermatitis bullous4,
Musculoskeletal     Arthralgia4               Muscle spasms                         Myositis4 and connective                                (leg cramps) tissue disorders


Renal and                                     Blood              Renal failure    Tubulointerstitial urinary disorders                             creatinine         acute4, hypo-    nephritis4, nephrotic increased,         natraemia4       syndrome4,
blood urea                          glomerulonephritis increased                           minimal lesion4
Reproductive                                                     Menstrual                                     Infertility system and                                                       disorder4                                     female breast disorders                                                                                               (female fertility decreased)
3

General             Influenza-like illness,   Face oedema,
disorders and       oedema peripheral/        chest pain4 administrative      fluid retention site conditions

Injury, poisoning                  Injury (accidental and procedural                     injury) complications
SGOT - serum glutamic oxaloacetic transaminase
SGPT - serum glutamic pyruvic transaminase
1 Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with celecoxib                     400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials). The adverse drug reactions listed above for the polyp prevention trials are only those that have been previously recognized in the post-marketing surveillance experience or have occurred more frequently than in the arthritis trials.

2 Furthermore, the following previously unknown adverse reactions occurred in polyp prevention trials,
representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials): Common: angina pectoris, irritable bowel syndrome, nephrolithiasis, blood creatinine increased, benign prostatic hyperplasia, weight increased. Uncommon: helicobacter infection, herpes zoster, erysipelas, bronchopneumonia, labyrinthitis, gingival infection, lipoma, vitreous floaters, conjunctival haemorrhage, deep vein thrombosis, dysphonia, haemorrhoidal haemorrhage, frequent bowel movements, mouth ulceration, allergic dermatitis, ganglion, nocturia, vaginal haemorrhage, breast tenderness, lower limb fracture, blood sodium increased.
3 Women intending to become pregnant are excluded from all trials, thus consultation of the trial database for the frequency of this event was not reasonable.


4 Frequencies are based on cumulative meta-analysis with pooling of trials representing exposure in 38102 patients.


In final data (adjudicated) from the APC and PreSAP trials in patients treated with celecoxib 400 mg daily for up to 3 years (pooled data from both trials; see section 5.1 for results from individual trials), the excess rate over placebo for myocardial infarction was 7.6 events per 1,000 patients (uncommon) and there was no excess rate for stroke (types not differentiated) over placebo.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form at https://sideeffects.health.gov.il/.
Additionally, please report to the following email: safety@trima.co.il