Adverse reactions : תופעות לוואי

4.8. Undesirable effects
In the table below the incidence of adverse drug reactions reported in controlled clinical studies where Arthrotec was administered to more than 2000 patients are listed. Additionally, adverse drug reactions reported during post-marketing surveillance are whose frequency cannot be estimated from the available data, such as spontaneous reports, have been listed at frequency 'unknown'. The most commonly observed adverse events are gastrointestinal in nature.

Organ System      Very          Common          Uncommon      Rare           Very Rare      Frequency: Unknown Common        (≥1/100         (≥1/1,000     (≥1/10,000,    (<1/10,000)    (Post-marketing (≥ 1/10)      and <1/10)      and <1/100)   and                           experience) <1/1,000)
Infections and                                                                             Aseptic meningitis1 infestations
Blood and                                       Thrombo-                                   Aplastic anaemia, lymphatic                                       cytopenia                                  agranulocytosis, system                                                                                     haemolytic anaemia, disorders                                                                                  leucopenia 
Immune system                                                 Anaphylac                    Hypersensitivity disorders                                                     tic reaction Metabolism                                                                                 Anorexia and nutrition disorders
Psychiatric                     Insomnia                                                   Psychotic reaction, disorders                                                                                  disorientation, depression, anxiety,
nightmares, mood change, irritability
Nervous system                  Headache,                                                  Convulsions, memory disorders                       dizziness                                                  disturbance, drowsiness, tremor, taste disturbance,
paraesthesia
Eyes disorders                                                                             Visual disturbances, blurred vision
Ear and                                                                                    Tinnitus labyrinth disorders
Cardiac                                                                                    Cardiac failure, disorders                                                                                  palpitations Vascular                                                                                   Shock, hypertension, disorders                                                                                  hypotension, vasculitis Respiratory,                                                                               Asthma, pneumonitis, thoracic and                                                                               dyspnoea mediastinal disorders
Gastrointestina   Abdominal     Gastritis,      Stomatitis                                  GI perforation 3, l disorders       pain,         vomiting,                                                   gastrointestinal diarrhoea2,   flatulence,                                                 bleeding 3, melaena, nausea,       eructation,                                                 haematemesis, colitis, dyspepsia     constipation,                                               Crohn's disease, peptic ulcer                                                oesophageal disorder, mouth ulceration,
glossitis, tongue odema, dry mouth
Hepato-biliary                  Alanine                       Hepatitis,     Hepatic        Hepatitis fulminant, disorders                       amino-                        jaundice       failure        blood bilirubin transferase                                                 increased increased,
aspartate aminotransfe rase increased


Skin and                      Erythema      Purpura,    Angio-                Toxic epidermal subcutaneous                  multiforme,   urticaria   edema                 necrolysis4, Stevens- tissue                        rash,                                           Johnson syndrome4, disorders                     pruritus                                        dermatitis exfoliative4, dermatitis bullous,
Henoch Schonlein purpura,
mucocutaneous rash,
rash vesicular,
photosensitivity reaction, alopecia,
urticaria
Renal and                                                                     Renal failure, acute urinary                                                                       renal failure, renal disorders                                                                     papillary necrosis, nephritis interstitial,
nephrotic syndrome,
proteinuria, haematuria
Pregnancy,                                                                    Intra-uterine death, puerperium                                                                    uterine rupture, and perinatal                                                                 incomplete abortion, conditions                                                                    premature baby, anaphylactoid syndrome of pregnancy, retained placenta or membranes,
uterine contractions abnormal
Reproductive                                Menorr-                           Uterine haemorrhage system and                                  hagia,
breast                                      metrorr- disorders                                   hagia,
vaginal haemo- rrhage,
postmeno- pausal haemorr- hage
Congenital,                                                                   Birth defects familial and genetic disorders
General                                                                       Oedema5, chest pain, disorders and                                                                 face oedema, fatigue, administration                                                                pyrexia, chills, site conditions                                                               inflammation 
Investigations                Blood                                           Decreased alkaline                                        haemoglobin phosphatase increased
Injury,                                                                       Uterine perforation poisoning and procedural complications
1
Symptoms of aseptic meningitis (stiff neck, headache, nausea, vomiting, fever or impaired consciousness) have been reported during treatment with NSAIDs. Patients suffering from autoimmune disease (e.g. lupus erythematosus, mixed connective tissue disorders) seem to be more susceptible.
2
Diarrhoea is usually mild to moderate and transient and can be minimised by taking Arthrotec 50 with food and by avoiding the use of predominantly magnesium-containing antacids.
3
GI perforation or bleeding can sometimes be fatal, particularly in the elderly (see section 4.4).
4
Serious skin reactions, some of them fatal, have been reported very rarely (see section 4.4).
5
Especially in patients with hypertension or impaired renal function (see section 4.4).

Given the lack of precise and/or reliable denominator and numerator figures, the spontaneous adverse event reporting system through which post marketing safety data are collected does not allow for a medically meaningful frequency of occurrence of any undesirable effects.

With regard to the relative frequency of reporting of adverse reactions during post marketing surveillance, the undesirable effects at the gastrointestinal level were those received most frequently by the MAH (approximately 45% of all case reports in the company safety database) followed by cutaneous/hypersensitivity-type reactions, which is in agreement with the known side effects profile of the NSAIDs drug class.

Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use).

Other adverse experiences reported occasionally or rarely with ARTHROTEC, diclofenac or other NSAIDs, or misoprostol are:

Body as a whole: Asthenia, death, fatigue, fever, infection, malaise, sepsis.

Cardiovascular system: Arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased CPK, increased LDH, myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis.

Central and peripheral nervous system: Coma, convulsions, dizziness, drowsiness, headache, hyperesthesia, hypertonia, hypoesthesia, insomnia, meningitis, migraine, neuralgia, paresthesia, somnolence, tremor, vertigo.

Digestive: Anorexia, appetite changes, constipation, dry mouth, dysphagia, enteritis, esophageal ulceration, esophagitis, eructation, gastritis, gastroesophageal reflux, GI bleeding, GI neoplasm benign, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, peptic ulcer, stomatitis and ulcerative stomatitis, tenesmus, vomiting.

Female reproductive disorders: Breast pain, dysmenorrhea, intermenstrual bleeding, leukorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.

Hemic and lymphatic system: Agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, epistaxis, hemolytic anemia, leukocytosis, leukopenia, lymphadenopathy, melena, pancytopenia, pulmonary embolism, purpura, rectal bleeding, thrombocythemia, thrombocytopenia.

Hypersensitivity: Angioedema, laryngeal/pharyngeal edema, urticaria.

Liver and biliary system: Abnormal hepatic function, bilirubinemia, hepatitis, jaundice, liver failure, pancreatitis.

Male reproductive disorders: Impotence, perineal pain.

Metabolic and nutritional: Alkaline phosphatase increased, BUN increased, dehydration, glycosuria,  gout,    hypercholesterolemia,    hyperglycemia, hyperuricemia, hypoglycemia, hyponatremia, periorbital edema, porphyria, weight changes.

Musculoskeletal system: Arthralgia, myalgia.

Psychiatric: Anxiety, concentration impaired, confusion, depression, disorientation, dream abnormalities, hallucinations, irritability, nervousness, paranoia, psychotic reaction.insomia 
Respiratory system: Asthma, coughing, dyspnea, hyperventilation, pneumonia, respiratory depression.

Skin and appendages: Acne, alopecia, bruising, eczema, erythema multiforme, exfoliative dermatitis, pemphigoid reaction, photosensitivity, pruritus, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, sweating increased, toxic epidermal necrolysis, purpura.

Special senses: Hearing impairment, taste loss, taste perversion, tinnitus.

Urinary system: Cystitis, dysuria, hematuria, interstitial nephritis, micturition frequency, nocturia, nephrotic syndrome, oliguria/polyuria, papillary necrosis, proteinuria, renal failure, urinary tract infection.

Vision: Amblyopia, blurred vision, conjunctivitis, diplopia, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal.