Adverse reactions : תופעות לוואי

4.8 Undesirable effects

• Blood and lymphatic disorders:
Blood dyscrasias (such as thrombocytopenia, neutropenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia), bone marrow depression, petechiae, ecchymoses, purpura, and disseminated intravascular coagulation may occur infrequently. As some patients manifest anaemia secondary to obvious or occult gastro-intestinal bleeding, appropriate blood determinations are recommended.

• Immune system disorders:
Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, rhinitis or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis, erythema multiforme).

• Metabolic and nutrition disorders:
Hyperglycaemia, glycosuria, hyperkalaemia has been reported rarely.

• Nervous system disorders:
Visual disturbances, optic neuritis, tinnitus, headaches, dizziness and lightheadedness are common side effects. Starting therapy with a low dose and increasing gradually minimises the incidence of headache. These symptoms frequently disappear on continued therapy or reducing the dosage, but if headache persists despite dosage reduction, indomethacin should be withdrawn. Other CNS effects include reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus or mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4), depression, vertigo, fatigue , malaise, dysarthia, syncope, coma, cerebral oedema, nervousness, confusion, anxiety and other psychiatric disturbances, depersonalisation, hallucinations, drowsiness, convulsions and aggravation of epilepsy and Parkinsonism, peripheral neuropathy, paraesthesia, involuntary movements and insomnia. These effects are often transient and abate or disappear on reduced or stopping treatment. However, the severity of these may, on occasion, require cessation of the therapy.

• Eye disorders:
Visual disturbances, blurred vision, diplopia, optic neuritis and orbital and peri-orbital pain are seen infrequently. Corneal deposits and retinal or macular disturbances have been reported in some patients with rheumatoid arthritis on prolonged therapy with Indovis. Ophthalmic examinations are desirable in patients given prolonged treatment.

• Ear and labyrinth disorders:
Tinnitus or hearing disturbances (rarely deafness) have been reported.

• Cardiac Disorders:
There have been reports of oedema, hypertension, hypotension, tachycardia, chest pain, arrhythmia, palpitations, syncope and cardiac failure.

•   Vascular disorders:
Flushing has been reported rarely.

• Respiratory, thoracic and mediastinal disorders:
Pulmonary eosinophilia. There may be bronchospasm in patients with a history of bronchial asthma or other allergic disease. Epistaxis has been reported rarely.

• Gastrointestinal disorders
The most commonly-observed adverse events are gastrointestinal in nature. Anorexia, epigastric discomfort, ulceration at any point in the gastro-intestinal tract (even with resultant stenosis and obstruction), bleeding (even without obvious ulceration or from a diverticulum) and perforation of pre-existing sigmoid lesions (such as diverticulum or carcinoma), increased abdominal pain or exacerbation of the condition in patients with ulcerative colitis or Crohns disease (or the development of this condition), intestinal strictures and regional ileitis have been rarely reported.
Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). If gastro-intestinal bleeding does occur treatment with Indovis should be discontinued.
Gastrointestinal disorders which occur can be reduced by giving Indovis with food, milk or antacids. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis exacerbation of colitis and Crohn’s disease (See section 4.4) have been reported following administration.
Less frequently, gastritis, duodenal ulcer, gastric ulcer and gastrointestinal perforation have been observed. Pancreatitis has been reported very rarely.

• Hepato-biliary disorders:
Cholestasis, borderline elevations of one or more liver tests may occur, and significant elevations of ALT (SGPT) or AST (SGOT) have been seen in less than 1% of patients receiving therapy with NSAIDs in controlled clinical trials. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations such as rash or eosinophilia occur, Indovis should be stopped. Abnormal liver function, hepatitis and jaundice.

• Skin and subcutaneous tissue disorders:
Pruritus, urticaria, angioneurotic oedema, angiitis, erythema nodosum, skin rash and photosensitivity, exfoliative dermatitis, Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (very rare).
Photosensitivity, erythema multiforme, hair loss, sweating and exacerbation of psoriasis.

• Musculo-skeletal, connective tissue and bone disorders:
Muscle weakness and acceleration of cartilage degeneration.

• Renal and urinary disorders:
Haematuria, nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure, renal insufficiency, proteinuria have all been reported. In patients with renal, cardiac or hepatic impairment, caution is required since the use of non-steroidal anti- inflammatory drugs may result in deterioration of renal function. The dose should be kept as low as possible and renal function should be monitored.

• Reproductive system and breast disorders:
Vaginal bleeding, breast changes (enlargement, tenderness, gynaecomastia) 
•   Clinical trial and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/