Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Adverse reactions are listed in the Table in CIOMS frequency categories under MedDRA system/organ classes.
The frequency of adverse reactions is defined using the following convention: Common: (≥1/100 to <1/10)
Uncommon: (≥1/1,000 to <1/100)
Rare: (≥1/10,000 to <1/1,000)
Very Rare: (<1/10,000)
Not known (cannot be estimated from the available data)

MedDRA system organ class        Adverse Drug Reaction
Infections and infestations
Very rare                        Oral and anogenital candidiasis, vulvovaginitis.
Blood and lymphatic system disorders
Rare                             Eosinophilia, leucopenia, neutropenia, thrombocytopenia
Very rare                        Haemolytic anaemia, pancytopenia.
Not known                        Agranulocytosis
Immune system disorders
Rare                             Anaphylaxis/anaphylactoid reaction (including shock and fatalities).
Not known                        Hypersensitivity, pulmonary infiltrates, anaphylactoid purpura, polyarteritis nodosa.
Endocrine disorders
Very rare                        Abnormal thyroid function, brown-black discolouration of the thyroid.
Metabolism and nutrition disorders
Rare                             Anorexia.
Nervous system disorders
Common                           Dizziness (lightheadedness).
Rare                             Headache, hypaesthesia, paraesthesia, intracranial hypertension, vertigo.
Very rare                        Bulging fontanelle.
Not known                        Convulsions, sedation.
Ear and labyrinth disorders
Rare                             Impaired hearing, tinnitus.
Cardiac disorders
Rare                             Myocarditis, pericarditis.
Respiratory, thoracic and mediastinal disorders
Rare                             Cough, dyspnoea.
Very rare                        Bronchospasm, exacerbation of asthma, pulmonary eosinophilia.
Not known                        Pneumonitis.
Gastrointestinal disorders

Rare                             Diarrhoea, nausea, stomatitis, discolouration of teeth, vomiting.
Very rare                        Dyspepsia, dysphagia, enamel hypoplasia, enterocolitis, oesophagitis, oesophageal ulceration, glossitis, pancreatitis,
pseudomembranous colitis.
Hepatobiliary disorders
Rare                             Increased liver enzymes, hepatitis, autoimmune hepatoxicity. (See Section 4.4).
Very rare                        Hepatic cholestatis, hepatic failure (including fatalities), hyperbilirubinaemia, jaundice.
Not known                        *Autoimmune hepatitis
Skin and subcutaneous tissue disorders
Rare                             Alopecia, erythema multiforme, erythema nodosum, fixed drug eruption, hyperpigmentation of skin, photosensitivity, pruritis, rash, urticaria,
vasculitis.
Very rare                        Angioedema, exfoliative dermatitis, hyperpigmentation of nails, Stevens-Johnson
Syndrome, toxic epidermal necrolysis.
Not known                        Drug rash with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Rare                             Arthralgia, lupus-like syndrome, myalgia.
Very rare                        Arthritis, bone discolouration, cases of or exacerbation of systemic lupus erythematosus
(SLE)(See Section 4.4), joint stiffness, joint swelling.
Renal and urinary disorders
Rare                             Increased serum urea, acute renal failure, interstitial nephritis.
Reproductive system and breast disorders
Very rare                        Balanitis.
General disorders and administration site conditions
Uncommon                         Fever
Very rare                        Discolouration of secretions.

* Autoimmune hepatitis: See Section 4.4.


The following syndromes have been reported. In some cases involving these syndromes, death has been reported. As with other serious adverse reactions, if any of these syndromes are recognised, the drug should be discontinued immediately:
• Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present.
• Lupus-like syndrome consisting of positive antinuclear antibody, arthralgia, arthritis, joint stiffness or joint swelling, and one or more of the following: fever, myalgia, hepatitis, rash, vasculitis.
• Serum sickness-like syndrome consisting of fever, urticaria or rash, and arthralgia, arthritis, joint stiffness or joint swelling. Eosinophilia may be present.

Hyperpigmentation of various body sites including the skin, nails, teeth, oral mucosa, bones, thyroid, eyes (including sclera and conjunctiva), breast milk, lacrimal secretions and perspiration has been reported. This blue/black/grey or muddy-brown discolouration may be localised or diffuse. The most frequently reported site is in the skin. Pigmentation is often reversible on discontinuation of the drug, although it may take several months or may persist in some cases. The generalised muddy-brown skin pigmentation may persist, particularly in areas exposed to the sun.

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/