Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Bone marrow depression is the dose limiting toxicity. Gastrointestinal side effects are common but rarely require dose reduction or cessation of treatment.

The frequencies of adverse events are categorised using the following convention: Very common (≥ 1/10), 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).

Infections and Infestations      Rare
Gangrene

Neoplasms Benign and             Common
Malignant(including cysts        Skin Cancer (squamous cell cancer, basal cell carcinoma) and polyps)

Blood and lymphatic system       Very common disorders                        Bone marrow depression, CD4 lymphocytes decreased, leukocytopenia, anaemia,thrombocytopenia

Common
Megaloblastosis

Not known
Haemolytic anaemia
Immune system disorders          Rare
Hypersensitivity reaction

Metabolism and nutrition         Very common disorders                        Anorexia

Rare
Tumour lysis syndrome
Not known
Hyperkalaemia

Psychiatric disorders            Common
Hallucinations, disorientation
Nervous system disorders       Common
Peripheral neuropathy1, somnolence, neurological disturbances including headache, dizziness and convulsion

Respiratory, thoracic and      Common mediastinal disorders          Pulmonary fibrosis, pulmonary oedema, acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnoea

Not known
Interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis, cough

Gastrointestinal disorders     Very common
Pancreatitis1, nausea, vomiting, diarrhoea, constipation,
stomatitis, mucositis, stomach discomfort, dyspepsia,
abdominal pain, melaena
Hepatobiliary disorders        Common
Hepatotoxicity1, hepatic enzyme increased, cholestasis,
hepatitis

Uncommon
Blood bilirubin increased

Skin and subcutaneous tissue Very common disorders                    Skin ulcers (especially leg ulcers), cutaneous vasculitis, pruritus, violet papules, dermatomyositis-like skin changes,
alopecia, maculopapular rash, skin exfoliation, skin atrophy,
erythema (e.g. facial erythema, acral erythema), skin hyperpigmentation, nail disorder (e.g. nail pigmentation, nail atrophy)

Uncommon
Actinic keratosis

Very rare
Systemic and cutaneous lupus erythematosus
Not known
Dry skin

Renal and urinary disorders    Very common
Dysuria, transient renal tubular dysfunction accompanied by increased blood uric acid, increased blood urea and increased blood creatinine

Very rare
Renal impairment
Reproductive system and        Very common breast disorders               Azoospermia, oligospermia

General disorders and          Very common administration site            Drug fever, asthenia, chills, malaise conditions
1
Fatal and non-fatal pancreatitis and hepatotoxicity and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxycarbamide in combination with antiretroviral agents, in particular didanosine plus stavudine.
Neoplasms benign, malignant and unspecified (incl. cysts and polyps) 
In patients receiving long-term treatment with hydroxycarbamide for myeloproliferative disorders such as polycythaemia vera and thrombocythaemia, secondary leukaemia may develop. To what extent this relates to the underlying disease or to treatment with hydroxycarbamide is presently unknown.

Blood and lymphatic system disorders

During hydroxycarbamide therapy megaloblastosis may occur which does not respond to treatment with folic acid or B12.
Bone-marrow suppression subsides, however, when therapy is discontinued.
Hydroxycarbamide can reduce plasma iron clearance and iron utilisation by erythrocytes. However, it does not appear to alter the red blood cell survival time.

Immune system disorders

Hypersensitive reactions: High fever (>39°C) requiring hospitalisation in some cases has been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular manifestations. Onset typically occurred within 6 weeks of initiation and resolved promptly after discontinuation of hydroxycarbamide. Upon readministration fever re-occurred within 24 hours.

Metabolism and nutrition disorders

Cases of hyponatraemia have been observed during post-marketing surveillance.
Gastrointestinal disorders

Severe gastric distress (nausea, emesis, anorexia) resulting from combined hydroxycarbamide and irradiation therapy may usually be controlled by temporarily discontinuing hydroxycarbamide administration.

Skin and subcutaneous tissue disorders

Hydroxycarbamide may aggravate the inflammation of mucous membranes secondary to irradiation. It can cause a recall of erythema and hyperpigmentation in previously irradiated tissues.
Erythema, atrophy of skin and nails, skin exfoliation, violet papules, alopecia, dermatomyositis-like skin changes, actinic keratosis, cutaneous ulcers (especially leg ulcers), cutaneous vasculitis, pruritus, hyperpigmentation of skin and nails, and dry skin have been observed partly after years of long-term daily maintenance therapy with hydroxycarbamide.

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/ In addition, you may report by sending an e-mail message to: safety@tzamal-medical.co.il