Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Haematological toxicities
Hydroxycarbamide can cause bone marrow depression with leukopenia as the first and most commonly occurring sign. Thrombocytopenia and anaemia occur less frequently and are rare without preceding leukopenia. Complete blood counts including determination of haemoglobin level, total leukocyte differentiation counts, and platelet counts should be performed regularly also after the individual optimal dose has been established. The control interval should be individualised, but is normally once a week. If the white cell count falls below 2.5 x 109/l, or the platelet count below 100 x 109/l, therapy should be interrupted until the counts rise significantly towards normal (see section 4.2).

In case of anaemia before or during ongoing treatment red blood cells may be replaced when needed.
Megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of hydroxycarbamide therapy. The morphologic change resembles pernicious anaemia, but is not related to vitamin B12 or folic acid deficiency. Cases of haemolytic anaemia in patients treated with hydroxycarbamide for myeloproliferative diseases have been reported. Patients who develop severe anaemia should have laboratory tests evaluated for haemolysis. If diagnosis of haemolytic anaemia is established, hydroxycarbamide should be discontinued.

Monitoring during therapy

During therapy with Hydroxyurea medac frequent monitoring of blood counts should be conducted as well as monitoring of hepatic and renal function. Experience is limited in patients with impaired renal and/or liver function. Therefore, special care should be taken in the treatment of these patients, especially at the beginning of therapy.

Secondary leukaemia

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.
Skin cancer

Skin cancer has been reported in patients receiving long-term hydroxycarbamide. Patients should be advised to protect skin from sun exposure. In addition, patients should conduct self-inspection of the skin during the treatment and after discontinuation of the therapy with hydroxycarbamide and be screened for secondary malignancies during routine follow-up visits.

Leg ulcers

Hydroxycarbamide can induce painful leg ulcers which are usually difficult to treat and require cessation of therapy. Discontinuation of hydroxycarbamide usually leads to slow resolution of the ulcers over some weeks.

Vasculitic toxicities

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued if cutaneous vasculitic ulcerations develop and treatment with alternative cytoreductive medicinal products should be initiated as indicated.

Interstitial lung disease

Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis have been reported in patients treated for myeloproliferative neoplasm and may be associated with fatal outcome. Patient developing pyrexia, cough, dyspnoea or other respiratory symptoms should be closely monitored, investigated and treated. Promptly discontinue of hydroxyurea and treatment with corticosteroids appears to be associated with resolution of the pulmonary events (see section 4.8).

Serum uric acid increase

The possibility of an increase in serum uric acid, resulting in the development of gout or, at worst, uric acid nephropathy, should be borne in mind in patients treated with hydroxycarbamide, especially when used with other cytotoxic agents. It is therefore important to monitor uric acid levels regularly.
Patients should be instructed to drink abundantly.

Interference with laboratory tests

A published study has shown increases of laboratory values of urea, uric acid (5 – 9 %) and lactic acid (6 – 11 %) measured by in vitro enzymatic assays, in the presence of hydroxycarbamide (0.1 – 1 mM), indicating an analytical interference. The clinical relevance of these results is unknown.

Reverse transcriptase inhibitors

The combination of hydroxycarbamide and nucleoside reverse transcriptase inhibitors (NRTI) may enhance the risk of side effects of NRTI, see also section 4.5.

Fertility

Hydroxycarbamide may be genotoxic. Therefore, women of childbearing potential should use effective contraceptive measures while being treated with hydroxycarbamide and for 6 months following completion of treatment. Men under therapy are advised to use safe contraceptive measures during and for 3 months after therapy. They should be informed about the possibility of sperm conservation before the start of therapy.

Hydroxyurea medac should not be administered to patients who are pregnant or to mothers who are breast-feeding, unless the benefits outweigh the possible hazards (see section 4.6).
Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.

Vaccinations

Concomitant use of Hydroxyurea medac with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase some of the adverse reactions of the vaccine virus because normal defence mechanisms may be suppressed by hydroxycarbamide. Vaccination with a live vaccine in a patient taking Hydroxyurea medac may result in severe infection. The patient’s antibody response to vaccines may be decreased. The use of live vaccines should be avoided during treatment and for at least six months after treatment has finished and individual specialist advice has been sought (see section 4.5).

Effects on Driving

4.7    Effects on ability to drive and use machines

The ability to react may be impaired during treatment with Hydroxyurea medac. This should be borne in mind when heightened attention is required, e.g. for driving and using machines.