Hydroxyurea medac

/ Tzamal

Therapy should only be conducted by a physician experienced in oncology or haematology. Doses are based on real or ideal bodyweight of the patient, whichever is the less.
In CML hydroxycarbamide is usually given at an initial dose of 40 mg/kg daily dependent on the white cell count. The dose is reduced by 50 % (20 mg/kg daily) when the white cell count has dropped below 20 x 10^9/l. The dose is then adjusted individually to keep the white cell count at 5-10 x 10^9/l. The hydroxycarbamide dose should be reduced if white cell counts fall below 5 x 109/l, and increased if white cell counts > 10 x 10^9/l are observed.
If the white cell count falls below 2.5 x 10^9/l, or the platelet count below 100 x 10^9/l, therapy should be interrupted until the counts rise significantly towards normal.
An adequate trial period for determining the antineoplastic effect of Hydroxycarbamide is six weeks. Therapy should be interrupted indefinitely if there is significant progress of the disease. If there is significant clinical response therapy may be continued indefinitely.
In essential thrombocythaemia, hydroxycarbamide is usually given at starting doses of 15 mg/kg/day with dose adjustment to maintain a platelet count below 600 x 10^9/l without lowering the white blood cell count below 4 x 10^9/l.
In polycythaemia vera, hydroxycarbamide should be started at a dose of 15-20 mg/kg/day. The  hydroxycarbamide dose should be adjusted individually to maintain the haematocrit below 45 % and platelet count below 400 x 109/l. In most patients this can be achieved with hydroxycarbamide given continuously at average daily doses of 500 to 1,000 mg.
If haematocrit and platelet count can be sufficiently controlled therapy may be continued indefinitely.
Elderly
Elderly patients may be more sensitive to the effects of hydroxycarbamide, and may require a lower dose regimen.

Treatment of patients with chronic myeloid leukaemia (CML) in the chronic or accelerated phase of the disease.
Treatment of patients with essential thrombocythaemia or polycythaemia vera with a high risk for thromboembolic complications.

* Hypersensitivity to the active substance or to any of the excipients
* Severe bone marrow depression, leukocytopenia (< 2.5 x 10^9 leukocytes/l), thrombocytopenia (< 100 x 10^9 platelets/l) or severe anaemia.

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 10^9/l, or the platelet count below 100 x 10^9/l, therapy should be interrupted until the counts rise significantly towards normal .
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 Hydroxycarbamide 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.
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.
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.
Interference with Continuous Glucose Monitoring Systems
Hydroxycarbamide may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems which may lead to hypoglycaemia if sensor glucose results are relied upon to dose insulin.
If CGM systems are to be used concurrently with hydroxycarbamide treatment, consult with the CGM prescriber about the need to consider alternative glucose monitoring methods.
Reverse transcriptase inhibitors
The combination of hydroxycarbamide and nucleoside reverse transcriptase inhibitors (NRTI) may enhance the risk of side effects of NRTI.
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.
Hydroxycarbamide should not be administered to patients who are pregnant or to mothers who are breast-feeding, unless the benefits outweigh the possible hazards.
Vaccinations
Concomitant use of Hydroxycarbamide 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 Hydroxycarbamide  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 prescribing information for full details.

Common: Skin cancer (squamous cell cancer, basal cell carcinoma), megaloblastosis, hallucinations, disorientation, peripheral neuropathy, somnolence, neurological disturbances including headache, dizziness, convulsion, pulmonary fibrosis, pulmonary oedema, acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnoea, hepatotoxicity1, hepatic enzyme increased, cholestasis, hepatitis.
Very common: bone marrow depression, CD4 lymphocytes decreased, leukocytopenia, anaemia, thrombocytopenia, anorexia, pancreatitis1, nausea, vomiting, diarrhoea, constipation, stomatitis, mucositis, stomach discomfort, dyspepsia, abdominal pain, melaena, 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), dysuria, transient renal tubular dysfunction accompanied by increased blood uric acid, increased blood urea and increased blood creatinine, azoospermia, oligospermia, drug fever, asthenia, chills, malaise.
See prescribing information for full details.

Hydroxycarbamide should be given with caution to patients with previous or concomitant radiotherapy or cytotoxic therapy. In these cases the patients have an increased risk to develop bone marrow depression, gastric irritation and mucositis (more severe, higher frequency). Furthermore, an exacerbation of erythema caused by previous or simultaneous irradiation may occur.
In-vitro studies have demonstrated hydroxycarbamide’s ability to enhance the cytotoxicity of both ara-C and fluoropyrimidines.
Hydroxycarbamide may enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors like didanosine and stavudine. Hydroxycarbamide inhibits HIV DNA synthesis and HIV replication by decreasing the amount of intracellular deoxynucleotides. Patients treated with hydroxycarbamide in combination with didanosine, stavudine, and indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3. Hydroxycarbamide may also enhance potential side effects of nucleoside reverse transcriptase inhibitors such as hepatotoxicity, pancreatitis and peripheral neuropathy.
Vaccinations
There is an increased risk of severe or fatal infections with the concomitant use of live vaccines. Live vaccines are not recommended in immunosuppressed patients.

Contraception in males and females
Due to the genotoxic potential of hydroxycarbamide, women of childbearing potential should use effective contraceptive measures while being treated with hydroxycarbamide and for 6 months following completion of treatment.
Men are recommended to use effective contraceptive measures and to not father a child while receiving hydroxycarbamide and for 3 months following completion of treatment.
Pregnancy
Hydroxycarbamide may be a potent mutagenic agent. Hydroxycarbamide should not be used during pregnancy unless the clinical condition of the woman requires treatment with hydroxycarbamide.
If pregnancy still occurs during treatment the possibility of genetic consultation should be offered. Hydroxycarbamide crosses the placenta.
Lactation: Hydroxycarbamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydroxycarbamide, a decision should be made whether to discontinue nursing or to discontinue Hydroxycarbamide, taking into account the importance of the drug to the mother.

Acute mucocutaneous symptoms have been observed in patients receiving hydroxycarbamide doses several times the recommended dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hands and feet, severe generalised hyperpigmentation of the skin and stomatitis have also been observed.
Immediate treatment consists of gastric lavage, followed by supportive care and monitoring of the haematopoietic system.