Hydroxycarbamide (capsules 0.25 g)
Capsulae Hydroxycarbamidi 0.25
International Non-proprietary Name
Antineoplastic agents. Antimetabolites.
1 capsule contains 250 mg of hydroxycarbamide.
Mechanism of antineoplastic activity is associated with the ability of hydroxycarbamide to inhibit RNA-phosphate reductase — one of the main enzymes participating in DNA biosynthesis. The preparation rapidly interferes with DNA synthesis, not influencing protein and RNA synthesis, which leads to the cytotoxic effect.
Hydroxycarbamide exhibits specific antineoplastic effect against quickly proliferating transformed cells and does not have pronounced cytotoxic activity against weakly proliferating or non proliferating normal cells.
Adequate period for the assessment of antineoplastic efficacy of the preparation is 6 weeks. The reduction of the tumour size or stopping of the tumor growth is indicative of the effect of the preparation.
Following oral administration hydroxycarbamide is well absorbed from the gastrointestinal tract and immediately penetrates into tissues. It crosses blood-brain barrier. Maximum blood plasma concentration (Cmax) is reached within 2 h after administration of the preparation. After 24 h following administration plasma levels of the preparation reach zero. Elimination half-life (T1/2) is 3—4 h. It is metabolized in the liver with the formation of urea and other metabolites. Excreted predominantly by kidneys. About 80% of the orally administered preparation at dosages of 7 - 30 mg/kg, is excreted with urine within 12 h after intake.
The preparation is intended for the treatment of acute and chronic myeloleukemia, recurrence of acute lymphoblastic leukemia in children, osteomyelofibrosis, erythremia, thrombocytosis during myeloproliferative disease, lymphogranuloma, melanoma, head tumor (with the exception of lips) and neck when radical surgery or radiotherapy is impossible, metastasis of breast and stomach cancer, colon cancer, prostate cancer, lung cancer, ovarian cancer, uterus trophoblastoma, cervical cancer (to increase the efficacy of radiotherapy).
Administration and dosing regimen
The preparation is administered orally before meals. On the request of the patient, or in case of difficulties with swallowing the contents of the capsule can be transferred into a glass of water, which should be drunk immediately not waiting for complete dissolution. Usually the therapy is conducted in cycles. There are two main regimes of administration - intermittent (80 mg/kg once every three days), which is usually used in combined treatment of solid tumors (in conjunction with radiotherapy) and has some advantages regarding the decrease of toxicity of the preparation; and – continuous (daily administration of the preparation at a dosage of 20-30 mg/kg). Recommended treatment schemes for continuous regime: in myelosis and thrombocytosis – initial dose is 20-40 mg/kg/daily, then -10-30 mg/kg, for exacerbation – 25-60 mg/kg; in myelofibrosis – initial dose is 20 mg/kg, maintenance – 10 mg/kg; in erythremia: exacerbation - 15-20 mg/kg, maintenance dose - 10 mg/kg; cancer and melanocarcinoma - 20-30 mg/kg/daily.
The adequate period for the assessment of antineoplastic efficacy of the preparation is 4-6 weeks. The presence of the effect is indicated by the reduction of the tumour size or cessation of the tumor growth; in that case the therapy should be continued indefinitely, till the appearance of the signs of intramedullary hemopoiesis suppression (leucopenia (less than 2500 cells/mm3), thrombocytopenia (less than 100000 cells/mm3),marked anemia).
Usually therapy is conducted in cycles.
Doses of the preparation, frequency of the administration and duration of a treatment cycle should be determined by the doctor individually, in accordance with the indications and the patient's state.
There are two main regimens of administration: intermittent and continuous.
During intermittent regimen the preparation should be administered in a dosage of 80 mg/kg once every three days. Mentioned regimen is often used in combined treatment of solid tumors (in conjunction with radiotherapy).
During continuous regimen the preparation is administered daily at a dosage of 20—30 mg/kg. Recommended treatment schemes for continuous regimen are as follows: in myelosis and thrombocytosis the initial dose is 20-40 mg/kg/daily, then -10-30 mg/kg, for exacerbation the dose should be increased up to 25-60 mg/kg; in myelofibrosis the initial dose is 20 mg/kg daily, maintenance – 10 mg/kg; in erythremia: during exacerbation the dose is 15-20 mg/kg daily, maintenance dose - 10 mg/kg; in cancer and melanocarcinoma the preparation should be administered in a dose of 20-30 mg/kg/daily.
In case of anemia it should be treated without the interrupting of treatment cycle with hydroxycarbamide, with the help of substituting transfusions of packed red cells.
Combination with radiotherapy can lead to the enhancement of side effects, which are associated with myelosuppression, damage of stomach mucosa.
During treatment the following can occur: anemia, thrombocytopenia, leucopenia, dyspeptic disorders, stomatitis, pyrexia, headaches, dizziness, disorientation, hallucinations, interstitial nephritis, hyperuricemia, increase of serum transaminase levels, alopecia, face erythema, maculopapular rash. In rare cases diffusive infiltrative lung damage and allergic skin reactions.
Hydroxycarbamide is contraindicated in the following: hypersensitivity, acute renal and hepatic insufficiency, thrombocytopenia (less than 100,000 cells/mm3), leucopenia (less than 2500 cells/mm3), profound anemia, pregnancy, lactation.
Caution must be exercised when prescribing hydroxycarbamide to elderly patients and children (dose reduction is required), as well as to patients previously treated with radiotherapy or cytostatic agents. Before treatment initiation correction of profound anemia should be considered (whole blood transfusion). During the treatment it is necessary to control blood picture (not less than once a month). In case of the decrease of leucocyte count below 2500 cells/mm3 and platelets below 100000 cells/mm3 the treatment cycle should be interrupted until clear trend to the of normalization haematological parameters is observed. It is also recommended to carry out dynamic monitoring of urinary acid, creatinine, transaminase levels; when creatinine clearance is below
10 ml/min the dose should be decreased 2-fold. During treatment the patients should be adequately hydrated.
Interactions with other drugs
Hydroxycarbamide enhances effects of cytarabine and decreases the activity of 5-fluorouracil and methotrexate. It increases (mutually) myelotoxicity of the preparation that inhibits bone marrow function. When used concomitantly with uricosuric agents the risk of nephropathy is increased. In conjunction with antidepressants, antihistaminic, sedative, hypnotic, narcotic preparations and alcohol hydroxycarbamide enhance the suppression of reactions rate.
Capsules 250 mg. 16 or 20 capsules in jars of fluid glass; 10 capsules in blisters.