Hydroxyurea Mechanism

2.15. DRUG DESRIPTION 38

2.15.1 General Pharmacology of Hydroxyurea Hydroxyurea is an antineoplastic agent available for oral use as capsules providing 500 mg hydroxyurea. Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is as stated below

2.15.2 Mechanism of Action of Hydroxyurea The mechanisms by which hydroxyurea produces its beneficial effects in patients with SCA are uncertain. The main effects of hydroxyurea that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, it suppresses the bone marrow and decreases neutrophils, it also increasing the water content of RBCs, it increase deformability of sickled cells, and altering the adhesion

Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea.

Distribution 36

Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.

Metabolism 37

Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion 38

Excretion of hydroxyurea in humans is likely a linear first-order renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea was about 40% of the administered

Hydroxyurea also used in Resistant Chronic Myelocytic Leukemia

2.15.7 Adverse Effects of Hydroxyurea 39 Common adverse effects found with hydroxyurea are hematological, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. And Non-hematologic events that possibly are associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding, and parvovirus B-19 infection; however, these non- hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving hydroxyurea for SCA.

2.15.8 Warning and precautions for Hydroxyurea39 • Hydroxyurea should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm3 ; a platelet count below 80,000/mm3 ; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3 when the hemoglobin concentration is below 9