Source: FDA, National Drug Code (US) Revision Year: 2024
The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.
Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration.
Following oral administration of HYDREA, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose.
There are no data on the effect of food on the absorption of hydroxyurea.
Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water.
Hydroxyurea concentrates in leukocytes and erythrocytes.
Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria.
In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.
The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell disease and renal impairment. Patients with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50‑80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. Patients with ESRD received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. The exposure to hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with ESRD was 64% higher than in patients with normal renal function (CrCl >60 mL/min). Reduce the dose of HYDREA when it is administered to patients with creatinine clearance of <60 mL/min or with ESRD following hemodialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].
Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m² basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype.
Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m² basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.
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