CLINICAL PHARMACOLOGY
Mechanism of Action
The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support 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.
The mechanisms by which DROXIA (hydroxyurea capsules, USP) produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.
Pharmacokinetics
Absorption
Hydroxyurea is readily absorbed after oral administration. 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
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
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
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 dose.
Special Populations
Geriatric, Gender, Race
No information is available regarding pharmacokinetic differences due to age, gender or race.
Pediatric
No pharmacokinetic data are available in pediatric patients treated with hydroxyurea for SCA.
Renal Insufficiency
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study 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 hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (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. In this study the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) The table below describes the recommended dosage modification.
| *On dialysis days, hydroxyurea should be administered to patients with ESRD following hemodialysis. |
Creatinine Clearance
(mL/min) | Recommended DROXIA Initial Dose
(mg/kg daily) |
| ≥60 | 15 |
<60 or
ESRD* | 7.5 |
Close monitoring of hematologic parameters is advised in these patients.
Hepatic Insufficiency
There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
Drug Interactions
There are no data on concomitant use of hydroxyurea with other drugs in humans.
Clinical Studies
The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia).1
The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea.
Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises.
Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months.
EVENT | HYDROXYUREA
(N=152) | PLACEBO
(N=147) | PERCENT CHANGE
VS PLACEBO |
P-VALUE |
|---|
| * A painful crisis was defined in the study as acute sickling-related pain that resulted in a visit to a medical facility, that lasted more than 4 hours, and that required treatment with a parenteral narcotic or NSAID. Chest syndrome, priapism, and hepatic sequestration were also included in this definition. |
| Median yearly rate of painful crises* | 2.5 | 4.6 | -46 | =0.001 |
| Median yearly rate of painful crises requiring hospitalization | 1.0 | 2.5 | -60 | =0.0027 |
| Median time to first painful crisis (months) | 2.76 | 1.35 | +104 | =0.014 |
| Median time to second painful crisis (months) | 6.58 | 4.13 | +59 | =0.0024 |
| Incidence of chest syndrome (# episodes) | 56 | 101 | -45 | =0.003 |
| Number of patients transfused | 55 | 79 | -30 | =0.002 |
| Number of units of blood transfused | 423 | 670 | -37 | =0.003 |
No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo-treated patients. (See ADVERSE REACTIONS.)
Fetal Hemoglobin
In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages.
A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency.
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