September 2, 2015
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Droxia

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Droxia




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 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 red blood cells (RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

Pharmacokinetics

Absorption

Following oral administration of DROXIA, 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.

Distribution

Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water.

Hydroxyurea concentrates in leukocytes and erythrocytes.

Metabolism

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.

Excretion

In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.

Specific Populations

Renal Impairment

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. Creatinine clearance values were obtained using 24-hour urine collections. 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 DROXIA when it is administered to patients with creatinine clearance of < 60 mL/min or with ESRD following hemodialysis [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

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) (see Table 2).

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.

Table 2: Results from the Multicenter Study of Hydroxyurea in Sickle Cell Anemia

Event Hydroxyurea
(N=152)
Placebo
(N=147)
Percent Change Versus Placebo P-value
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
* 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.

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.

Last reviewed on RxList: 8/6/2015
This monograph has been modified to include the generic and brand name in many instances.

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