Hydroxyurea in the Treatment: PREVENTION

In: Disease

2 Jun 2010

Genetic counseling is recommended for all known carriers of the sickle cell trait. Prenatal diagnosis of sickle cell anemia is also available. Prompt treatment of infections, adequate oxygena-tion, avoidance of extreme temperatures, and prevention of dehydration may prevent sickling of the RBCs in these patients.

Children of carriers should receive prophylactic penicillin from birth until they are six years of age. The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommends the 7-valent pneumococcal polysaccharide-protein conjugate vaccine for children with sickle cell disease from 24 to 59 months of age.
General health visits with a physician are recommended to ensure that patients are getting adequate nutrition, receiving scheduled vaccinations, and maintaining proper activity levels.


Treatment of sickle cell disease usually focuses on alleviating the symptoms. Although bone marrow transplantation can be curative, it is indicated for only a minority of patients because of the difficulty in finding suitable donors and the high risk of the procedure. Folic acid supplementation is required for all patients because of the rapid RBC turnover, and antibiotics and vaccines are given to children to prevent common bacterial infections. Acute painful crises are treated with analgesics and adequate liquid intake. Non-narcotic medications may be effective, but narcotics are sometimes required.

Therapy has been effective in preventing complications in sickle cell disease, reducing the need for transfusions, decreasing pain, and reducing the need for hospitalization. Hydroxy-urea was previously approved by the Food and Drug Administration as a therapy for certain kinds of leukemia and other cancers. The doses that are approved for use in sickle cell crises are lower than those used in the treatment of cancer.


Hydroxyurea is an orally administered, tasteless, white crystalline powder. It is approved for use in patients 18 years of age and over who have had at least three painful crises in the previous year.

The main side effect is a decrease in blood counts, particularly of the white blood cells (neutropenia) and platelets (thrombocytopenia). The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known, although several studies suggest that it 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.

Some of the known pharmacological effects of hydroxyurea that might contribute to its beneficial effects in sickle cell disease include:
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  • increasing fetal hemoglobin (hemoglobin F) levels in RBCs (thus preventing the formation of hemoglobin S polymers)
  • decreasing the number of neutrophils
  • increasing the water content of RBCs
  • increasing the deformability of sickled cells
  • altering the adhesion of RBCs to the endothelium

The product is available in 200-, 300-, and 400-mg capsules.


Hydroxyurea is readily absorbed after oral administration, and peak plasma levels are reached in one to four hours. With increasing doses, disproportionately greater mean peak plasma concentrations and area-under-the-curve (AUC)


A large-scale, double-blind, randomized, placebo-controlled clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), assessed the efficacy of hydroxyurea in 299 adults with moderate to severe disease. The investigators evaluated the severity of disease according to the number of painful crises experienced by patients in a year (all patients experienced three or more painful crises per year). A painful crisis was defined as acute sickling-related aching that resulted in a visit to a medical facility, lasted more than four hours, and required treatment with a parenteral narcotic or a nonsteroidal anti-inflammatory drug (NSAID). Priapism, acute chest syndrome, and hepatic sequestration were also included in this definintion.

Compared with patients receiving placebo, patients taking hydroxyurea showed (1) a significant decrease in the yearly rate of painful crises, including those requiring hospitalization; (2) a reduced incidence of acute chest syndrome; and (3) a decrease in the number of units needed for blood transfusions.
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Hydroxyurea treatment significantly increased the average time between the first and second painful crises. Most of the benefits in crisis reduction were seen in the patients with six or more painful crises during the preceding 12 months, although patients with three or more painful crises during the preceding year were eligible for the study (Table 1).

Table 1   Hydroxyurea in Sickle Cell Anemia: Multicenter Study Results

Hydroxyurea Placebo   Change vs. Placebo
Event (N = 152) (N = 147)

P Value

P Value

Median yearly rate of painful crises 2.5 4.6



Median yearly rate of painful crises requiring hospitalization 1.0 2.5



Median time to first painful crisis (months) 2.76 1.35

+ 104


Median time to second painful crisis (months) 6.58 4.13



Incidence of acute chest syndrome (number of episodes) 56 101



Number of patients receiving transfusions 55 79



Number of units of blood transfused 423 670



Data from (hydroxyurea) prescribing information. Bristol-Myers Squibb, March 2001.

In the MSH Patient Follow-up Study, conducted from 1996 to 2001, the objective was to determine whether hydroxy-urea reduced mortality in patients with sickle cell anemia. During the follow-up, patients could continue, stop, or start hydroxyurea. Complete data were available for 233 of 299 patients from the original MSH study.

Of the original 299 patients, 75 died. Pulmonary disease accounted for 28% of the deaths. In patients with reticulocyte counts below 250,000/mm3 and hemoglobin levels lower than 9 g/dl, mortality rates were increased (P = .002). The cumulative mortality rate, at nine years, was 28% when hemoglobin F levels were lower than 0.5 g/dl, and 15% when hemoglobin F levels were 0.5 g/dl or higher (P = .03).

During the trial, the mortality rate for patients with acute chestsyndrome was 32%; for patients without the syndrome, it was 18% (P = .02). For patients with three or more painful episodes per year, the mortality rate was 27%; for patients with fewer episodes, the rate was 17% (P = .06).
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Hydroxyurea therapy was associated with an overall 40% reduction in mortality (P = .04) in this observational follow-up with self-selected treatment. Three patients had cancer, and one of them died.

The main contributing factors to the survival of the sickle cell patients in the follow-up study were increased hemoglobin F levels and a reduction in the number of painful crises. It is believed that hydroxyurea works, at least in part, by restarting the production of hemoglobin F in adults with sickle cell anemia. In these affected individuals, having more hemoglobin F is very beneficial because that version of the hemoglobin molecule is not affected by the problematic mutation. Hemoglobin F can function as the protein in the RBCs that enables them to carry oxygen throughout the body.

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