Sickle Cell Disease (SCD)

Hydrea and Droxia are brand names for hydroxyurea, a myelosuppressive agent.^1-3 Hydroxyurea is indicated for the treatment of resistant chronic myeloid leukemia and locally advanced squamous cell carcinomas of the head and neck.¹ This drug has also been approved for reducing the frequency of pain crises in patients with sickle cell disease (SCD) and their need for blood transfusions.² 

In 1967, hydroxyurea was first approved by the US Food and Drug Administration as an antineoplastic agent.⁴ Since then, it has been used to treat myeloproliferative syndromes, such as leukemia, and melanoma.³ Later, in 1998, hydroxyurea was approved for the treatment of adults with severe sickle cell anemia (SCA).⁵ 

SCD is a rare genetic blood disorder characterized by the presence of sickled and stiff red blood cells (RBCs) with a shorter-than-normal lifetime. The altered shape and flexibility of the abnormal RBCs result in the development of acute and chronic anemia. Sickle-shaped RBCs also cause vaso-occlusion, disrupting vascular blood flow and compromising the functioning of vital organs.⁴

Mechanism of Action 

The precise mode of action of hydroxyurea that produces beneficial effects in patients with SCA is not completely described. Hydroxyurea is a recognized antimetabolite that in vivo inhibits the enzyme ribonuclease reductase (RR).⁴ RR converts ribonucleosides to deoxyribonucleosides. RR inhibition by hydroxyurea prevents the S phase of cell division, inhibiting DNA and causing cellular toxicity. Hydroxyurea inhibits hematopoiesis and alters erythroid kinetics, leading to the recruitment of erythroid progenitors and an increase in hemoglobin F (HbF). RBCs carrying HbF are relatively large and deformable.⁴ Hydroxyurea also reduces the number of neutrophils, increases the water content of RBCs, and decreases the surface expression of adhesion molecules that cause RBCs to adhere to vascular endothelium.⁴

Hydroxyurea is available as capsules for oral administration. The initial dose for patients with SCD is 15 mg/kg once a day. The blood cell count must be closely monitored. The dose can then be increased by 5 mg/kg per day every 12 weeks up to 35 mg/kg per day provided no toxic blood cell counts develop over 24 consecutive weeks.² After the oral administration of hydroxyurea, peak plasma levels occur in 1 to 4 hours. The drug is rapidly and widely distributed in the body, concentrating in leukocytes and RBCs.^2,3

Get full prescribing information for Hydrea and Droxia at MPR

Efficacy and Safety 

Clinical data on the use of hydroxyurea have been gathered for more than 25 years. A phase I/II clinical trial confirmed that increased levels of HbF could be observed in adult patients with hydroxyurea treatment.⁶ Subsequently, a double-blind, placebo-controlled, randomized phase III clinical trial, the MultiCenter Study of Hydroxyurea in Sickle Cell Anemia, was performed to evaluate the efficacy of hydroxyurea.⁷ This study enrolled 299 adult patients at least 18 years of age who had moderate to severe disease.² The trial was halted by the sponsor, the National Heart, Lung, and Blood Institute, because of the observed clinical efficacy of hydroxyurea in preventing vaso-occlusive events. The study also reported that hydroxyurea decreased the yearly rates of pain crises and the number of blood transfusions and hospitalizations.⁷

Other clinical trials have demonstrated the benefits of hydroxyurea as well as mild toxicity in pediatric patients.^8-10 The pediatric phase I/II trial HUG-KIDS revealed that the efficacy and toxicity of hydroxyurea in children were similar to those observed in adults.⁹

Side effects of hydroxyurea are typically mild and include headache and gastrointestinal issues such as nausea, vomiting, and diarrhea.² Reversible myelosuppression in the most common short-term side effect observed in patients with SCA.³ Hydroxyurea is a human carcinogen, and patients treated with this drug should be monitored for the development of leukemia.² 

References

1.Hydrea full prescribing information. Food and Drug Administration. Accessed November 13, 2021.

2. Droxia full prescribing Information. Food and Drug Administration. Accessed November 13, 2021.

3. Agrawal RK, Patel RK, Shah V, Nainiwal L, Trivedi B. Hydroxyurea in sickle cell disease: drug review. Indian J Hematol Blood Transfus. 2014;30(2):91-96. doi:10.1007/s12288-013-0261-4

4. McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf. 2015;14(11):1749-58. doi:10.1517/14740338.2015.1088827

5. Segal JB, Strouse JJ, Beach MC, et al. Hydroxyurea for the treatment of sickle cell disease. Evid Rep Technol Assess (Full Rep). 2008;(165):1-95. PMID:18457478

6. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992;79(10):2555-2565. PMID: 1375104

7. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;332(20):1317-22. doi:10.1056/NEJM199505183322001

8. Jayabose S, Tugal O, Sandoval C, et al. Clinical and hematologic effects of hydroxyurea in children with sickle cell anemia. J Pediatr. 1996;129(4):559-565. doi:10.1016/s0022-3476(96)70121-x

9. Kinney TR, Helms RW, O’Branski EE, et al. Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Blood. 1999;94(5):1550-1554. PMID: 10477679

10. Wang WC, Wynn LW, Rogers ZR, Scott JP, Lane PA, Ware RE. A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. J Pediatr. 2001;139(6):790-796. doi:10.1067/mpd.2001.119590

Reviewed by Kyle Habet, MD, on 11/15/2021.

---

Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.