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Review on the use of hydroxyurea – 50 years of FDA approval

By: Jonathan Mercado, PharmD Candidate c/o 2019

Hydroxyurea is a versatile, multi-functional drug that has been used for decades in the United States. It was originally approved in 1967 as an antineoplastic drug for use in multiple cancers including melanoma, ovarian cancer, and most prominently chronic myeloid leukemia (CML).1 Although approved as a chemotherapeutic agent, its diverse set of mechanisms eventually led to FDA approval for the treatment of sickle cell disease (SCD) in 1998.2 While its use has evolved over the past half century, hydroxyurea remains a viable tool in the modern chemotherapeutic arsenal, and is the pillar for the pharmacological treatment of SCD.

In contemporary medical practice, hydroxyurea’s primary use is for the treatment of SCD. SCD is a hereditary red blood cell disorder that alters hemoglobin, the protein responsible for carrying oxygen, into what is commonly called hemoglobin S (HbS; SCD specific hemoglobin). Two critical changes occur as a result. First, there is reduced transportation of oxygen that leads to a plethora of issues such as chronic pain, acute severe pain crises, and ongoing fatigue. Second, hemoglobin S morphs the normal voluminous disk shape of red blood cells into a thin crescent shape; this change promotes clotting and can lead to coagulopathy.3

While hydroxyurea is classified as a ribonucleotide reductase inhibitor, the drug’s ability to increase hemoglobin F levels (HbF; hemoglobin found in fetuses) makes it effective in treating SCD. An increase in HbF levels have been shown to help prevent the sickling of red blood cells and improve symptoms in SCD patients.4 Not only that, hydroxyurea has multiple other functions such as decreasing the quantity of leukocytes and reticulocytes in circulation, modifying adhesion molecules, and providing vasodilation which further improve coagulopathy induced by SCD.5 Hydroxyurea has also been shown to provide protection to the spleen and kidney and is often used in conjunction with red blood cell transfusions. The combination allows for an active attempt at countering the effects of SCD while providing a healthy supply of fresh red blood cells as support. Hydroxyurea is dosed orally at 20 mg/kg/day for children and 15 mg/kg/day for adults once daily for the treatment of SCD, even in patients who are asymptomatic.4 Patients must be over nine months old to use this medication. It is well tolerated at these doses with side effects that include mostly rashes and less commonly, mouth or skin ulcers.4

While hydroxyurea is a mainstay in SCD, it’s original indication for a variety of cancers has changed over several decades. Due to the advancement of medicine, cancer is now treated with drugs that target highly specific receptors in the body. Hydroxyurea is a drug that is nonspecific in its nature, which is why it has been phased out of modern therapy due to the rise of agents such as tyrosine kinase inhibitors (i.e. imatinib, nilotinib) that have pinpoint targets based on the cancer’s pathophysiology.6 Currently hydroxyurea is reserved as an option in CML rather than the various cancers it was initially approved for.

Hydroxyurea plays an emergency role in situations when treatment needs to be initiated immediately and BCR-ABL1 gene has yet to be confirmed as the cause of CML. Hydroxyurea’s nonspecific mechanism helps reduce white blood cell (WBC) counts significantly when patients are experiencing leukocytosis, symptoms of splenomegaly, or other severe symptoms.7 In these cases, hydroxyurea is dosed at anywhere between 20 to 40 mg/kg/day as deemed appropriate based on the WBC count. As the count reduces, so should the dose of hydroxyurea. Before switching from hydroxyurea to one of the tyrosine kinase inhibitors, it is recommended to taper gradually.8 At higher doses, the risk for adverse events such as ulcers, edema, changes in skin color, and seizures increases.

While ulcers and rash are by far the most common symptoms that are encountered with use, hydroxyurea has two major black box warnings. First is the risk of bone marrow suppression, a common risk in many chemotherapeutic agents. This makes it essential to consistently monitor blood counts throughout its use and adjust doses accordingly. Second is secondary malignancy; while hydroxyurea is a chemotherapeutic agent, it is also carcinogenic. While risks are very low for secondary malignancy, it is still important to monitor patients to ensure there are no new complications that arise due to therapy. Furthermore, hydroxyurea is classified as a category D drug in pregnancy, and therefore it must be avoided in pregnant women. Women taking this medication must not plan on becoming pregnant and must use contraceptives to avoid pregnancy. This drug also passes into breast milk, so breastfeeding must be avoided while on this medication.1 In regards to handling the medication, the drug is cytotoxic and thus requires healthcare providers and patients to wear disposable gloves when making physical contact with it. Hands should be washed before and after doing so, and proper flushing of the skin and eyes are necessary if the drug comes in contact with those areas.  If the drug spills on a surface, there is a cleaning protocol with detergent that must be followed; patients taking this medication should be counseled on all these safety issues.1

Hydroxyurea, although five decades old, is an essential drug in treating SCD and retains a niche but important role in treating CML. While it has its risks, the medication is safer than most nonspecific chemotherapeutic agents and is significantly less expensive. Nevertheless it should be prescribed and counseled on appropriately. While the growth in pharmacotherapeutic options continues to advance, it appears that hydroxyurea will remain a backbone in the treatments for SCD and CML for years to come.


  1. Droxia® (Hydroxyurea) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Revised 03/01/2016.
  2. Chabner B, Barnes J, Neal J, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In: Brunton L, Chabner B, Knollman B, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill, 2011:1731-54.
  3. Rees D, Williams T, Gladwin M. Sickle-cell disease. Lancet. 2010;376(9757):2018-31.
  4. PL Detail-Document, Management of Sickle Cell Disease. Pharmacist’s Letter/Prescriber’s Letter. Published 02/01/2015. Accessed 10/20/2017.
  5. National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report 2014. Published 09/012014. Accessed 10/20/2017.
  6. Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994;84(12):4064-77.
  7. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 2012;120(7):1390-7.
  8. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv41-51.
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