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Hydroxyurea

Contributor: Keith Quirolo, MD

Hydroxyurea for sickle cell disease comes in capsule, tablet and liquid form.

Hydroxyurea became the first drug approved for treatment of sickle cell disease the U.S. Food and Drug Administration (FDA) in 1998. Hydroxyurea increases fetal hemoglobin when taken by people who have sickle cell disease. This decreases the chance that the red blood cells will transform into sickle shaped cells and occlude blood vessels1.

Fetal hemoglobin is the hemoglobin in the fetus and has a higher affinity for oxygen than normal hemoglobin. In the weeks and months after we are born, our fetal hemoglobin levels usually decrease to very low levels. That is why people who have sickle cell disease typically don’t experience symptoms until they are more than 6 months old, although some infants do have early symptoms. 

Hydroxyurea has many potential benefits. First, fetal hemoglobin in the red cell decreases sickling. In fact, if you look at a patient’s red blood cells under a microscope, you can see that after taking hydroxyurea for a few months, many of the red cells look normal, this decreases the breakdown of the red cells and leads to a higher hemoglobin. Hydroxyurea also decreases the stickiness of the red blood cells which makes them less adherent to the walls of blood vessels. It also decreases the numbers of white blood cells that also contribute to vaso-occlusion. There are other positive effects that were not anticipated when this therapeutic agent was approved by the FDA.

Although hydroxyurea has been shown to be potentially effective in hemoglobin SC disease18, the data is not as clear in patients with other types of sickle cell disease and patients should talk to their doctors about whether hydroxyurea is the right choice for them.

Hydroxyurea in Clinical Trials

Hydroxyurea use was first studied and reported in adults who had sickle cell anemia (SS or S beta zero thalassemia), it was found to decrease the number of hospitalizations for pain crises and decrease the frequency of acute chest syndrome by half, and also decrease transfusion requirements2.

Based on this study, hydroxyurea was FDA-approved for the treatment of adults with sickle cell anemia in 1998.

Multiple studies have shown that patients with sickle cell anemia who take hydroxyurea live longer than those who do not take hydroxyurea6-8. Therefore, the recommendation has now been made that adults who have sickle cell anemia should take hydroxyurea. It is also recommended that hydroxyurea should be offered to children as young as 9 months of age, including those who do not have symptoms9.

Hydroxyurea for Children

After hydroxyurea was approved for adults with sickle cell disease, subsequent studies were reported in children and infants with sickle cell anemia showing that hydroxyurea was safe for use in even very young children3,4.

Hydroxyurea was not studied in children using a placebo (determining whether it is as effective as taking no medication), as some researchers felt it would be unethical knowing that hydroxyurea is beneficial and safe in children; because of this, hydroxyurea was not approved for children until 2007, although children have been prescribed hydroxyurea for decades.

The study for approval in children was done in Europe with subjects 2 to 18 years of age and enrolled 1906 participants5.  The findings in this study were the same as in the adult study. Incidentally in this  study there were 101 pregnancies and there were no birth defects reported.

Children who are at risk of stroke by the criteria in the STOP Study can be switched from transfusion to hydroxyurea without further risk of stroke10.

Side Effects of Hydroxyurea

The main side effects associated with hydroxyurea are that red cells can decrease causing anemia, white blood cells (the cells that help to fight infection) and platelets (the cells that help prevent excessive bleeding) can also decrease to low levels11. Therefore, patients who take hydroxyurea must have their blood counts monitored, initially every 2-4 weeks when the medicine is first started and then every 2-3 months when the dose is stable. Some patients are more sensitive than others, so a lower dose is initially started, and the dose can be slowly increased every 8 weeks until the ideal dose is reached.

Occasionally patients who take hydroxyurea for long periods of time will notice darkening of their fingernails. Rarely, patients may experience nausea and vomiting and extremely rarely a rash and diarrhea. Also, because of the theoretical risk that hydroxyurea can have a negative impact on the fetus, appropriate contraception should be used and patients should talk to their physicians if they are interested in either getting pregnant or getting their partner pregnant.

Hydroxyurea can also decrease sperm counts in men who take it, though it must be recognized that men with sickle cell anemia have reduced sperm counts compared to those without sickle cell disease. Not to the degree that they would be sterilized, and the sperm count may return to the level it was if hydroxyurea is discontinued12,13.  Women also have premature menopause, but it is not known if hydroxyurea exacerbates this change14.  It is recognized that both men and women stop taking hydroxyurea if they are planning on having children. Birth defects have not been reported in women taking hydroxyurea in the early stages of pregnancy before they knew they were pregnant.

Doctors have been treating patients with sickle cell anemia for more than 20 years, there is no evidence that hydroxyurea increases the risk of leukemia in many studies15, nor does hydroxyurea increase infections in children taking hydroxyurea16. There does not appear to be an association of hydroxyurea with avascular necrosis in at least one study17.  However even though the benefits of hydroxyurea greatly outweigh the risks in most patients with sickle cell anemia investigation continues concerning whether there are any genetic effects of long term use of hydroxyurea. Therefore, anyone with sickle cell anemia (HbSS or HbSb0-thalassemia disease) should talk to their hematologist about hydroxyurea as a means to decrease events and to live a longer healthier life.

Sources

1. Herrick JB. Peculiar Elongated and Sickle-shaped Red Blood Corpuscles in a Case of Severe Anemia. Yale J Biol Med 2001;74:179-184.

2. 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. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7715639

http://www.nejm.org/doi/pdf/10.1056/NEJM199505183322001).

3. Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial. Blood 1996;88(6):1960-4. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8822914

http://bloodjournal.hematologylibrary.org/content/88/6/1960.full.pdf).

4. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377(9778):1663-72. DOI: 10.1016/S0140-6736(11)60355-3.

5. de Montalembert M, Voskaridou E, Oevermann L, et al. Real-Life experience with hydroxyurea in patients with sickle cell disease: Results from the prospective ESCORT-HU cohort study. Am J Hematol 2021;96(10):1223-1231. DOI: 10.1002/ajh.26286.

6. Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010;85(6):403-8. (In eng). DOI: 10.1002/ajh.21699.

7. Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 2010;115(12):2354-63. (In eng). DOI: 10.1182/blood-2009-05-221333.

8. Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect of hydroxcarbamide therapy on survival of children with sickle cell disease. Br J Haematol 2013;161(6):852-60. (Clinical Trial

Research Support, Non-U.S. Gov’t). DOI: 10.1111/bjh.12323.

9. Buchanan G, Yawn BP. Evidence Based Management of Sickle Cell Disease. NIH Consens State Sci Statements 2014.

10. Ware RE, Schultz WH, Yovetich N, et al. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH): a phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload. Pediatr Blood Cancer 2011;57(6):1011-7. (In eng). DOI: 10.1002/pbc.23145.

11. 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.

12. DeBaun MR. Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review. Expert Rev Hematol 2014;7(6):767-73. DOI: 10.1586/17474086.2014.959922.

13. Joseph L, Jean C, Manceau S, et al. Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease. Blood 2021;137(6):826-829. DOI: 10.1182/blood.2020006270.

14. Pecker LH, Hussain S, Christianson MS, Lanzkron S. Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide. Br J Haematol 2020;191(5):880-887. DOI: 10.1111/bjh.16976.

15. McGann PT, Ware RE. Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain? Curr Opin Hematol 2011;18(3):158-65. DOI: 10.1097/MOH.0b013e32834521dd.

16. Lederman HM, Connolly MA, Kalpatthi R, et al. Immunologic effects of hydroxyurea in sickle cell anemia. Pediatrics 2014;134(4):686-95. DOI: 10.1542/peds.2014-0571.

17. Adekile AD, Gupta R, Al-Khayat A, Mohammed A, Atyani S, Thomas D. Risk of avascular necrosis of the femoral head in children with sickle cell disease on hydroxyurea: MRI evaluation. Pediatr Blood Cancer 2019;66(2):e27503. DOI: 10.1002/pbc.27503.

18. Luchtman-Jones L, Pressel S, Hilliard L, et al. Effects of hydroxyurea treatment for patients with hemoglobin SC disease. Am J Hematol 2016;91(2):238-42. DOI: 10.1002/ajh.24255.