Sickle Cell Information Center Guidelines

Edited by James Eckman, M.D. and Allan Platt, PA-C

Hydroxyurea Therapy by Hiba Tamim, MD

Hydroxyrea Patient Consent - Information Form -click here

Daily administration of oral hydroxyurea (Hydrea) is the first effective pharmacological intervention documented to provide clinically significant prevention of complications in sickle cell disease. Treatment with Hydrea has recently been shown to reduce pain events, hospital admissions and the need for blood transfusions by 50%. Hydrea has been demonstrated to reduce mortality by 40%.  Hydroxyurea increases hemoglobin F concentration, thus preventing the formation of hemoglobin S polymers. It also reduces the reticulocyte, monocyte and neutrophil counts which could also provide clinical benefit. It is used in doses starting at 10-15 mg/kg/day and increased slowly until a favorable response is obtained or toxicity signs appear (neutrophil count < 2,000/mm3, platelets < 80,000/mm3, hemoglobin drop of 2 g/dl, or absolute reticulocyte count < 80,000/mm3), or a total dose of 35 mg/kg is reached. When a good clinical response is observed, the patient’s fetal hemoglobin increases and total hemoglobin increases about one gram/dl. Patients must be monitored with CBCs every two weeks for evidence of bone marrow suppression and only a two-week supply of hydrea with no refills should be given at each visit. Once a stable or maximally tolerated dose is obtained, the patient can be monitored monthly. The long term benefits of hydroxyurea and toxicities are unknown.

Small studies on the use of hydrea in children have shown similar results causing decrease in the pain episodes and hospitalizations. There may also be a decrease in acute chest syndrome and blood transfusion requirements. The short-term toxicities were mild, however, no data is available on the long-term toxicity. Larger studies on the safety and efficacy in children are currently underway.

Very few patients with sickle-b -thalassemia and sickle cell-hemoglobin C disease have been treated with hydrea.

a)Any patient who has:

• More than three pain crises in one year
• Symptomatic anemia with alloimmunization

b)Persistent occurrences of priapism despite standard therapy

c)Creatinine levels < 1.7 mg

d)Retic count of > 150,000 average value

Patients should also be warned of routine side effects of hydroxyurea prior to starting the medication, those are:

a)Weight gain

b)Hair loss, skin pigment changes, and nail darkening.

c)Reversible bone marrow suppression (greater than desired)

d)Patient on hydroxyurea should not become pregnant because of potential for birth defects. All patients must be on documented effective birth control method.

e)Patients that are HgbSC are only experimental candidates. Those with Hgb S beta Thal may have to be phlebotomized once per month if they get very good bone marrow response and hemoglobin levels exceed 12 g/dl.

f)Long term complications are unknown, (i.e. the potential for leukemia or cancer is a concern).

a)Patients (female) unwilling to use contraception.

b)Patient receiving large numbers of narcotics regularly

c)Patient with creatinine > 2.0 mg/dl

d)Patients with active liver disease

e)Positive HIV test without special informed consent

f)Recent CVA

g)History of non-compliance

• a current physical exam, with all vitals, including documented weight.
• hemoglobin electrophoresis with Hgb F levels
• CBC with diff, retic count, chem profile and liver profile
• B-12 and folate within 1 year (ensure no current deficiency)
• retic count (if <150,000, measured erythropoietin and consider combined erythropoietin therapy if level < 300 MIU/ml)

Patient should have informed consent documented in the medical chart including a signed informed consent form. At least, informed consent must be documented in a note that documents all aspects of short-term and long-term complications have been presented to the patient; that the patient understands; and that the patient agrees to take the medication because they feel the benefits exceed the risk.

Patient placed on hydroxyurea must understand that initially they must have blood work checks every 2 weeks. At these follow up visits the patient will have the following done:

a) weight measured

b) blood drawn (CBC & Diff, retic) every 2 weeks

c) Chem-profile, hepatic profile and clinic visit visit every 3 months

d) Demographic update (telephone and address)

e) Inquiry about side-effects

1) rash, pigment changes

2) nausea/GI symptoms

3) hair loss

4) unusual bleeding tendency

5) patient should call and reschedule visit if scheduled appointment is missed

f) Flow sheet in chart with laboratory date entered on same day the patient was seen

g) Re-evaluation of the current hydroxyurea dosage (increase in the dosage must be considered every 6 weeks, after start date) until maximum tolerated dose (MTD) is reached.

h) Documentation of STOP orders must be charted with indications of the toxic levels.Follow-up appointment for one week must be made.

i) Non compliance after beginning hydroxyurea will be addressed on an individual basis.

Starting dose of hydroxyurea is 10 mg/kg to be increased by 5 mg/kg after 12 weeks by standard dosing. Due to confinesin the dose of hydroxyurea available at Grady, patients are started on 500 mg PO QD (one tablet) to be increased to1000 mg QD (two tablets) after 6-8 weeks and by 500 mg every six weeks up to 2000 mg.

a)absolute neutrophil counts < 2,500/mm3

b)absolute reticulocyte counts < 95,000/mm3 (if hemoglobin concentration is below 9gm/dl)

c)platelet counts < 95,000 mm3

d)fall of 15% or more in hgb concentration from Hgb starting treatment.

a)absolute neutrophil counts < 2000/mm3

b)absolute reticulocyte < 80,000/mm3

c)platelet counts : 80,000/mm3

d)fall of 20% or more in Hgb concentrate (or high concentrate l0.0 gm/dl)

a)50% or more increase in serum creatinine of an increase of > 0.5 mg/dl in this time period!

b)100% increase in GGTP

c)unexplained GI disturbance

d)unexplained appearance of rash or hair loss.

Restart hydroxyurea at a 25% reduced dose if this is the first toxic episode. Reduce the dose 50% if there have been previous pretoxic or toxic levels. Monitor every two weeks until counts are documented to be stable. Restart the medication when all of these criteria are met.

a)absolute neutrophil counts > 3,000/mm3

b)absolute reticulocyte counts > 150,000/mm3 (if hemoglobin concentration is below 9gm/dl)

c)platelet counts >150,000 mm3

d)no further fall in Hgb concentration from Hgb starting hold.

Restart hydroxyurea at the same dose if this is the first pretoxic episode. Reduce the dose 25% if there have been previouspretoxic or toxic levels. Monitor every two weeks until counts are documented to be stable. Restart the medicationwhen all of these criteria are met.

a)absolute neutrophil counts > 3,000/mm3

b)absolute reticulocyte counts > 150,000/mm3 (if hemoglobin concentration is below 9gm/dl)

c)platelet counts >150,000 mm3

d)no further fall in Hgb concentration from Hgb starting hold.

Nursing Considerations

 Encourage patient to focus on the benefits of the medication, if possible, arrange for patient to talk to other patients already on Hydroxyurea therapy.

Review and explain side effects of medications and instruct patient to report immediately any bleeding, hematuria, fever, jaundice, rash, skin discoloration.

Inform patient that compliance is the key to successful treatment with Hydroxyurea. Emphasize the importance of taking the medicine as scheduled. Medication could be taken at night to avoid nausea and vomiting.

 Emphasize that lab tests are important for effective monitoring of blood levels as patient can become toxic. Patient should expect changes in dosage of medication as dictated by lab results.

Instruct patients/and partners on various birth control measures as needed.

Hydroxyrea Patient Consent - Information Form -click here

Charache S, Terrin M, Moore R, Dover G, et al. Effect of Hydroxyurea on the frequency of painful crises in sickle cell anemia. NEJM 1995:332:1317-22.

Ferster A, Vermylen C, Cornu G. Hydroxyurea for the treatment of svere sickle cell anemia: A pediatric clinical trial. Blood, 88: 1960-1964, 1996.

Bunn HF. Pathogenesis and treatment of sickle cell disease. NEJM 337: 762-1393, 1997.

Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Seminars in Hematology, 34:15-21, 1997.

Rogers ZR. Hydroxyurea therapy for diverse pediatric populations with sickle cell disease. Seminars in hematology, 34: 42-47, 1997.

Steinberg MH, Lu Z-H, et al. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea: Multicenter study of hydroxyurea. Blood 89: 1078-1088, 1997.

Steinberg MH. Management of sickle cell disease. NEJM 340:1021-1030, 1999.

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. Blood 94: 1550 - 1554, 1999.

Sickle Cell Pain & Hydroxyurea  AJN, American Journal of Nursing November 2000  Volume 100 Number 11 Page 34 By Sara W. Day, BSN, RN, and Lynn Witte Wynn, BSN, RN http://www.nursingcenter.com/prodev/ce_article.asp?tid=53378
This is a wonderful summary about Hydrea treatment .

Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell Anemia  JAMA. 2003;289:1645-1651. http://jama.ama-assn.org/cgi/content/abstract/289/13/1645
Patients Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients. 
Intervention In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147). 
Main Outcome Measure Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality. 
Results Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P = .002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P = .03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P = .02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P = .06). Taking hydroxyurea was associated with a 40% reduction in mortality (P = .04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal. 
Conclusions Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown. 

Hoppe C, Vichinsky E, Quirolo K, van Warmerdam J, Allen K, Styles L. Use of hydroxyurea in children ages 2 to 5 years with sickle cell disease. J Pediatr Hematol Oncol. 2000 Jul-Aug;22(4):330-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10959903&dopt=Abstract

Medication Warning: Warning for Hydroxyurea

Risk of Serious Skin Complications, Including Gangrene, Says Maker

Jan. 27, 2006 -- Drug company Bristol-Myers Squibb is alerting doctors about the risk of serious skin complications, including ulcers and gangrene, with its drug hydroxyurea.

Hydroxyurea is used to treat precancerous blood conditions called myeloproliferative disorders and may also be used to treat sickle cell disease. It's sold as Hydrea and Droxia.

Hydroxyurea's prescribing information will be updated to warn of the risk. The warning will advise doctors to stop using the drug in patients who experience those skin problems, switching those patients to other medicines.

The warning will also note that elderly patients may be more sensitive to hydroxyurea's effects and may need lower doses.

The skin reactions have mainly been reported in patients taking hydroxyurea who are also using the drug interferon or who have taken interferon in the past, states Bristol-Myers Squibb's letter to doctors. The letter is posted on the FDA's web site.

Specific wording of hydroxyurea's new warning is pending FDA review and approval, states an FDA news release.

SOURCES: News release, FDA. Bristol-Myers Squibb Co., letter to health care providers, Jan. 20, 2006. http://webcenter.health.webmd.netscape.com/content/article/117/112803.htm

Send mail to aplatt@emory.edu with questions or comments about this web site.
Copyright © 1997 Sickle Cell Information Center
Last modified: March 12, 2006