Continuing Education Activity

Hydroxyurea is an antineoplastic agent used alone or in combination with other chemotherapeutic drugs or radiation in the treatment of resistant leukemias and carcinomas of the head and neck. It is also used to increase fetal hemoglobin concentration, thus reducing the frequency of severe crisis and reducing the necessity for blood transfusions in patients with sickle cell anemia. Despite its utility, hydroxyurea is an extremely toxic drug with a low therapeutic index. This activity reviews the etiology, presentation, evaluation, and management of hydroxyurea toxicity and the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Describe the toxicokinetics of hydroxyurea toxicity.
• Summarize the presenting signs and symptoms typically seen with hydroxyurea toxicity.
• Review treatment strategies for hydroxyurea toxicity.
• Explain the importance of improving care coordination amongst interprofessional team members to optimize outcomes for patients with hydroxyurea toxicity.

Introduction

Hydroxyurea is an antineoplastic agent used alone or in combination with other chemotherapeutic drugs or radiation in the treatment of resistant leukemias and carcinomas of the head and neck. It is also useful to increase fetal hemoglobin concentration, thus reducing the frequency of severe crisis and reducing the necessity for blood transfusions in patients with sickle cell anemia.

They also use hydroxyurea off-label in the treatment of polycythemia vera, essential thrombocythemia, psoriasis, acute myeloid leukemia, meningioma, melanoma, and ovarian cancer.[1][2]

Etiology

Hydroxyurea is an extremely toxic drug with a low therapeutic index.

Since hydroxyurea inhibits DNA synthesis, it can result in significant toxicity, including myelosuppression. Furthermore, inhibition of DNA synthesis without affecting RNA synthesis may result in red blood cells becoming megaloblastic.

Epidemiology

Overdose data is limited, but case reports exist. One such case is an accidental overdose of hydroxyurea in a 2-year-old child resulted in mild myelosuppression.[3] The clinicians observed the patient in the emergency department for 8 hours and then discharged home. They monitored blood counts for myelosuppression for two weeks as an outpatient. 

In another case, a woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and myelosuppression after ingesting 60 grams of hydroxyurea.

Another case series reported acute mucocutaneous toxicity in three patients with advanced acute myelogenous leukemia treated with oral high dose hydroxyurea at a dose of 10 grams for 8 to 10 days.[4] All three patients developed severe acute stomatitis. Two patients developed acute cutaneous toxicity associated with soreness, violet erythema, and edema of palms and soles, followed by intense hyperpigmentation of the skin.

Pathophysiology

Hydroxyurea is a hydroxylated analog of urea, inhibiting DNA synthesis by inhibiting ribonucleotide diphosphatase reductase and blocking the conversion of ribonucleotides to deoxyribonucleotides.[5][6]

Hydroxyurea is cell-cycle specific for the S phase, causing cell arrest at G1 to S.

Hydroxyurea increases HbF levels by stimulating HbF production, but the exact mechanism of HbF production is unknown. It also has antioxidant properties, alters the RBC membrane, increases red blood cell (RBC) deformability by increasing intracellular water content, and decreases RBC adherence to the endothelium.[7][8][9]

Toxicokinetics

Hydroxyurea is administered orally, is readily absorbed, and has 100% bioavailability. The half-life is 1.9 to 3.9 hours in adults and 1.7 hours in children.[10][11]

Hydroxyurea is excreted in the urine with recommendations of dose change in patients with kidney function impairment.

History and Physical

Hematology-Oncology

Bone marrow suppression: myelosuppression leads to anemia, leukopenia (more common), and thrombocytopenia. This toxicity is reversible by withholding the medication for two weeks and can potentially be resumed at a lower dose.

Hydroxyurea causes macrocytosis, seen early in treatment, and may be confused with pernicious anemia. While unrelated to vitamin B12 or folic acid deficiency, prophylactic folic acid supplementation is the recommended intervention to assist with macrocytosis.[12]

Hydroxyurea used to manage myeloproliferative disorders can cause secondary leukemias. A case series detailed three patients with essential thrombocythemia who were continuously receiving hydroxyurea for 47, 81, and 90 months had a leukemic transformation.[13]

Long-term use of hydroxyurea can cause skin cancer; cutaneous carcinomas are a severe side effect of hydroxyurea.[14] This condition can occur after several years of treatment with hydroxyurea. Patients on HU treatment need to be monitored and follow up for the long term.

Gastrointestinal

Hydroxyurea has correlations with gastric distress, gastritis, mucositis, and oral mucosa ulcer.[15][16]

There are reports of elevation of serum concentrations of hepatic enzymes in patients receiving hydroxyurea. While rare, there are reports of hepatotoxicity resulting in fatal hepatic failure in patients with HIV infection receiving the drug in combination with antiretroviral agents. Fatal hepatotoxicity occurred most frequently in patients receiving combination therapy with hydroxyurea, didanosine, and stavudine. 

Fatal and nonfatal pancreatitis has been reported in patients with HIV infection, during therapy with hydroxyurea and didanosine, with or without stavudine. In these patients, close monitoring of signs and symptoms of pancreatitis the recommendation, along with permanent discontinuation hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Dermatology

Long-term treatment with hydroxyurea is associated with painful skin ulcers, aphthous ulcers, non-ulcerative toxicity with erythema, and skin infiltration.[17] Rarely, long-term therapy with hydroxyurea is associated with gangrene of the toes and digits.[18][19] The recommendation is to discontinue the drug.

Reproductive

Hydroxyurea decreases sperm count and sperm motility in males and is considered pregnancy category D.  Breastfeeding is not recommended during hydroxyurea treatment.[20]

Pulmonary

Hydroxyurea can cause severe interstitial pneumonitis.[21] It can even occur after several years of initial treatment with hydroxyurea. If not diagnosed, drug-induced interstitial pneumonitis can lead to lung fibrosis and respiratory failure. The recommendation is to discontinue the drug.

Cardiology

There is a case reported in the literature, a patient with chronic myelogenous leukemia receiving hydroxyurea treatment who had an acute myocardial infarction. The pathogenesis of this adverse effect is unclear.[22]

Neurology

Rare side effects include headache, dizziness, disorientation, hallucinations, and seizures.

Evaluation

As with most medicines, patients on hydroxyurea should have their electrolytes and renal function monitored, especially in patients with severe nausea, vomiting, and diarrhea. For those with myelosuppression, the practitioner should monitor signs of infection as well as CBC with differential count and platelet counts.

Treatment / Management

Treatment:

• Pre-hospital GI decontamination is not recommended.
• Activated charcoal administration if an overdose is recent and patient, not vomiting, and able to maintain the airway.
• Airway management. Intubation in patients with severe respiratory symptoms.

Treatment is symptomatic and supportive.

In patients with nausea and vomiting, treat with antiemetics, and administer intravenous fluids as needed.

In patients with myelosuppression, treat with colony-stimulating factors in patients with neutropenia, platelets transfusion in patients with severe thrombocytopenia, and packed red blood cell transfusion in patients with anemia.

In patients with seizures, treat with antiepileptics.

Mild mucositis treatment is with bland oral rinses like 0.9 % normal saline, sodium bicarbonate, and water. In moderate cases with pain, a local anesthetic is added. Treatment for moderate to severe mucositis is with local anesthetic and systemic analgesics. Oral antimicrobial mouthwashes can help to decrease the risk of infection. 

Differential Diagnosis

Myelosuppression and gastrointestinal side effects were present with other chemotherapeutic agents used in combination with hydroxyurea. 

Consultations

If there is any concern for hydroxyurea toxicity, consultation with poison control is recommended.

Enhancing Healthcare Team Outcomes

Hydroxyurea toxicity management requires an interprofessional team of healthcare professionals, including nursing staff, pharmacists, emergency medicine physicians, internists, and hematology-oncologist. Emergency medicine physicians should monitor for signs of respiratory depression and stabilize the patient’s airway. Consultation with a medical toxicologist/and or contact the poison center in patients with an unclear diagnosis may be necessary. Hematologists care for inpatients. Critical care and oncology nurses monitor patients and notify the team of issues.

Nurses and pharmacists should educate patients on the side effects of medication and signs of symptoms that require monitoring while taking the drug, and the pharmacist should work with the clinicians to perform medication reconciliation and verify the absence of drug-drug interactions. This interprofessional approach will lead to better outcomes in cases of hydroxyurea toxicity. [Level 5]

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References

1.

Finazzi G, Barbui T. How I treat patients with polycythemia vera. Blood. 2007 Jun 15;109(12):5104-11. [PubMed: 17264301]

2.

Barbui T, Barosi G, Grossi A, Gugliotta L, Liberato LN, Marchetti M, Mazzucconi MG, Rodeghiero F, Tura S. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2004 Feb;89(2):215-32. [PubMed: 15003898]

3.

Miller ST, Rey K, He J, Flanagan J, Fish BJ, Rogers ZR, Wang WC, Ware RE., BABY HUG Investigators. Massive accidental overdose of hydroxyurea in a young child with sickle cell anemia. Pediatr Blood Cancer. 2012 Jul 15;59(1):170-2. [PMC free article: PMC3193862] [PubMed: 21744485]

4.

Brincker H, Christensen BE. Acute mucocutaneous toxicity following high-dose hydroxyurea. Cancer Chemother Pharmacol. 1993;32(6):496-7. [PubMed: 8258201]

5.

Yarbro JW. Mechanism of action of hydroxyurea. Semin Oncol. 1992 Jun;19(3 Suppl 9):1-10. [PubMed: 1641648]

6.

Krakoff IH, Brown NC, Reichard P. Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. Cancer Res. 1968 Aug;28(8):1559-65. [PubMed: 4876978]

7.

Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 11;376(9757):2018-31. [PubMed: 21131035]

8.

Eridani S, Mosca A. Fetal hemoglobin reactivation and cell engineering in the treatment of sickle cell anemia. J Blood Med. 2011;2:23-30. [PMC free article: PMC3262355] [PubMed: 22287860]

9.

Hankins J, Aygun B. Pharmacotherapy in sickle cell disease--state of the art and future prospects. Br J Haematol. 2009 May;145(3):296-308. [PMC free article: PMC3175763] [PubMed: 19222472]

10.

Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, Smeltzer MP, Kimble AC, Aygun B, Wu S, Howard T, Sparreboom A. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood. 2011 Nov 03;118(18):4985-91. [PMC free article: PMC3208303] [PubMed: 21876119]

11.

Gwilt PR, Tracewell WG. Pharmacokinetics and pharmacodynamics of hydroxyurea. Clin Pharmacokinet. 1998 May;34(5):347-58. [PubMed: 9592619]

12.

Randi ML, Ruzzon E, Luzzatto G, Tezza F, Girolami A, Fabris F. Safety profile of hydroxyurea in the treatment of patients with Philadelphia-negative chronic myeloproliferative disorders. Haematologica. 2005 Feb;90(2):261-2. [PubMed: 15710584]

13.

Liozon E, Brigaudeau C, Trimoreau F, Desangles F, Fermeaux V, Praloran V, Bordessoule D. Is treatment with hydroxyurea leukemogenic in patients with essential thrombocythemia? An analysis of three new cases of leukaemic transformation and review of the literature. Hematol Cell Ther. 1997 Feb;39(1):11-8. [PubMed: 9088933]

14.

Estève E, Georgescu V, Heitzmann P, Martin L. [Multiple skin and mouth squamous cell carcinomas related to long-term treatment with hydroxyurea]. Ann Dermatol Venereol. 2001 Sep;128(8-9):919-21. [PubMed: 11590345]

15.

Antonioli E, Guglielmelli P, Pieri L, Finazzi M, Rumi E, Martinelli V, Vianelli N, Luigia Randi M, Bertozzi I, De Stefano V, Za T, Rossi E, Ruggeri M, Elli E, Cacciola R, Cacciola E, Pogliani E, Rodeghiero F, Baccarani M, Passamonti F, Finazzi G, Rambaldi A, Bosi A, Cazzola M, Barbui T, Vannucchi AM., AGIMM Investigators. Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN. Am J Hematol. 2012 May;87(5):552-4. [PubMed: 22473827]

16.

Hernández-Boluda JC, Alvarez-Larrán A, Gómez M, Angona A, Amat P, Bellosillo B, Martínez-Avilés L, Navarro B, Teruel A, Martínez-Ruiz F, Besses C. Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia. Br J Haematol. 2011 Jan;152(1):81-8. [PubMed: 21083657]

17.

Latagliata R, Spadea A, Cedrone M, Di Giandomenico J, De Muro M, Villivà N, Breccia M, Anaclerico B, Porrini R, Spirito F, Rago A, Avvisati G, Alimena G, Montanaro M, Andriani A., Gruppo Laziale SMPC Ph1 neg. Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer. 2012 Jan 15;118(2):404-9. [PubMed: 21692060]

18.

Leo E, Krämer A, Hochhaus A, Krasniqi F, Hehlmann R, Ho AD. Gangrene of the toes in a patient with chronic myelogenous leukemia after long-term hydroxyurea therapy. Ann Hematol. 2002 Aug;81(8):467-9. [PubMed: 12224005]

19.

Salmon-Ehr V, Leborgne G, Vilque JP, Potron G, Bernard P. [Secondary cutaneous effects of hydroxyurea: prospective study of 26 patients from a dermatologic consultation]. Rev Med Interne. 2000 Jan;21(1):30-4. [PubMed: 10685452]

20.

Berthaut I, Guignedoux G, Kirsch-Noir F, de Larouziere V, Ravel C, Bachir D, Galactéros F, Ancel PY, Kunstmann JM, Levy L, Jouannet P, Girot R, Mandelbaum J. Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males. Haematologica. 2008 Jul;93(7):988-93. [PubMed: 18508803]

21.

Internullo M, Giannelli V, Sardo L, Antonaglia C, Villani T, Angelici E, Palange P. Hydroxyurea-induced interstitial pneumonitis: case report and review of the literature. Eur Rev Med Pharmacol Sci. 2014;18(2):190-3. [PubMed: 24488907]

22.

Kälsch H, Wieneke H, Erbel R. Acute myocardial infarction in a patient with chronic myelocytic leukemia during chemotherapy with hydroxyurea. Herz. 2010 Sep;35(6):420-2. [PubMed: 20721521]

Disclosure: Sruthi Jinna declares no relevant financial relationships with ineligible companies.

Disclosure: Paras Khandhar declares no relevant financial relationships with ineligible companies.