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Hydroxyurea Toxicity Cite this Page

Sruthi Jinna; Paras B. Khandhar.

Author Information and Affiliations In this Page

Last Update: August 8, 2023. Continuing Education Activity

Introduction
Continuing Education Activity Go to:
Etiology
Hydroxyurea is an antineoplastic agent used alone or in combination with other chemotherapeutic drugs or radiation
Epidemiology
in the treatment of resistant leukemias and carcinomas of the head and neck. It is also used to increase fetal
Pathophysiology
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 Toxicokinetics
therapeutic index. This activity reviews the etiology, presentation, evaluation, and management of hydroxyurea History and Physical
toxicity and the role of the interprofessional team in evaluating, diagnosing, and managing the condition.
Evaluation
Objectives: Treatment / Management

Describe the toxicokinetics of hydroxyurea toxicity. Differential Diagnosis

Consultations
Summarize the presenting signs and symptoms typically seen with hydroxyurea toxicity.
Enhancing Healthcare Team Outcomes
Review treatment strategies for hydroxyurea toxicity.
Review Questions
Explain the importance of improving care coordination amongst interprofessional team members to optimize
References
outcomes for patients with hydroxyurea toxicity.

Access free multiple choice questions on this topic.

Bulk Download
Bulk download StatPearls data from FTP
Introduction Go to:

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 Related information
hemoglobin concentration, thus reducing the frequency of severe crisis and reducing the necessity for blood PMC
transfusions in patients with sickle cell anemia. PubMed

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]
Similar articles in PubMed
Hydroxyurea and sickle cell anemia. Clinical utility of a
Etiology Go to:
myelosuppressive "switching" agent. The
[Medicine
Multicenter
(Baltimore).
Study of1996]
Hydroxyurea in Sickle Cell Anemia.
Hydroxyurea is an extremely toxic drug with a low therapeutic index. Leukemogenic risk of hydroxyurea therapy in polycythemia vera,
essential thrombocythemia, and myeloid metaplasia
[Am J Hematol.
with 1996]
Since hydroxyurea inhibits DNA synthesis, it can result in significant toxicity, including myelosuppression. myelofibrosis.
Furthermore, inhibition of DNA synthesis without affecting RNA synthesis may result in red blood cells becoming Review New drugs in essential thrombocythemia and
polycythemia vera. [Blood Rev. 1997]
megaloblastic.
Review Therapeutic options for essential thrombocythemia and
polycythemia vera. [Semin Oncol. 2002]
Epidemiology Go to:
Review Contemporary approach to essential thrombocythemia
Overdose data is limited, but case reports exist. One such case is an accidental overdose of hydroxyurea in a 2-year- and polycythemia vera. [Curr Opin Hematol. 2016]
old child resulted in mild myelosuppression.[3] The clinicians observed the patient in the emergency department for 8
See reviews...
hours and then discharged home. They monitored blood counts for myelosuppression for two weeks as an outpatient.
See all...
In another case, a woman developed agitation, widespread myoclonic jerks, oculogyric crisis, sinus tachycardia, and
myelosuppression after ingesting 60 grams of hydroxyurea.
Recent Activity
Another case series reported acute mucocutaneous toxicity in three patients with advanced acute myelogenous Turn Off Clear
leukemia treated with oral high dose hydroxyurea at a dose of 10 grams for 8 to 10 days.[4] All three patients Hydroxyurea Toxicity - StatPearls
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. See more...

Pathophysiology Go to:

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 Go to:

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 Go to:

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 Go to:

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 Go to:

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 Go to:

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

Consultations Go to:

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

Enhancing Healthcare Team Outcomes Go to:

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]

Review Questions Go to:

Access free multiple choice questions on this topic.

Comment on this article.

References Go to:

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[PubMed]
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
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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] [PubMed]
4. Brincker H, Christensen BE. Acute mucocutaneous toxicity following high-dose hydroxyurea. Cancer Chemother
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leukaemic transformation and review of the literature. Hematol Cell Ther. 1997 Feb;39(1):11-8. [PubMed]
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Disclosure: Sruthi Jinna declares no relevant financial relationships with ineligible companies.

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

Copyright © 2023, StatPearls Publishing LLC.

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