Class: Antineoplastic Agents
VA Class: AN300
Molecular Formula: CH4N2O2
CAS Number: 127-07-1
Brands: Droxia, Hydrea
Highly toxic drug with a low therapeutic index.c
Possible severe, sometimes life-threatening or fatal, adverse effects.177 178
- Limit to Qualified Personnel
Administer only under supervision of qualified clinicians experienced in use of cytotoxic therapy.177 178 (See Adequate Patient Evaluation and Monitoring under Cautions.)
Hydroxyurea is genotoxic and is a presumed human carcinogen;177 178 also, mutagenic and clastogenic in vitro.177 178
Secondary leukemias have been reported in patients receiving long-term therapy for myeloproliferative disorders (e.g., polycythemia vera, thrombocythemia).177 178
Carefully consider risks of developing secondary malignancies against the benefits of therapy.a (See Carcinogenicity under Cautions.)
Antineoplastic agent; exhibits beneficial effects against sickle cell anemia; exhibits antiviral activity.100 101 102
Uses for Hydroxyurea
Chronic Myelogenous Leukemia
Treatment of resistant chronic myelogenous leukemia (CML).166 177 212
Used as an alternative agent for the palliative treatment of chronic-phase CML in patients who cannot undergo allogeneic bone marrow or stem cell transplantation;166 167 212 superior to busulfan for the palliative treatment of CML.212 213
Used as an alternative agent for the palliative treatment of the accelerated phase of CML.166 212
Used to reduce WBC count prior to bone marrow transplantation or initiation of interferon alfa therapy.212
Sickle Cell Anemia
Palliative treatment of sickle cell anemia generally in patients with recurrent moderate to severe painful crises occurring on at least 3 occasions during the preceding 12 months (designated an orphan drug by FDA for this use).106 107 111 113 114 116 117 118 122 123 124 125 151 155 156 157 158 178 179
Therapy is prophylactic; the drug has no role in the treatment of a crisis in progress.117
Management of polycythemia vera† including use as an adjunct to intermittent phlebotomy.136 143 144 145 146 152 164 171 174 176
Has been used for treatment of cervical cancer†;206 207 208 however, other agents are considered more effective.203 204 205 209
Head and Neck Cancer
Has been used in combination with radiation therapy for local control of primary squamous cell (epidermoid) carcinoma of the head and neck, excluding the lip.177
Has been used for treatment of melanoma;177 however, other agents are preferred.166
Has been used for treatment of recurrent, metastatic, or inoperable ovarian cancer;177 however, other agents are preferred.166
Hydroxyurea Dosage and Administration
Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.b
Individualize dosage according to actual or ideal body weight, whichever is less.a b
Consult published protocols for the dosage of hydroxyurea and other chemotherapeutic agents and the method and sequence of administration.c
Chronic Myelogenous Leukemia
An adequate trial period for determining the antineoplastic effectiveness is 6 weeks.177
Sickle Cell Anemia
Following initiation of therapy, monitor patient's blood cell count every 2 weeks and adjust dosage accordingly.178 (See Dosage under Dosage and Administration.)
Some clinicians perform less frequent monitoring (e.g., weekly until stabilization occurs and then every 2 weeks for the initial months of therapy, followed by monthly or less frequent monitoring once response has been established) when the drug is used chronically and dosage is titrated carefully for sickle cell anemia.117 164
Individualize dosage according to hematocrit response (usually to less than 45–50%) and hematologic tolerance of the patient.164 171
Supplemental phlebotomy can be performed as necessary to control hematocrit.164
Administer orally.177 178
If the patient is unable to swallow the commercially available capsules, the contents may be emptied into a glass of water and administered immediately.227
Handle the drug with care; the powder should not be allowed to come in contact with skin or mucous membranes.177 To minimize risk of exposure, wear impervious gloves at all times when handling the drug or bottles containing the drug, including unpacking and inspection, transport within a facility, dose preparation, and dose administration.a b 229 230 Wash hands before and after contact with the drug or bottles containing the drug.229 230 If the contents of the capsule are spilled, wipe the powder immediately with a damp disposable towel and discard in a closed container.177 Caution patients on proper handling, storage, and disposal of the drug.177 229 230 (See Advice to Patients.)
Chronic Myelogenous Leukemia
20–30 mg/kg as a single dose daily.177
Continue therapy indefinitely in patients who show regression or arrest of tumor growth.177
80 mg/kg as a single dose every third day.177 Alternatively, 20–30 mg/kg as a single dose daily.177
Head and Neck Cancer
80 mg/kg as a single dose every third day.177
Administration should begin at least 7 days before initiation of radiation therapy; continue during irradiation as well as afterward provided patient is closely monitored and no unusual or severe reactions occur.177
Sickle Cell Anemia
Initially, 15 mg/kg as a single dose.178
Adjust dosage according to patient's blood cell count.178 If blood cell count is in an acceptable range, dosage may be increased in increments of 5 mg/kg daily once every 12 weeks to a maximum tolerated dosage of up to 35 mg/kg daily.178 Dosage should not be increased if blood cell counts are between the acceptable range and the toxic range.178
If blood cell count is in the toxic range, discontinue hydroxyurea until hematologic recovery occurs; treatment may then be resumed at a reduced daily dose.178 (See Hematologic Toxicity under Dosage and Administration.)
Initially, 15–20 mg/kg daily.164
Most adults respond adequately to dosages of 500 mg to 1 g daily; some patients may respond to as little as 1.5–2 g weekly (along with occasional phlebotomy), while others may require dosages as high as 1.5–2 g or more daily.164
Dosage Modification for Toxicity
In patients receiving hydroxyurea for antineoplastic therapy, withhold therapy when leukocyte count is <2500/mm3 or platelet count is <100,000/mm3.177 Reevaluate leukocyte and platelet counts after 3 days; therapy may be resumed when the counts return to acceptable levels.177 Severe anemia may be managed without interrupting hydroxyurea therapy.177
If hematologic recovery does not occur promptly during combined hydroxyurea and radiation therapy, irradiation may be interrupted.177
In patients receiving hydroxyurea for sickle cell anemia, withhold therapy when neutrophil count is <2000/mm3, the platelet count is <80,000/mm3, the hemoglobin concentration is <4.5 g/dL, or the reticulocyte count is <80,000/mm3 with a hemoglobin concentration of <9 g/dL.178 Following hematologic recovery, resume therapy at a reduced daily dose of 2.5 mg/kg less than the dose that resulted in toxicity.178 Resume titration of the dosage by increasing or decreasing the daily dose in increments of 2.5 mg/kg once every 12 weeks to a maximum tolerated dosage (up to 35 mg/kg daily) at which the patient does not experience hematologic toxicity during 24 consecutive weeks of therapy.178 Further attempts should not be made to titrate to a dosage level that resulted in hematologic toxicity during 2 separate periods of dosage adjustment.178
Temporarily discontinue hydroxyurea if severe gastric distress (e.g., nausea, vomiting, anorexia) resulting from combined hydroxyurea and radiation therapy occurs.177
Discontinue hydroxyurea if cutaneous vasculitic toxicity (e.g., vasculitic ulcerations, gangrene) occurs in patients with myeloproliferative disorders; initiate alternative cytoreductive agents as clinically indicated.228 229
Sickle Cell Anemia
Maximum 35 mg/kg daily.178
No specific dosage adjustment recommended, however close monitoring of hematologic parameters is recommended.177 178
Dosage reduction may be necessary; close monitoring of hematologic parameters recommended.177 178 a b
Sickle Cell Anemia
If Clcr ≥60 mL/min, reduce initial dosage to 15 mg/kg daily.a
If Clcr is <60 mL/min, reduce initial dosage to 7.5 mg/kg daily.a
For hemodialysis patients, administer 7.5 mg/kg following dialysis.a
Careful dosage selection recommended due to possible age-related decrease in renal function; lower dosages may be required.b (See Renal Impairment under Dosage and Administration.)
Cautions for Hydroxyurea
Marked bone marrow depression.177 178 (See Hematologic Effects under Cautions.)
Known hypersensitivity to hydroxyurea or any component of the formulation.177 178
Risk of bone marrow depression (manifested commonly as leukopenia and less commonly as thrombocytopenia and anemia);177 178 usually reversible following discontinuance of the drug.116 117 121 178
Do not initiate therapy for neoplasms in patients with myelosuppression (i.e., leukocyte count <2500/mm3, platelet count <100,000/mm3, or severe anemia).177
Do not initiate therapy for sickle cell anemia in patients with myelosuppression (i.e., neutrophil count <2000/mm3, platelet count <80,000/mm3, hemoglobin concentration <4.5 g/dL, or reticulocyte count <80,000/mm3 with a hemoglobin concentration of <9 g/dL).178
Prior Irradiation or Myelosuppressive Therapy
Possible additive myelosuppressive effects; use with caution in patients who have recently received other cytotoxic drugs or radiation therapy.177
Possible self-limiting megaloblastic erythropoiesis; resembles pernicious anemia but not related to vitamin B12 or folic acid deficiency.177 b Often occurs soon after initiation of therapy and becomes less pronounced as therapy continues.177 b
Hydroxyurea may delay plasma iron clearance and reduce the rate of iron utilization by the erythrocytes; red blood cell survival time not altered.177
Hydroxyurea-induced macrocytosis may mask incidental folic acid deficiency; prophylactic administration of folic acid recommended.178
Patients with HIV Infection
Potentially fatal pancreatitis and hepatotoxicity and potentially severe peripheral neuropathy reported in patients with HIV infection receiving concomitant therapy with antiretroviral agents.177 178 (See Specific Drugs under Interactions.)
Use of hydroxyurea in combination with antiretroviral agents is not recommended.187 Close monitoring for clinical manifestations of pancreatitis and hepatotoxicity is necessary in patients with HIV infection receiving hydroxyurea, especially when the drug is administered in combination with didanosine and/or stavudine.177 178 Permanently discontinue hydroxyurea if signs and/or symptoms of pancreatitis or hepatotoxicity develop.177 178
Possible leukemia or secondary malignancies; assess risk/benefits of therapy for nonmalignant disease (e.g., sickle cell anemia,116 117 118 119 120 151 152 178 polycythemia vera).116 117 136 143 145 146 152 164 171 172
Skin cancer has been reported in patients receiving long-term therapy.177 178
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.127 128 129 131 133 134 135 177 178
Use during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.214 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.177 178
Cutaneous Vasculitic Toxicity
Potentially severe cutaneous vasculitic toxicities (e.g., vasculitic ulcerations, gangrene) reported in patients with myeloproliferative disorders; reported most often in patients with a history of, or concomitantly receiving, interferon therapy.228 229 230 a b
If cutaneous vasculitic ulcerations occur, discontinue hydroxyurea therapy and initiate alternative cytoreductive therapy as indicated.228 229 a b
Adequate Patient Evaluation and Monitoring
Highly toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.c Administer only under constant supervision by clinicians experienced in therapy with cytotoxic agents or the use of this agent for sickle cell anemia.177 178
Monitor hematologic status carefully before initiation of therapy and repeatedly during therapy.177 178 Perform blood counts (e.g., hemoglobin, total leukocyte counts, platelet counts, reticulocyte counts) at least weekly during therapy for neoplasms177 and at least every 2 weeks during therapy for sickle cell anemia;178 bone marrow examination also may be necessary.177 178
Evaluate renal and hepatic function before initiation of therapy and check repeatedly during therapy.177 178
Impairment of Fertility
Testicular atrophy, decreased spermatogenesis, and reduced ability to impregnate females were observed in male rats.177 178
Distributed into milk.177 178 Discontinue nursing or the drug.177
Safety and efficacy not established.116 117 124 177 178 179
Possibility exists of greater sensitivity to the drug in some geriatric individuals.b Select dosage with caution.b (See Geriatric Patients under Dosage and Administration.)
Substantially eliminated by kidneys; assess renal function periodically and select dosage with caution since geriatric patients are more likely to have decreased renal function.229 b
Pharmacokinetics not evaluated in geriatric patients.a b
Possible decreased elimination; close monitoring of hematologic parameters is recommended.177 178
Substantially eliminated by kidneys; increased risk of toxicity.b Use with caution.a b
Possible decreased elimination; reduced dosage and close monitoring of hematologic parameters is recommended.177 178 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Bone marrow suppression.a b
Interactions for Hydroxyurea
Antiretroviral agents (didanosine, stavudine)
Potentially fatal pancreatitis and hepatotoxicity reported in patients with HIV infection receiving concomitant therapy177 178
Concomitant use is not recommended;187 if used, close monitoring for clinical manifestations of pancreatitis and hepatotoxicity is necessary177 178
Potentially severe cutaneous vasculitic toxicities reported in patients with myeloproliferative disorders with a history of, or concomitantly receiving, interferon therapya b
Discontinue hydroxyurea if cutaneous vasculitic ulcerations occura b (see Cutaneous Vasculitic Toxicity under Cautions)
Possible additive bone marrow depression177
Dosage adjustment may be required177
Potential increased serum uric acid concentrations177
Dosage adjustment of uricosuric agent may be required177
Readily absorbed from the GI tract.177 178
Peak serum concentrations are attained within 1–4 hours following oral administration.177 178
Effect of food on absorption is not known.177 178
Rapidly distributed throughout the body; concentrates in leukocytes and erythrocytes.177 178 Crosses the blood-brain barrier and is distributed into ascitic fluid.177 178
Hydroxyurea crosses the placenta and is distributed into milk.177 178
Up to 50% of an orally administered dose is metabolized in the liver; however, precise metabolic pathways not determined.177 178
Nonlinear excretion via 2 separate routes: A saturable pathway most likely involving hepatic metabolism, and a linear pathway involving first-order renal excretion.177 178
Renal and/or hepatic impairment may decrease elimination.177 178
Tight, light-resistant containers at 25°C.177 178
Store out of reach of children and pets.177
Exact mechanism of antineoplastic activity not known; appears to interfere with the synthesis of DNA without interfering with the synthesis of RNA or protein.177 178
Inhibits the incorporation of thymidine into DNA; also may directly damage DNA.
Destroys the tyrosyl free radical that is formed as the catalytic center of ribonucleoside diphosphate reductase, the enzyme that catalyzes the reductive conversion of ribonucleotides to deoxyribonucleotides; this conversion is a critical and probably rate-limiting step in the synthesis of DNA.c
An S-phase inhibitor; may cause cells to arrest at the G1—S border, decreases the rate of cell progression into the S phase, and/or causes cells to accumulate in the S phase as a result of inhibiting DNA synthesis.c
Cytotoxic effects are limited to those tissues with high rates of cellular proliferation; effects are evident only in those cells that are actively synthesizing DNA.c
Stimulates production and increases concentrations of fetal hemoglobin (HbF).106 107 108 109 110 111 112 113 116 117 118 122 123 124 125 155 156 157 158 178
May interfere with the polymerization of hemoglobin S (Hb S) and diminish some of the manifestations of sickle cell disease.106 107 116 117 118 123 124 125 126
Increases water content117 161 162 178 and secondarily increases deformability of red blood cells;117 124 162 178 alters the permeability of vascular endothelial cells and decreases adhesion of red blood cells to these cells;117 163 and alters properties of red blood cell membranes.178
Advice to Patients
Importance of close medical supervision in patients receiving hydroxyurea.c
Importance of informing patients on proper handling, storage, and disposal of the drug, and that hydroxyurea capsules must be handled with care.177 229 230 a b
Importance of informing patients that hydroxyurea powder (contained in the capsules) should not be allowed to come in contact with skin or mucous membranes.177 To decrease risk of exposure, disposable gloves should be worn when patients handle the drug or bottles containing the drug and patients should wash their hands before and after contact with the bottle or capsules.229 230 a b
Importance of informing patients that if the contents of the capsule are spilled, the powder should be wiped up immediately with a damp disposable towel and discarded in a closed container (e.g., plastic bag).177 230
Importance of contacting clinician for instructions on how to discard unused or expired drug.229 230
Importance of informing patients that the capsules should be stored out of reach of children and pets.177 230
Importance of informing patients of the increased risk of a secondary malignancy associated with use of the drug.a b
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.c
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy; advise pregnant women of risk to the fetus.c
Importance of informing patients of other important precautionary information.c (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS DI Essentials. © Copyright 2017, Selected Revisions July 30, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
Only references cited for selected revisions after 1984 are available electronically.
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a. Bristol-Myers Squibb. Droxia (hydroxyurea capsules, USP) prescribing information. Princeton, NJ; 2005 Oct.
b. Bristol-Myers Squibb. Hydrea (hydroxyurea capsules, USP) prescribing information. Princeton, NJ; 2005 Oct.
c. AHFS drug information 2005. McEvoy GK, ed. Hydroxyurea. Bethesda, MD: American Society of Health-System Pharmacists; 2005:1035-40.
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