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Hydroxyurea

Pronunciation

Class: Antineoplastic Agents
VA Class: AN300
Molecular Formula: CH4N2O2
CAS Number: 127-07-1
Brands: Droxia, Hydrea

Warning(s)

  • Toxicity
  • 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.)

  • Carcinogenicity
  • 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.)

Introduction

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

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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

Polycythemia Vera

Management of polycythemia vera including use as an adjunct to intermittent phlebotomy.136 143 144 145 146 152 164 171 174 176

Cervical Cancer

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

Melanoma

Has been used for treatment of melanoma;177 however, other agents are preferred.166

Ovarian Cancer

Has been used for treatment of recurrent, metastatic, or inoperable ovarian cancer;177 however, other agents are preferred.166

Hydroxyurea Dosage and Administration

General

  • 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

Polycythemia Vera

  • 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

Administration

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.)

Dosage

Adults

Chronic Myelogenous Leukemia
Oral

20–30 mg/kg as a single dose daily.177

Continue therapy indefinitely in patients who show regression or arrest of tumor growth.177

Solid Tumors
Oral

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
Oral

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
Oral

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.)

Polycythemia Vera
Oral

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
Hematologic 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

GI Toxicity

Temporarily discontinue hydroxyurea if severe gastric distress (e.g., nausea, vomiting, anorexia) resulting from combined hydroxyurea and radiation therapy occurs.177

Dermatologic Toxicity

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

Prescribing Limits

Adults

Sickle Cell Anemia
Oral

Maximum 35 mg/kg daily.178

Special Populations

Hepatic Impairment

No specific dosage adjustment recommended, however close monitoring of hematologic parameters is recommended.177 178

Renal Impairment

Dosage reduction may be necessary; close monitoring of hematologic parameters recommended.177 178 a b

Sickle Cell Anemia
Oral

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

Geriatric Patients

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

Contraindications

  • Marked bone marrow depression.177 178 (See Hematologic Effects under Cautions.)

  • Known hypersensitivity to hydroxyurea or any component of the formulation.177 178

Warnings/Precautions

Warnings

Hematologic Effects

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

Erythrocytic Abnormalities

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

Carcinogenicity

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

General Precautions

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

Specific Populations

Pregnancy

Category D.

Lactation

Distributed into milk.177 178 Discontinue nursing or the drug.177

Pediatric Use

Safety and efficacy not established.116 117 124 177 178 179

Geriatric Use

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

Hepatic Impairment

Possible decreased elimination; close monitoring of hematologic parameters is recommended.177 178

Renal Impairment

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

Specific Drugs

Drug

Interaction

Comments

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

Interferon

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)

Myelosuppressive agents

Possible additive bone marrow depression177

Dosage adjustment may be required177

Uricosuric agents

Potential increased serum uric acid concentrations177

Dosage adjustment of uricosuric agent may be required177

Hydroxyurea Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from the GI tract.177 178

Peak serum concentrations are attained within 1–4 hours following oral administration.177 178

Food

Effect of food on absorption is not known.177 178

Distribution

Extent

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

Elimination

Metabolism

Up to 50% of an orally administered dose is metabolized in the liver; however, precise metabolic pathways not determined.177 178

Elimination Route

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

Special Populations

Renal and/or hepatic impairment may decrease elimination.177 178

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 25°C.177 178

Store out of reach of children and pets.177

Actions

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Hydroxyurea

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg

Droxia

Bristol-Myers Squibb

250 mg

Hydroxyurea Capsules

300 mg

Droxia

Bristol-Myers Squibb

400 mg

Droxia

Bristol-Myers Squibb

500 mg*

Hydrea

Bristol-Myers Squibb

Hydroxyurea Capsules

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Droxia 300MG Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 30/$32.99 or 90/$95.97

Hydrea 500MG Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 100/$139.08 or 300/$406.58

Hydroxyurea 500MG Capsules (TEVA PHARMACEUTICALS USA): 100/$90.99 or 300/$251.99

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 30, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Budavari S, ed. The Merck Index. 11th ed. Rahway, NJ: Merck & Co, Inc; 1989:10.

101. Fishbein WN, Winter TS, Davidson JD. Urease catalysis. I. Stoichiometry, specificity, and kinetics of a second substrate: hydroxyurea. J Biol Chem. 1965; 240:2402-6. [PubMed 14304844]

102. Fishbein WN, Carbone PP. Urease catalysis. II. Inhibition of the enzyme by hydroxyurea, hydroxylamine, and acetohydroxamic acid. J Biol Chem. 1965; 240:2407-14. [PubMed 14304845]

103. Smith MJV. Hydroxyurea and infected stones. Urology. 1978; 11:274-7. [PubMed 636134]

104. Martelli A, Buli P, Cortecchia V. Urease inhibitor therapy in infected renal stones. Eur Urol. 1981; 7:291-3. [PubMed 7250161]

105. Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med. 1978; 89:167-72. [PubMed 677578]

106. Rodgers GP, Dover GJ, Noguchi CT et al. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med. 1990; 322:1037-45. [IDIS 265191] [PubMed 1690857]

107. Goldberg MA, Brugnara C, Dover GJ et al. Treatment of sickle cell anemia with hydroxyurea and erythropoeitin. N Engl J Med. 1990; 323:366-72. [IDIS 269366] [PubMed 1695325]

108. Letvin NL, Linch DC, Beardsley GP et al. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N Engl J Med. 1984; 310:869-73. [PubMed 6199670]

109. Adamson JW. Hemoglobin—from F to A, and back. N Engl J Med. 1984; 310:917-8. [PubMed 6199671]

110. Miller BA, Platt O, Hope S et al. Influence of hydroxyurea on fetal hemoglobin production in vitro. Blood. 1987; 70:1824-9. [PubMed 2445401]

111. Charache S, Dover GJ, Moyer MA et al. Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia. Blood. 1987; 69:109-16. [IDIS 224952] [PubMed 2431728]

112. Advani SH, Venugopal P, Charak BS et al. Effect of hydroxyurea on foetal haemoglobin in myeloproliferative & myelodysplastic syndromes. Indian J Med Res. 1990; 92:83-5. [PubMed 1695200]

113. Noguchi CT, Rodgers GP, Serjeant G et al. Levels of fetal hemoglobin necessary for treatment of sickle cell disease. N Engl J Med. 1988; 318:96-9. [PubMed 2447498]

114. Dover GJ, Humphries RK, Moore JG et al. Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production. Blood. 1986; 67:735-8. [IDIS 213190] [PubMed 2418898]

115. Lori F, Malykh A, Cara A et al. Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science. 1994; 266:801-5. [PubMed 7973634]

116. National Heart, Lung, and Blood Institute. Clinical alert: drug treatment for sickle cell anemia announced January 30, 1995. Bethesda, MD: National Library of Medicine; 1995 Jan 30.

117. Charache S, Terrin ML, Moore RD et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995; 332:1317-22. [IDIS 346526] [PubMed 7715639]

118. Schechter AN, Rodgers GP. Sickle cell anemia: basic research reaches the clinic. N Engl J Med. 1995; 332:1372-4. [IDIS 346529] [PubMed 7536300]

119. Ho PTC, Murgo AJ. Hydroxyurea and sickle cell crisis. N Engl J Med. 1995; 332:1008.

120. Silver RT. Hydroxyurea and sickle cell crisis. N Engl J Med. 1995; 332:1008.

121. Charache S, Dover GJ, Moore RD et al. Hydroxyurea and sickle cell crisis. N Engl J Med. 1995; 332:1009.

122. Charache S, Dover GJ, Moore RD et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992; 79:2555-65. [IDIS 296766] [PubMed 1375104]

123. Charache S. Pharmacological modification of hemoglobin F expression in sickle cell anemia: an update of hydroxyurea studies. Experientia. 1993; 49:126-32. [PubMed 7680002]

124. Charache S. Experimental therapy of sickle cell disease: use of hydroxyurea. JAMA. 1994; 16:62-6.

125. Rodgers GP. Recent approaches to the treatment of sickle cell anemia. JAMA. 1991; 265:2097-101. [IDIS 279927] [PubMed 1707463]

126. Eaton WA, Hofrichter J. The biophysics of sickle cell anemia hydroxyurea therapy. Science. 1995; 268:1142-3. [IDIS 347785] [PubMed 7539154]

127. Scott WJ, Ritter EK, Wilson JG. DNA synthesis inhibition and cell death associated with hydroxyurea teratogenesis in rat embryos. Dev Biol. 1971; 26:306-15. [PubMed 5158536]

128. Soukup S, Takacs E, Warkany J. Chromosome changes in embryos treated with various teratogens. J Embryol Exp Morphol. 1967; 18:215-26. [PubMed 6059964]

129. Timson J. Hydroxyurea. Mutat Res. 1975; 32:115-32. [PubMed 765790]

130. Wyarobek AJ, Bruce WR. Chemical induction of sperm abnormalities in mice. Proc Natl Acad Sci USA. 1975; 56:1023-34.

131. DePass LR, Weaver EV. Comparison of teratogenic effects of aspirin and hydroxyurea in the Fisher 344 and Wistar strains. J Toxicol Environ Health. 1982; 10:297. [PubMed 7143483]

132. Evenson DP, Jost LK. Hydroxyurea exposure alters mouse testicular kinetics and sperm chromatin structure. Cell Prolif. 1993; 26:147-59. [PubMed 8471672]

133. DeSesso JM, Goeringer GC. The nature of the embryoprotective interaction of prophylgallate with hydroxyurea. Reprod Tox. 1990; 4:145-52.

134. Ferm VH. Severe developmental malformations: malformations induced by urethane and hydroxyurea in the hamster. Arch Pathol. 1966; 81:174-7.

135. Adlard BPF, Dobbing J. Maze learning by adult rats after inhibition of neuronal multiplication in utero. Pediatr Res. 1975; 9:139-42. [PubMed 1168328]

136. Kaplan ME, Mack K, Goldberg JD et al. Long term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol. 1986; 23:167. [PubMed 3749925]

137. Gebhart E. Sister chromatid exchange (SCE) and structural chromosome aberration in mutagenicity testing. Human Genet. 1981; 58:235-54.

138. Donehower RC. An overview of the clinical experience with hydroxyurea. Semin Oncol. 1992; 19(Suppl):11-9. [PubMed 1641651]

139. Chan PC, Goldman A, Wynder EL. Hydroxyurea: suppression of two-stage carcinogenesis in mouse skin. Science. 1970; 168:130. [PubMed 5417054]

140. Kenzel V, Loerhrke H, Goerttler K et al. Suppression of the first stage of phorbol 12-tetradecanoate 13-acetate-effected tumor promotion in mouse skin by non-toxic inhibition of DNA synthesis. Proc Natl Acad Sci USA. 1984; 81:5858. [PubMed 6435122]

141. Muranyi-Kovacs I, Rudali G. Comparative study of hydroxyurea and urethane in XVII/G mice. Rev Eur Etudes Clin Biol. 1972; 17:93.

142. Philips FS, Sternberg SS. Tests for tumor induction by antitumor agents. In: Grundmann E, Gross R, eds. The ambivalence of cytostatic therapy. New York: Springer-Verlag; 1975:29.

143. Fruchtmann SM, Kaplan ME, Peterson P et al. Acute leukemia (AL), hydroxyurea (HU), and polycythemia vera (PV); an analysis of risk from the polycythemia vera study group. Blood. 1994; 84(Suppl 1):A518.

144. Boivin P. Indications, procedure, and results for the treatment of polycythemia vera by bleeding, pipobroman, and hydroxyurea. Nouv Rev Fr Haematol. 1993; 35:491-8.

145. Weinfeld A, Swolin B, Westin J. Acute leukaemia after hydroxyurea therapy in polycythemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications. Eur J Haematol. 1994; 52:134-9. [PubMed 8168592]

146. Nand S, Messmore H, Fisher SG et al. Leukemic transformation in polycythemia vera: analysis of risk factors. Am J Hematol. 1990; 34:32-6. [PubMed 2327402]

147. Hawkins TE, Carter JM, Romeril KR et al. Lymphoma transformation in polycythemia vera treated with hydroxyurea. Am J Hematol. 1993; 44:290. [PubMed 8238005]

148. Triadou P, Maier-Redelsperger M, Krishnamooorty R et al. Fetal hemoglobin variations following hydroxyurea treatment in patients with cyanotic congenital heart disease. Nouv Rev Fr Hematol. 1994; 36:367-72. [PubMed 7534399]

149. De Montalembert M, Belloy M, Bernaudin F et al. Clinical and hematological response of sickle cell children to treatment with hydroxyurea. Blood. 1994; 84(Suppl):A219.

150. Ohene-Frempong K, Horiuchi K, Stoeckert C et al. Sustained effect of hydroxyurea on HB-F production in children with sickle cell disease. Presented at the 20th annual meeting of the National Sickle Cell Disease Program, Boston, March 18-21, 1995. 1995:A215. Abstract.

151. Vichinsky EP, Lupin BH. A cautionary note regarding hydroxyurea in sickle cell disease. Blood. 1994; 83:1124-8. [IDIS 325308] [PubMed 7509209]

152. Landaw SA. Acute leukemia in polycythemia vera. In: Wasserman LR, Berk PD, Berlen NI, eds. Polycythemia vera and the myeloproliferative disorders. Philadelphia: WB Saunders; 1995:154-65.

153. Patel M, Dukes IAF, Hull JC. Use of hydroxyurea in chronic myeloid leukemia during pregnancy: a case report. Am J Obstet Gynecol. 1991; 165:565-6. [IDIS 294693] [PubMed 1892181]

154. Jackson N, Shuku A, Kamarupaman A. Hydroxyurea treatment for chronic myeloid leukemia during pregnancy. Br J Haematol. 1993; 85:203-4. [PubMed 8251394]

155. Dover GJ, Charache S. HU induction of fetal hemoglobin synthesis in sickle-cell disease. Semin Oncol. 1992; 19(Suppl 9):61-6. [PubMed 1379374]

156. Charache S. HU as treatment for sickle cell anemia. Hemat Oncol Clin North Am. 1991; 5:571-83.

157. Rodgers G. Spectrum of fetal hemoglobin responses in sickle cell patients treated with hydroxyurea: the National Institutes of Health experience. Semin Oncol. 1992; 19(Suppl 9):67-73. [PubMed 1379375]

158. Orringer EP, Parker JP. Hydroxyurea and sickle cell disease. Haematol Pathol. 1992; 6:171-8.

159. Mozzarelli A, Hofrechter J, Eaton WA. Delay time of hemoglobin S polymerization prevents most cells from sickling in vivo. Science. 1987; 237:500-6. [PubMed 3603036]

160. Noguchi CT, Torchia DA, Schechter AN. Intracellular polymerization of sickle hemoglobin: effects of cell heterogeneity. J Clin Invest. 1983; 72:846-52. [PubMed 6886006]

161. Orringer EP, Blythe DS, Johnson AE et al. Effects of hydroxyurea on hemoglobin F and H2content in the rb cells of dogs and patients with sickle cell anemia. Blood. 1991; 78:212-6. [PubMed 1712641]

162. Ballas SK, Dover GJ, Charache S. Effect of hydroxyurea on the rheological sickle erythrocytes in vivo. Am J Hematol. 1989; 32:104-11. [PubMed 2757007]

163. Adragna NC, Fonseca P, Lauf PK. Hydroxyurea affects cell morphology, cation transport, and red blood cells adhesion in cultured vascular endothelial cells. Blood. 1994; 83:553-60. [PubMed 8286751]

164. Wasserman LR, Berk PD, Berlin NI. Polycythemia vera and the myeloproliferative disorders. Philadelphia: WB Saunders; 1995:188-93.

165. Reviewers’ comments (personal observations).

166. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. [PubMed 15529105]

167. Hehlman R, Heimpel H, Hasford J et al. Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. Blood. 1993; 82:398-407. [IDIS 317267] [PubMed 8329700]

168. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994; 330:820-5. [IDIS 326794] [PubMed 8114834]

169. Kantarjian HM, Smith TL, O’Brien S et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-α therapy. Ann Intern Med. 1995; 122:254-61. [IDIS 341915] [PubMed 7825760]

171. Myeloproliferative disorders. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1996 Jan 2.

172. Gruppo Italiano Policitemia. Polycythemia Vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med. 1995; 123:656-64. [PubMed 7574220]

173. Najean Y, Dresch C, Rain JD. The very-long-term course of polycythaemia: a complement to the previously published data of the Polycythaemia Vera Study Group. Br J Haematol. 1994; 86:233-5. [PubMed 8011542]

174. Lofvenberg E, Wahlin A. Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea. Eur J Haematol. 1988; 41:375-81. [PubMed 3197824]

175. West WO. Hydroxyurea in the treatment of polycythemia vera: a prospective study of 100 patients over a 20-year period. South Med J. 1987; 80:323-7. [IDIS 226969] [PubMed 3824016]

176. Sharon R, Tatarsky I, Ben-Arieh Y. Treatment of polycythemia vera with hydroxyurea. Cancer. 1986; 57:718-20. [IDIS 211906] [PubMed 3943010]

177. Bristol-Myers Squibb. Hydrea (hydroxyurea capsules, USP) prescribing information. Princeton, NJ; 2001 Mar.

178. Bristol-Myers Squibb. Droxia (hydroxyurea capsules, USP) prescribing information. Princeton, NJ; 2001 Mar.

179. Charache S, Barton FB, Moore RD et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive switching agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore). 1996; 75:300-26. [IDIS 379062] [PubMed 8982148]

180. Claster S, Vichinsky E. First report of reversal of organ dysfunction in sickle cell anemia by the use of hydroxyurea: splenic regeneration. Blood. 1996; 88:1951-3. [IDIS 374651] [PubMed 8822912]

181. Best PJ, Daoud MS, Pittelkow MR et al. Hydroxyurea-induced leg ulceration in 14 patients. Ann Intern Med. 1998; 128:29-32. [IDIS 398424] [PubMed 9424978]

182. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997; 337:762-9. [IDIS 390959] [PubMed 9287233]

183. Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Semin Hematol. 1997; 34(3 Suppl 3):15-21. [PubMed 9317197]

184. Gao WY, Cara A, Gallo RC et al. Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA. 1993; 90:8925-8. [PubMed 7692440]

185. Gelone SP, Kostman JR. Hydroxyurea in the treatment of human immunodeficiency virus infection. Am J Health-Syst Pharm. 1999; 56:1554-7. [IDIS 429570] [PubMed 10478997]

186. Romanelli F, Pomeroy C, Smith KM. Hydroxyurea to inhibit human immunodeficiency virus-1 replication. Pharmacotherapy. 1999; 19:196-204. [IDIS 418871] [PubMed 10030769]

187. U.S. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2003). Supplement: Hydroxyurea (July 14, 2003). .

188. Montaner JSG, Zala C, Conway B et al. A pilot study of hydroxyurea among patients with advanced human immunodeficiency virus (HIV) disease receiving chronic didanosine therapy: Canadian HIV Trials Network Protocol 080. J Infect Dis. 1997; 175:801-6. [IDIS 384133] [PubMed 9086133]

189. Rossero R, McKinsey D, Green S et al. Open label combination therapy with stavudine, didanosine, and hydroxyurea in nucleoside experienced HIV-1 infected patients. In: Abstracts of the 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1998 Feb 1–5. 1998:A653. Abstract.

190. Rutschmann OT, Opravil M, Iten A et al. A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study. AIDS. 1998; 12:F71-7. [PubMed 9631134]

191. Lori F, Malykh AG, Foli A et al. Overcoming drug resistance to HIV-1 by the combination of cell and virus targeting. In: Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, 1997 Jan 22–26. 1997:A517. Abstract.

192. Drezin NA. Warning letter regarding corrective action required by Bristol-Myers Squibb Company following September 26–28, 1999, presentations on hydroxyurea in the treatment of HIV disease. Rockville, MD: US Food and Drug Administration; 1999 Oct 27.

193. Giacca M, Zanussi S, Comar M et al. Treatment of human immunodeficiency virus infection with hydroxyurea: virologic and clinical evaluation. J Infect Dis. 1996; 174:204-9. [IDIS 368619] [PubMed 8655996]

194. Simonelli C, Nasti G, Vaccher E et al. Hydroxyurea treatment in HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1996; 13:462-4. [IDIS 378690] [PubMed 8970475]

195. Biron F, Lucht F, Peyramond D et al. Anti-HIV activity of the combination of didanosine and hydroxyurea in HIV-1-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 10:36-40. [IDIS 353504] [PubMed 7648282]

196. De Antoni A, Foli A, Lisziewicz J et al. Mutations in the pol gene of human immunodeficiency virus type 1 in infected patients receiving didanosine and hydroxyurea combination therapy. J Infect Dis. 1997; 176:899-903. [IDIS 394085] [PubMed 9333147]

197. Lori F, Jessen H, Foli A et al. Long-term suppression of HIV-1 by hydroxyurea and didanosine. JAMA. 1997; 277:1437-8. [IDIS 384635] [PubMed 9145714]

198. Frank I, Boucher H, Fiscus S et al. Phase I/II dosing study of once-daily hydroxyurea (HU) alone vs didanosine (ddI) alone vs ddI + HU. In: Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1999 Jan 31–Feb 4. 1999:A402. Abstract.

199. Vila J, Nugier F, Bargues G et al. Absence of viral rebound after treatment of HIV-infected patients with didanosine and hydroxycarbamide. Lancet. 1997; 350:635-6. [PubMed 9288048]

200. Vila J, Biron F, Nugier F et al. 1-year follow-up of the use of hydroxycarbamide and didanosine in HIV infection. Lancet. 1996; 348:203-4. [IDIS 369135] [PubMed 8684186]

201. Luzzati R, Di Perri G, Fendt D et al. Pharmacokinetics, safety and anti-human immunodeficiency virus (HIV) activity of hydroxyurea in combination with didanosine. J Antimicrob Chemother. 1998; 42:565-6. [IDIS 414566] [PubMed 9818769]

202. Lisziewicz J, Jessen H, Finzi D et al. HIV-1 suppression by early treatment with hydroxyurea, didanosine, and a protease inhibitor. Lancet. 1998; 352:199-200. [IDIS 407973] [PubMed 9683211]

203. Rose PG, Bundy BN, Watkins EB et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999; 340:1144-53. [IDIS 423013] [PubMed 10202165]

204. Whitney CW, Sause W, Bundy BN et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999; 17:1339-48. [IDIS 428331] [PubMed 10334517]

205. Thomas GM. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N Engl J Med. 1999; 340:1198-1200. [IDIS 423015] [PubMed 10202172]

206. Stehman FB, Bundy BN, Thomas G et al. Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial. J Clin Oncol. 1993; 11:1523-8. [PubMed 8336190]

207. Piver M, Khalil M, Emrich LJ. Hydroxyurea plus pelvic irradiation versus placebo plus pelvic irradiation in nonsurgically staged stage IIIB cervical cancer. J Surg Oncol. 1989; 42:120-5. [PubMed 2796346]

208. Bezwoda WR, Nissenbaum M, Derman DP. Treatment of metastatic and recurrent cervix cancer with chemotherapy: a randomised trial comparing hydroxyurea with cisdiamminedichloro-platinum plus methotrexate. Med Pediatr Oncol. 1986; 14:17-9. [PubMed 3512970]

209. Reviewers’ comments (personal observations) on cervical cancer.

210. National Pediatric and Family HIV Resource Center (NPHRC), Health Resources and Services Administration (HRSA), National Institutes of Health (NIH), and the Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection (the living document April 15, 1999). From web site ().

211. USPHS/IDSA. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep. 1997; 46(RR-12):1-46. [PubMed 9011775]

212. Chronic myelogenous leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jul 15.

213. Anon. Hydroxyurea versus busulphan for chronic myeloid leukaemia: an individual patient data meta-analysis of three randomized trials. Chronic myeloid leukemia trialists’ collaborative group. Br J Haematol. 2000; 110:573-6. [PubMed 10997966]

214. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.

215. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

216. Rutschmann OT, Vernazza PL, Bucher HC et al. Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study. AIDS. 2000; 14:2145-51. [PubMed 11061656]

217. Federici ME, Lupo S, Cahn P et al. Hydroxyurea in combination regimens for the treatment of antiretroviral naive, HIV-infected adults. Int Conf AIDS. 1998; 12:58-9.

218. Havlir DV, Gilbert PB, Bennett K et al. Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression. AIDS. 2001; 15:1379-88. [PubMed 11504959]

219. Weissman SB, Sinclair GI, Green CL et al. Hydroxyurea-induced hepatitis in human immunodeficiency virus-positive patients. Clin Infect Dis. 1999; 29:223-4. [IDIS 430841] [PubMed 10433603]

220. Moore RD, Wong WM, Keruly JC et al. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS. 2000; 14:273-8. [PubMed 10716503]

221. Cepeda JA, Wilks D. Excess peripheral neuropathy in patients treated with hydroxyurea plus didanosine and stavudine for HIV infection. AIDS. 2000; 14:332-3. [PubMed 10716516]

222. Goodrich J, Khardori N. Hydroxyurea toxicity in human immunodeficiency virus-positive patients. Clin Infect Dis. 1999; 29:692-3. [IDIS 440357] [PubMed 10530476]

223. Barreiro P, de Mendoza C, Soriano V et al. Hydroxyurea plus didanosine as maintenance therapy after 1 year on highly active antiretroviral therapy. AIDS. 2000; 14:207-8. [PubMed 10708295]

224. Hellinger JA, Iwane MK, Smith JJ et al. A randomized study of the safety and antiretroviral activity of hydroxyurea combined with didanosine in persons infected with human immunodeficiency virus type 1. American Foundation for AIDS Research Community-Based Clinical Trials Network. J Infect Dis. 2000; 181:540-7. [IDIS 443712] [PubMed 10669337]

225. Gonzalez OY, Jovanovich JF, Mayers DL et al. The lack of therapeutic benefit of adding hydroxyurea to highly active antiretroviral therapy (HAART). J Acquir Immune Defic Syndr. 2002; 30:363-4. [IDIS 483623] [PubMed 12131575]

226. Barry M, Clarke S, Mulcahy F et al. Hydroxyurea-induced neurotoxicity in HIV disease. AIDS. 1999; 13:1592-4. [PubMed 10465092]

227. Bristol Myers Squibb. Hydrea oral solution. Princeton, NJ: 2003 Mar.

228. Food and Drug Administration. MedWatch—Safety alert: Hydrea (hydroxyurea) and Droxia (hydroxyurea) [January 26, 2006]. From FDA web site .

229. Smyth AC. Dear healthcare provider letter regarding safety alert for Hydrea (hydroxyurea). Princeton, NJ: Bristol-Myers Squibb; 2006 Jan 20.

230. Smyth AC. Dear healthcare provider letter regarding safety alert for Droxia (hydroxyurea). Princeton, NJ: Bristol-Myers Squibb; 2006 Jan 20.

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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