Hydroxyurea is an antineoplastic agent that exhibits antiviral activity and beneficial effects against sickle cell anemia.100, 101, 102
Hydroxyurea is indicated in the treatment of resistant chronic myelogenous leukemia (CML).166, 177, 212 Hydroxyurea is an alternative drug for the palliative treatment of chronic-phase CML in patients who cannot undergo allogeneic bone marrow or stem cell transplantation, which is the only therapy known to be curative for this leukemia; interferon alfa, with or without cytarabine, is a preferred therapy in such patients.166, 167, 212 Unlike interferon alfa, hydroxyurea has not been associated with prolonged cytogenetic response (i.e., suppression of Philadelphia chromosome-positive cells) in patients with Philadelphia chromosome-positive CML.168, 169 Hydroxyurea is superior to busulfan for the palliative treatment of CML;212, 213 in a randomized trial, patients receiving hydroxyurea experienced prolonged median survival and less toxicity compared with those receiving busulfan.167
Hydroxyurea is an alternative agent for the palliative treatment of the accelerated phase of CML.166, 212 Hydroxyurea also is used to reduce the white blood cell count prior to bone marrow transplantation or initiation of interferon alfa therapy.212
Hydroxyurea is used in the 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 months106, 107, 111, 113, 114, 116, 117, 118, 122, 123, 124, 125, 151, 155, 156, 157, 158, 178, 179 and is designated an orphan drug by the US Food and Drug Administration for this use. Hydroxyurea is employed in patients with sickle cell anemia in an attempt to increase fetal hemoglobin (Hb F) synthesis and thus potentially reduce sickling of red blood cells and prevent associated clinical sequelae (e.g., painful crises).106, 107, 111, 113, 114, 116, 117, 118, 122, 123, 124, 125, 155, 156, 157, 158, 178, 179 Therapy with the drug in this condition is not curative, and any beneficial effect will be maintained only as long as an effective regimen of hydroxyurea is continued.116, 117, 178, 179 In addition, hydroxyurea therapy in patients with sickle cell anemia is prophylactic, and therefore the drug has no role in the treatment of a crisis in progress.117
Because hydroxyurea is a cytotoxic agent, the possible risks of therapy with the drug, including long-term risks such as secondary neoplasms (e.g., leukemia), should be weighed carefully against the potential benefits in treating a nonmalignant disease such as sickle cell anemia.116, 117, 118, 119, 120, 151, 152, 178 In assessing the benefit versus risk, it should be recognized that clinical efficacy to date has been evidenced principally by amelioration of the clinical course (e.g., reduction in painful crises), and the long-term effect, if any, on progression of organ damage and mortality remains to be elucidated.116, 117, 118 Reversal of previously documented splenic dysfunction has been reported in 2 patients with sickle cell anemia treated with long-term hydroxyurea therapy and may indicate a possible effect of the drug on disease-induced organ damage.180
Prophylactic hydroxyurea therapy may not be appropriate for all patients with sickle cell anemia, and evidence of clinical benefit to date has been established principally in patients with severe, recurrent painful episodes.116, 117, 118, 178, 179 In addition, current evidence suggests that patients with minimal or no increase in hemoglobin F concentrations after an adequate trial of hydroxyurea are not candidates for continued (i.e., long-term) therapy with the drug.118, 165
Early studies on the effects of hydroxyurea in patients with sickle cell anemia evaluated the hematologic response to treatment,106, 111, 113, 114, 122, 123, 124, 125, 151, 155, 156, 157, 158 the doses required to produce the responses,106, 111, 114, 122, 123, 124, 125, 151, 155, 157, 158 and the incidence and severity of myelosuppression associated with the drug.106, 114, 122, 123, 124, 125, 155, 156, 157 Patients considered responders to therapy exhibited substantial increases in Hb F concentrations,106, 111, 113 resulting from increased populations of F cells and F reticulocytes, increased concentrations of Hb F per F cell, and/or increased F-cell survival.106, 107, 108, 109, 110, 111, 112, 113, 114, 122, 123, 125, 155, 156, 157, 158 Increases in median corpuscular volume and median corpuscular hemoglobin also were noted in patients responding to hydroxyurea therapy.106, 111, 113, 122, 123, 124, 125, 155, 158 Initial dosages of hydroxyurea administered in these studies ranged from 3-50 mg/kg daily.106, 111, 114, 122, 123, 124, 125, 151, 155, 156, 157, 158 Patient response to hydroxyurea therapy exhibited marked variability in terms of drug-induced increases in Hb F concentrations, and the dose of drug and duration of treatment necessary to produce a hematologic response.106, 107, 113, 114, 122, 123, 124, 125, 155, 156, 157, 158 Although these early studies were not designed to specifically determine the efficacy of hydroxyurea in ameliorating clinical manifestations of the disease, there also was some evidence of potential clinical benefit from treatment.107, 111, 122, 123, 124, 155, 158
Clinical efficacy of hydroxyurea in ameliorating manifestations of sickle cell anemia has been established to date principally by the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), which was a well-designed, placebo-controlled study of the drug's efficacy in reducing the frequency of painful crises in adults with moderate to severe sickle cell anemia who had a history of 3 or more such crises per year.116, 117, 118, 123, 124, 178, 179 Hydroxyurea produced a 46% reduction in the annual rate of painful crises, with a median of 2.5 or 4.6 crises per year being experienced by patients receiving hydroxyurea or placebo, respectively.116, 117, 118, 119, 178 When only crises severe enough to result in hospitalization were considered, patients experienced a median of 1 or 2.5 crises per year, respectively.117, 178 Patients receiving hydroxyurea also developed fewer episodes of chest syndrome (56 versus 101), a life-threatening complication of sickle cell anemia characterized by chest pain, fever, prostration, and pulmonary infiltrates on chest radiographs, and fewer patients required blood transfusions (55 versus 79) than those receiving placebo.116, 117, 118, 119, 178, 179 Median times to development of the first and second vaso-occlusive crises were 2.76 versus 1.35 months and 6.58 versus 4.13 months in patients receiving hydroxyurea or placebo, respectively.117, 178, 179 There was no evidence of effect on mortality, stroke, or hepatic sequestration in this study.117, 118 However, because interim analysis of data from the study indicated important beneficial effects of hydroxyurea in the management of sickle cell anemia,116, 117, 178, 179 the trial's Data Safety and Monitoring Board recommended that the study be terminated 4 months earlier than the proposed scheduled end date.116, 117 As a result, the study was stopped, clinical investigators at the participating centers were notified of the safety and efficacy of hydroxyurea in the treatment of sickle cell anemia, patients who had been receiving placebo were immediately offered therapy with the drug, and the National Heart, Lung, and Blood Institute issued a clinical alert regarding potential benefits of hydroxyurea in the treatment of sickle cell anemia.116, 117 Because the study ended early, only 134 of 299 patients enrolled had completed the 2-year follow-up.117
The MSH trial did not address the reversibility of chronic organ damage induced by sickle cell disease,117, 118 and it currently is unknown whether inhibition of sickling could affect such preexisting lesions.117, 118, 124, 151 When the study ended, total hemoglobin concentrations, MCV, Hb F concentrations, and proportion of F cells were higher, and the leukocyte, platelet, reticulocyte, and dense cell counts were lower, in the hydroxyurea-treated patients compared with those receiving placebo.117, 179 Differences between the hydroxyurea and placebo groups in MCV and F-cell production were apparent within 8 weeks of treatment onset,117 reached a peak at approximately 40 weeks, and then declined.117 In patients with sickle cell anemia treated with hydroxyurea, fetal hemoglobin (HbF) increases 4-12 weeks following the start of treatment;178 however, a correlation between HbF or F-cell concentrations and reduced frequency of sickle cell crises has not been clearly demonstrated.178 In the MSH, the dose-related cytoreductive effect of hydroxyurea (particularly on neutrophils) correlated strongly with reduced crisis frequency.178, 179, 182, 183
Use in Children, Pregnancy, and Other Considerations
Safety and efficacy of hydroxyurea in children younger than 18 years of age with sickle cell anemia were not assessed in the multicenter study.116, 117, 124, 179 In addition, although there was no evidence of adverse effect on pregnancy outcome in this study, hydroxyurea currently is not recommended for use in patients with sickle cell anemia who are likely to become pregnant; therapy with the drug also is not recommended for those unwilling or unable to follow instructions regarding such therapy or give informed consent stating their willingness to comply with given instructions.116, 117, 121, 124, 179
Hydroxyurea has been used in the palliative treatment of polycythemia vera†, including use as an adjunct to intermittent phlebotomy.136, 143, 144, 145, 146, 152, 164, 171, 174, 176 The drug has been employed effectively for its cytoreductive (myelosuppressive) effects to reduce the excess production of platelets and red blood cells and control associated abnormal hematologic indices (e.g., hematocrit) in this condition and thus potentially prevent clinical sequelae such as thrombotic and hemorrhagic complications.136, 143, 164, 171, 174, 175, 176 Reduction in platelet counts generally occurs more rapidly than control of hematocrit, although at least 80% of patients appear to respond with reduced platelet counts and control of hematocrit within 12 weeks after initiating therapy with the drug.164
Therapy with hydroxyurea for polycythemia vera is not curative, and any beneficial effect of the drug will be maintained only as long as an effective regimen of hydroxyurea is continued.136, 164 If the drug is discontinued, unmaintained remissions usually are of short duration, with thrombocytosis commonly recurring within 7-10 days in patients with high pretreatment platelet counts.164 Because hydroxyurea is a cytotoxic agent, the possible risks of therapy with the drug, including long-term risks such as secondary neoplasms (e.g., leukemia), should be weighed carefully against the potential benefits in treating a myeloproliferative disorder such as polycythemia vera.116, 117, 136, 143, 145, 146, 152, 164, 171, 172 Optimum therapy for the management of polycythemia vera has not been established,136, 164, 171, 172, 173, 175 but drug therapy generally has been reserved for patients whose disease could not be adequately controlled by intermittent phlebotomy alone (i.e., those requiring cytoreductive therapy) or in whom phlebotomy has become impractical or has been associated with thrombotic or other complications.136, 164, 171, 172, 173 When hydroxyurea is used as an adjunct to phlebotomy, phlebotomy requirements are reduced.136, 164, 175 In addition, hydroxyurea-induced cytoreduction may be useful in providing symptomatic relief of severe pruritus that is unresponsive to antihistamines and/or phlebotomy in some patients and also may decrease symptomatic splenomegaly.164, 171, 176 Studies are ongoing to further define the potential risks and benefits and role of various therapies, including drug therapies (e.g., hydroxyurea, interferon alfa), in the management of polycythemia vera.164, 171, 175
Adjunctive Therapy for HIV Infection
Because the results of randomized trials have shown inconclusive benefit and serious, including fatal, toxicity, the use of hydroxyurea as an adjunct to antiretroviral therapy for HIV infection† is not recommended.187 Hydroxyurea has been used investigationally as an adjunct to certain antiretroviral drug regimens to enhance antiretroviral activity in the treatment of HIV infection.185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202 Early data reporting efficacy of hydroxyurea for this use was derived mostly from uncontrolled studies involving short-term follow-up of small numbers of patients, many of whom had early-stage HIV infection and were treatment-naive; limited data were available from controlled clinical trials.186, 190, 195, 217 Further study in randomized trials has not clearly demonstrated the benefit of hydroxyurea as an adjunct to HIV therapy.187 Because of a lack of data from large, randomized, multicenter clinical trials and the potential for serious, sometimes fatal, toxicity, the use of hydroxyurea as a component of combination therapy for HIV infection is not recommended.187
Serious toxicity, including fatal and nonfatal pancreatitis,177, 178, 218 hepatotoxicity (in some cases leading to fatal hepatic failure),177, 178, 218, 219 and peripheral neuropathy (sometimes severe),177, 178, 190, 218, 220, 221 has been reported in patients with HIV infection† receiving hydroxyurea in combination with antiretroviral agents. One randomized trial was terminated when 3 patients receiving the hydroxyurea-containing regimen died from pancreatitis.218 Clinical trends and risk analysis indicate an increased risk of peripheral neuropathy in patients receiving hydroxyurea in combination with didanosine and stavudine.190, 220, 221 Other risks associated with the use of hydroxyurea as an adjunct to antiretroviral therapy in HIV infection, including persistent cytopenias, teratogenic effects, and long-term adverse effects such as secondary neoplasms (e.g., leukemia), also must be considered.185, 187, 195, 222, 225 The risk of hydroxyurea-induced neutropenia is of particular concern in patients with HIV infection,185, 186, 189 and some experts have recommended that hydroxyurea not be administered to patients with a baseline absolute neutrophil count (ANC) of less than 1700/mm3.185
The addition of hydroxyurea to a regimen of didanosine and stavudine or didanosine alone results in moderately enhanced antiretroviral activity.187, 188, 189, 190 In a small randomized trial involving mostly treatment-naive patients with HIV infection, the addition of hydroxyurea 500 mg twice daily versus placebo to didanosine and stavudine was associated with a greater decrease in plasma HIV-1 RNA levels and a greater proportion of patients with undetectable viremia (defined as plasma HIV-1 RNA less than 200 copies/mL) over a 12-week period.190 At the end of 12 weeks, the study was unblinded, and patients receiving placebo who had plasma HIV-1 RNA greater than 200 copies/mL were given the option of adding hydroxyurea to their regimen.216 At a 2-year follow-up, patients receiving hydroxyurea in addition to didanosine and stavudine experienced more toxicity, including nausea and vomiting, fatigue, and peripheral neuropathy, and were more likely to discontinue the treatment than those receiving didanosine and stavudine; most patients in the study stopped the treatment to switch to other regimens containing protease inhibitors.216 When patients previously treated with a regimen of indinavir, zidovudine, and lamivudine were kept on the same regimen or switched to a regimen of didanosine, stavudine, and indinavir, with or without hydroxyurea (600 mg twice daily), patients receiving the hydroxyurea-containing regimen experienced the highest rate of treatment failure, principally because of drug-related toxicity.218
Although hydroxyurea appears to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as didanosine, and initially produce greater suppression of the plasma viral load,187, 188, 189, 190 it also is associated with a decrease in the median CD4+ T-cell count.187, 190, 218, 223, 224, 225 The lack of consistent increase, or eventual decrease, in CD4+ T-cell counts190, 198 may be related to the cytostatic activity and lymphopenic effects of hydroxyurea.185, 186, 188, 197, 201 The long-term clinical outcome of adding hydroxyurea to antiretroviral regimens is unknown.187
The optimum dosage and dosing schedule for hydroxyurea were not established.187 In the study that was terminated because of 3 deaths from pancreatitis, patients received a higher dose of hydroxyurea (600 mg twice daily) than the typical dose used in previous studies (500 mg twice daily).218 In a 12-week pilot study among patients receiving chronic didanosine therapy for advanced HIV infection, a greater reduction in plasma viremia was observed with the addition of hydroxyurea 500 mg twice daily versus hydroxyurea 500 mg once daily.188 In a phase II dosing study, a higher dosage of hydroxyurea (1500 versus 1000 mg daily) administered with didanosine in treatment-naive or previously treated patients with HIV infection was associated with similar efficacy but greater toxicity, particularly neutropenia.198
Hydroxyurea acts on a cellular enzyme that is less likely to mutate compared with viral enzymes that typically mutate to confer drug resistance, and suppression of HIV in response to didanosine in combination with hydroxyurea has been observed despite the onset of known genotypic mutations associated with didanosine resistance.191, 196 Continued suppression of plasma HIV-1 RNA levels has been reported at 1-year follow-up in some patients receiving hydroxyurea and didanosine.197, 200 Viral rebound did not occur up to 1 year following suspension of all antiretroviral therapy in 2 patients with high baseline CD4+ T-cell counts who achieved suppression of HIV-1 RNA levels in plasma and lymph nodes during 1 year of treatment with hydroxyurea and didanosine; this finding suggests that the combination of hydroxyurea and didanosine exerts anti-HIV activity in resting lymphocytes and macrophages, an important reservoir of HIV.199 Hydroxyurea is thought to contribute to the inhibition of HIV replication by enhancing the activity of nucleoside reverse transcriptase inhibitors (see Pharmacology: Antiviral Effects), and hydroxyurea monotherapy is not effective for the treatment of HIV infection.193, 194, 198
Use of hydroxyurea as an adjunct to antiretroviral therapy for HIV infection generally is not recommended;187 if further study is undertaken to explore the possible role of hydroxyurea in this condition (e.g., salvage regimens, therapy for early-stage disease), patients must be closely monitored for potentially serious toxicity.187, 218, 225
Hydroxyurea has been used for the treatment of cervical cancer†;206, 207, 208 however, other agents are considered more effective for the treatment of this neoplasm.203, 204, 205, 209
Hydroxyurea mainly has been used as a radiation sensitizer,206, 207 but evidence from randomized trials indicates that other agents, particularly cisplatin (used alone or in combination), are superior to hydroxyurea for concomitant use with radiation therapy for the treatment of locally advanced cervical cancer.203, 204, 205, 209 (See Uses: Cervical Cancer, in Cisplatin 10:00.) Limited evidence from a small randomized trial of patients with advanced cervical cancer suggests that cisplatin-based chemotherapy is superior to hydroxyurea, which has minimal activity as a single agent in the treatment of metastatic or recurrent cervical cancer.208, 209
Hydroxyurea 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
Although hydroxyurea also is labeled for use in the treatment of melanoma and recurrent, metastatic, or inoperable ovarian cancer,177 other agents are preferred for the treatment of these neoplasms.166 (See Uses: Melanoma in Dacarbazine 10:00 and Uses: Ovarian Cancer in Cisplatin 10:00.)
Hydroxyurea has been used in the treatment of psoriasis† and is reportedly beneficial in the treatment of hypereosinophilic syndrome† that does not respond to corticosteroid therapy.105
Hydroxyurea is administered orally.177, 178
If the patient is unable to swallow the commercially available hydroxyurea capsules, the contents may be emptied into a glass of water and administered immediately.227 Some inert materials may not dissolve and may float on the surface.227
Hydroxyurea is a potent drug that must be handled with care, and the powder should not be allowed to come in contact with skin or mucous membranes.177 Impervious gloves should be worn to reduce the risk of skin exposure to the drug when handling hydroxyurea or bottles containing hydroxyurea.229, 230 Impervious gloves should be worn during handling of hydroxyurea or bottles containing hydroxyurea at all times, including unpacking and inspection, transport within a facility, dose preparation, and dose administration.229, 230 The hands should be washed before and after contact with hydroxyurea or bottles containing hydroxyurea.229, 230 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., a plastic bag).177 Patients should be cautioned on proper handling, storage, and disposal of the drug.177, 229, 230 (See Precautions and Contraindications.)
Extemporaneously Compounded Oral Solution
An extemporaneously compounded oral solution of hydroxyurea has been prepared using the commercially available capsules and a flavored syrup.231
Standardized concentrations for an extemporaneously prepared oral solution of hydroxyurea have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252
Concentration Standards |
|---|
100 mg/mL |
Dosage of hydroxyurea must be individualized and should be based on actual body weight unless the patient is obese or has fluid retention. In these latter instances, dosage is based on ideal weight. Clinicians should consult published protocols for the dosage of hydroxyurea and other chemotherapeutic agents and the method and sequence of administration.
For the treatment of chronic myelogenous leukemia, an adult hydroxyurea dosage of 20-30 mg/kg administered as a single dose daily is recommended.177 An adequate trial period for determining the antineoplastic effectiveness of hydroxyurea is 6 weeks.177 Hydroxyurea therapy should be continued indefinitely in patients who show regression or arrest of tumor growth; however, if marked bone marrow depression occurs at any time, therapy should be interrupted.177 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hematologic Toxicity.)
For the treatment of solid tumors, the recommended adult dosage of hydroxyurea is 80 mg/kg administered as a single dose every third day.177 Alternatively, 20-30 mg/kg may be administered as a single dose daily.177
For the treatment of head and neck cancer during concomitant radiation therapy, the recommended adult dosage of hydroxyurea is 80 mg/kg administered as a single dose every third day.177 Administration of hydroxyurea should begin at least 7 days before initiation of radiation therapy and is continued during irradiation as well as afterwards provided the patient is closely monitored and no unusual or severe reactions occur.177
For the palliative treatment of sickle cell anemia with recurrent moderate to severe painful crises in adults, the recommended initial dosage of hydroxyurea is 15 mg/kg daily (based on the patient's actual or ideal weight, whichever is less) administered as a single dose.178 Some patients receiving the recommended initial dosage of hydroxyurea have experienced severe or life-threatening myelosuppression requiring interruption of therapy and subsequent dosage reduction.178
Following initiation of hydroxyurea therapy, dosage should then be adjusted according to the patient's blood cell count, which should be monitored every 2 weeks.178 If blood cell counts are in an acceptable range (i.e., neutrophil count at least 2500 cells/mm3, platelet count at least 95,000/mm3, hemoglobin concentration exceeding 5.3 g/dL, and reticulocyte count at least 95,000/mm3 if hemoglobin concentration is less than 9 g/dL), the dosage of hydroxyurea 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; the maximum tolerated dosage is defined as the highest daily dose that does not produce hematologic toxicity (i.e., neutrophil count less than 2000 cells/mm3, platelet count less than 80,000/mm3, hemoglobin concentration less than 4.5 g/dL, and reticulocyte count less than 80,000/mm3 if hemoglobin concentration is less than 9 g/dL) during 24 consecutive weeks of therapy.178 If blood cell counts are between the acceptable range and the toxic range, the dosage should not be increased.178 If a patient's blood cell count is in the toxic range, hydroxyurea should be discontinued until hematologic recovery occurs; treatment may then be resumed at a reduced daily dose of 2.5 mg/kg less than the dose that resulted in toxicity.178 Titration of the dosage of hydroxyurea may then be resumed 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
Optimum hydroxyurea dosage for the prevention of clinical manifestations of sickle cell anemia remains to be established.116, 179 Because the principal study to date establishing clinical benefit in this condition was designed to measure response among patients treated with maximally tolerated hydroxyurea dosages, it is possible that dosages lower than those employed in this study also may be beneficial.116, 117, 179
In adults enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), hydroxyurea therapy was initiated at a dosage of 15 mg/kg daily.116, 117, 179 Dosage then was increased in increments of 5 mg/kg daily at 12-week intervals as tolerated up to a maximum of 35 mg/kg daily.116, 117, 179 The median dosage at the time of closure of the study was 20 mg/kg daily, and the median maximum tolerated dosage was 17.5 mg/kg daily.179 Preliminary results from this trial suggested that the maximally tolerated dosage may not be required to achieve therapeutic benefits.117, 179
Hydroxyurea therapy has been initiated in a dosage of 15-20 mg/kg daily for the management of polycythemia vera.164 Although therapy also has been initiated with a dosage of 30 mg/kg daily for 1 week, followed by 15 mg/kg daily, omitting the loading dose has resulted in better patient tolerance of initial hydroxyurea therapy.164 Supplemental phlebotomy can be performed as necessary to control hematocrit.164 There is considerable interindividual variability in patient response to hydroxyurea, and dosage must be individualized according to hematocrit response (usually to less than 45-50%) and hematologic tolerance of the patient.164, 171 164 Although most adults with polycythemia vera respond adequately to hydroxyurea 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 Age-related Effects
Pediatric dosage regimens for hydroxyurea have not been established.177
Dosage reduction may be necessary in geriatric patients receiving hydroxyurea.177
Dosage Modification for Toxicity and Contraindications for Continued Therapy
In patients receiving the drug for antineoplastic therapy, hydroxyurea should be withheld when the leukocyte count is less than 2500/mm3 or the platelet count is less than 100,000/mm3.177 Leukocyte and platelet counts should be reevaluated after 3 days; therapy may be resumed when the counts return to acceptable levels.177 Because hematopoietic rebound is prompt, it is usually necessary to omit only a few doses.177 Severe anemia, if it occurs during treatment, may be managed without interrupting hydroxyurea therapy.177
If hematologic recovery has not occurred promptly during combined hydroxyurea and radiation therapy, radiation may be interrupted.177 The need for postponement of radiation therapy has been rare, and irradiation usually has been continued using the recommended dosage and technique.177
In patients receiving the drug for sickle cell anemia, hydroxyurea should be withheld when the neutrophil count is less than 2000/mm3, the platelet count is less than 80,000/mm3, the hemoglobin concentration is less than 4.5 g/dL, or the reticulocyte count is less than 80,000/mm3 with a hemoglobin concentration of less than 9 g/dL.178 Recovery from myelosuppression usually is rapid when therapy is interrupted.178 Following hematologic recovery, hydroxyurea therapy may be resumed at reduced dosage.178 (See instructions for dosage reduction in Dosage: Sickle Cell Anemia under Dosage and Administration.)
Fatal pancreatitis has occurred in patients receiving hydroxyurea in combination with antiretroviral agents, particularly didanosine, with or without stavudine.177, 178 Hydroxyurea should be permanently discontinued in patients who develop signs and/or symptoms of pancreatitis.177, 178
Fatal hepatotoxicity has occurred in patients receiving hydroxyurea in combination with antiretroviral agents, particularly didanosine, with or without stavudine.177, 178 Hydroxyurea should be discontinued permanently in patients who develop signs and/or symptoms of hepatotoxicity.177, 178
Hydroxyurea may potentiate some adverse reactions typically observed with radiation therapy alone, such as gastric distress and mucositis.177 Interruption of hydroxyurea therapy may be required in patients who experience severe GI toxicity.177
If cutaneous vasculitic toxicity, such as vasculitic ulcerations or gangrene, develops in patients with myeloproliferative disorders, hydroxyurea therapy should be discontinued and therapy with alternative cytoreductive agents should be initiated as clinically indicated.228, 229
Dosage in Renal and Hepatic Impairment
The effect of renal or hepatic impairment on the elimination of hydroxyurea has not been fully evaluated.177, 178 Specific dosage recommendations for patients with renal or hepatic impairment are not available; however, the manufacturer recommends close monitoring of hematologic parameters in such patients.177, 178 Reduction of hydroxyurea dosage should be considered for patients with impaired renal function.177, 178
Hydroxyurea's principal toxic effect is bone marrow depression.177, 178 Leukopenia is usually the first and most common manifestation of bone marrow toxicity.177, 178 Thrombocytopenia and anemia occur less often and are usually preceded by leukopenia.177, 178 Hematologic status must be carefully monitored in patients receiving hydroxyurea.177, 178 (See Cautions: Precautions and Contraindications.) Recovery from bone marrow depression is usually rapid when hydroxyurea therapy is interrupted;177, 178 however, persistent cytopenia may occur rarely.
Self-limiting megaloblastic erythropoiesis is often seen soon after the initiation of hydroxyurea therapy177 and becomes less pronounced as therapy continues. The morphologic change resembles pernicious anemia but is not related to vitamin B12 or folic acid deficiency177 and is not necessarily accompanied by anemia. Hydroxyurea-induced macrocytosis may mask incidental folic acid deficiency, and the manufacturer recommends prophylactic administration of folic acid.178 Hemolysis and decreased serum iron values have also been reported. Hydroxyurea may delay plasma iron clearance and reduce the rate of iron utilization by the erythrocytes, but it does not appear to alter the red blood cell survival time.177
The principal short-term risk of hydroxyurea in the treatment of sickle cell anemia also is myelosuppression.106, 122, 123, 125, 155, 156, 157, 158, 178 In early studies in patients receiving initial hydroxyurea dosages of 3-50 mg/kg daily,106, 111, 114, 122, 123, 124, 125, 151, 155, 156, 157, 158 myelosuppression generally was mild,106, 122, 123, 125, 155, 156, 157, 158 defined as a neutrophil count less than 2000/mm3 or reticulocyte or platelet count less than 80,000/mm3.123, 156 Patients did not experience any bleeding episodes156 nor an increased incidence of infection,122, 156 although severe anemia was noted rarely.122, 156 The reported incidence and degree of myelosuppression were greater in patients who responded to hydroxyurea therapy than in those who did not respond.106, 125, 157 In the multicenter study establishing efficacy of hydroxyurea in preventing painful crises in patients with sickle cell anemia receiving dosages up to 35 mg/kg daily (the Multicenter Study of Hydroxyurea in Sickle Cell Anemia [MSH]), bone marrow suppression, which was reversible following discontinuance of the drug, also was the principal adverse effect observed.116, 117, 121, 178 Patients were monitored carefully every 2 weeks for evidence of myelosuppression116, 117, 121 (defined by absolute neutrophil counts less than 2000/mm3, absolute reticulocyte counts less than 80,000/mm3, a decrease in hemoglobin concentrations from a baseline of 7 g/dL or more to 4.5-5 g/dL, reticulocyte counts less than 320,000/mm3, or hemoglobin concentrations less than 4.5 g/dL).116, 117, 178 No deaths were attributed to treatment with hydroxyurea and no neoplastic disorders developed during the study, which lasted for an average follow-up of 21 months.117, 178, 179 Treatment was discontinued permanently for medical reasons in about 10% of patients receiving hydroxyurea; in a few such patients, an unacceptable degree of myelotoxicity was experienced at the initial dosage of 2.5 mg/kg daily.117 Treatment was withheld temporarily in virtually all patients receiving the drug because of bone marrow depression, but blood counts generally recovered within 2 weeks.117, 178 No patient experienced life-threatening myelosuppression.116, 117, 121
Hemoglobin concentrations repeatedly exceeded 12.8 g/dL in about 7% of patients receiving hydroxyurea but not transfusions in the multicenter study of sickle cell anemia; such increase could result in potentially adverse consequences because of increased blood viscosity (if Hb-F levels were not sufficiently high to inhibit sickling of red cells in vivo).117 Thrombocytosis manifested as platelet counts exceeding 800,000/mm3 occurred in about 3% of patients receiving the drug in this study.117 However, no morbidity was associated with the markedly elevated hemoglobin concentrations or platelet counts.117
Although hydroxyurea-induced myelosuppression usually is made to therapeutic use in patients with polycythemia vera, dose-dependent myelotoxicity can occur during therapy with the drug in such patients; the risk of clinical toxicity generally can be minimized by adequate monitoring and titration of dosage (e.g., by reducing hydroxyurea dosage and increasing the use of supplemental phlebotomy if necessary).136, 164, 174, 175, 176 Despite good long-term hematologic control, thrombotic episodes can occur in patients receiving hydroxyurea for polycythemia vera.136, 172 However, some evidence indicates that the risk of thrombotic complications is reduced overall compared with phlebotomy therapy alone in patients with this disease, at least during for the first several years of such therapy.136, 164, 176
Adverse GI effects include stomatitis, nausea, vomiting, anorexia, constipation, and diarrhea;177, 178 ulceration of the buccal mucosa and GI epithelium may occur with severe hydroxyurea intoxication. Hydroxyurea may potentiate some adverse reactions typically observed with radiation therapy alone, such as gastric distress and mucositis.177
Severe gastric distress (e.g., nausea, vomiting, anorexia) resulting from combined hydroxyurea and radiation therapy may usually be controlled by temporarily discontinuing hydroxyurea administration.177 Severe GI intolerance, which can require discontinuance of the drug, also has occurred when hydroxyurea was used for the treatment of polycythemia vera;136 stomatitis also has been reported in patients receiving the drug for this disease.176
Although inflammation of mucous membranes (mucositis) at the site of irradiation may be attributed to radiation therapy alone, hydroxyurea may exacerbate this effect.177 Pain or discomfort from mucositis at the site of irradiation usually may be controlled by topical anesthetics and oral analgesics.177 If inflammation of the mucous membranes is severe, hydroxyurea therapy may be temporarily interrupted, and if it is extremely severe, radiation therapy also may be temporarily postponed; however, it has rarely been necessary to terminate these therapies.177
Pancreatitis, in some cases fatal, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents, particularly didanosine, with or without stavudine.177, 178, 192 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Pancreatic Toxicity.)
Hepatotoxicity, in some cases resulting in fatal hepatic failure, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents.177, 178 Fatal hepatotoxicity occurred most frequently in patients receiving combination therapy with hydroxyurea, didanosine, and stavudine.177, 178 Elevation of serum concentrations of hepatic enzymes has been reported in patients receiving hydroxyurea.177, 178 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hepatic Toxicity.)
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients receiving hydroxyurea for myeloproliferative disorders, particularly in patients who have received or who are receiving interferon therapy.228, 229, 230 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Dermatologic Toxicity.)
Maculopapular rash, skin ulceration, dermatomyositis-like skin changes, and peripheral and facial edema have been reported in patients receiving hydroxyurea.177, 178 Mild, reversible, dermatologic reactions such as maculopapular rash, facial erythema, and pruritus may occur in some patients.177, 178 Alopecia has occurred rarely.177, 178 Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have occurred in some patients after several years of daily maintenance therapy with the drug.177, 178 In addition, the development of cutaneous leg ulcers has been reported in patients receiving chronic treatment with hydroxyurea.181 In most cases, the ulcers resolved completely following discontinuance of the drug.181 Skin cancer also has been reported.177, 178
Peripheral neuropathy, in some cases severe, has occurred in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine.177, 178 Acute delirium has been reported in a patient receiving hydroxyurea and antiretroviral agents.225
Rarely, neurologic disturbances such as headache, dizziness, disorientation, hallucinations, and seizures, have been reported in patients receiving hydroxyurea.177, 178 The use of large doses of hydroxyurea may produce moderate drowsiness.177, 178
Acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea have been reported rarely in patients receiving hydroxyurea.177, 178 Pulmonary fibrosis also has occurred rarely in patients receiving the drug.177, 178
Suppression of renal tubular function has occurred in some patients receiving hydroxyurea and may be accompanied by hyperuricemia and elevated BUN and serum creatinine concentrations.177, 178 Abnormal retention of sulfobromophthalein also has been reported.177, 178
A median decrease in CD4+ T-cell count of approximately 100/mm3 was reported in patients with HIV infection receiving hydroxyurea, didanosine, stavudine, and indinavir in a clinical trial.177, 178, 218
Fever, chills, malaise, edema, and asthenia have occurred in patients receiving hydroxyurea.177, 178 Dysuria has occurred rarely.177, 178
Parvovirus B19 infection developed in at least one patient receiving hydroxyurea for the treatment of sickle cell anemia;117, 178, 179 however, this infection also occurred in several patients who received placebo in this controlled study, and the virus-induced aplastic crises were not prolonged, with all patients recovering uneventfully.117, 179 Alopecia, rash, fever, and GI disturbances also were reported in patients with sickle cell anemia, but they occurred comparably in patients receiving the drug or placebo.117, 178
Other adverse effects reported in patients receiving hydroxyurea for the treatment of polycythemia vera generally were mild174, 175, 176 and included fever176 and hyperbilirubinemia.176
Precautions and Contraindications
Hydroxyurea is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. Hydroxyurea therapy may be complicated by severe, sometimes life-threatening or fatal, adverse effects.177, 178 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents or the use of this agent for sickle cell anemia.177, 178
Hydroxyurea should be administered with caution to patients who have recently received other cytotoxic drugs or radiation therapy, since bone marrow depression is likely in these patients.177 In addition, an exacerbation of post-irradiation erythema may occur.177
Hematologic status, including bone marrow examination as clinically indicated, should be determined before initiation of therapy and checked repeatedly during treatment with hydroxyurea.177, 178 Antineoplastic therapy with hydroxyurea should not be initiated in patients with myelosuppression (i.e., leukocyte count less than 2500/mm3, platelet count less than 100,000/mm3, or severe anemia).177 Complete blood cell counts including determination of hemoglobin level, total leukocyte counts, and platelet counts should be performed at least weekly during therapy for neoplasms.177 Hydroxyurea therapy for sickle cell anemia should not be initiated in patients with myelosuppression (i.e., neutrophil count less than 2000/mm3, platelet count less than 80,000/mm3, hemoglobin concentration less than 4.5 g/dL, or reticulocyte count less than 80,000/mm3 with a hemoglobin concentration of less than 9 g/dL).178 Complete blood cell counts should be performed at least every 2 weeks during therapy for sickle cell anemia.178 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 or polycythemia vera.117, 164 Careful monitoring of hematologic status is necessary to determine the need for interruption of hydroxyurea therapy and dosage reduction in patients experiencing myelotoxicity (see Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hematologic Toxicity in Dosage and Administration: Dosage).177, 178
Renal and liver function should be evaluated before initiation of therapy and checked repeatedly during treatment with hydroxyurea.177, 178 Hydroxyurea should be used with caution in patients with renal dysfunction.177, 178
Hydroxyurea-induced macrocytosis may mask incidental folic acid deficiency; prophylactic administration of folic acid is recommended in patients receiving the drug.178
Patients receiving hydroxyurea for sickle cell anemia or polycythemia vera must understand that therapy with the drug is not a cure for these diseases (i.e., beneficial effects of hydroxyurea are maintained only as long as the patient complies with the prescribed dosage) and that the long-term risks associated with such therapy have not been established.116, 117, 118, 121, 124, 136, 164, 171, 178, 183 Secondary leukemias have been reported in patients receiving long-term therapy with hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia.177, 178 (See Cautions: Mutagenicity and Carcinogenicity.) Because of the potential risks of cytotoxic therapy, all patients with either of these diseases must be evaluated carefully before initiation of hydroxyurea therapy and monitored during treatment, including for potential myelotoxic effects.116, 117, 120, 121, 124, 136, 164, 171, 178 The beneficial effects of hydroxyurea usually are not apparent for several months, and its use must be carefully monitored.117, 118, 119, 120, 121, 136, 164
Use of hydroxyurea in combination with antiretroviral agents is not recommended because of the inconclusive benefit and serious toxicity associated with such regimens.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
Patients should be cautioned on proper handling of hydroxyurea.177 Hydroxyurea is a potent drug that must be handled with care, and the powder should not be allowed to come in contact with skin or mucous membranes.177 Disposable gloves should be worn to reduce the risk of skin exposure to the drug when handling hydroxyurea or bottles containing hydroxyurea.229, 230 The hands should be washed before and after contact with hydroxyurea or bottles containing hydroxyurea.229, 230 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., a plastic bag).177, 230 Hydroxyurea capsules should be stored out of reach of children and pets.177, 230 A clinician should be contacted for instructions on how to discard unused or expired hydroxyurea capsules.229, 230
Hydroxyurea is contraindicated in patients with known hypersensitivity to the drug or any component of the formulation.177, 178
Safety and efficacy of hydroxyurea in children have not been established.177, 178
Because geriatric patients may be particularly sensitive to the effects of hydroxyurea, they may require a lower dosage of the drug.177 Because hydroxyurea is excreted by the kidney, and renal function may be decreased in geriatric patients, dosage should be titrated carefully, usually initiating therapy at the low end of the dosage range, and renal function should be monitored.229
Mutagenicity and Carcinogenicity
Long-term risks, including possible carcinogenic potential, associated with hydroxyurea therapy for the treatment of sickle cell anemia or polycythemia vera are not clearly established.111, 116, 117, 118, 119, 120, 124, 136, 144, 145, 146, 147, 151, 152, 156, 164, 171, 172, 175, 177, 178, 183
Hydroxyurea is genotoxic in a wide range of test systems and is presumed to be a human carcinogen.177, 178 Intraperitoneal administration of hydroxyurea 125-250 mg/kg (approximately 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) 3 times weekly for 6 months to female rats resulted in an increased incidence of mammary tumors in rats surviving to 18 months.177, 178 In vitro tests have shown the drug to be mutagenic to bacteria, fungi, protozoa, and mammalian cells;177, 178 in addition, in vitro tests in hamster cells and human lymphoblasts and in vivo tests (i.e., SCE assay in rodents, mouse micronucleus assay) have shown hydroxyurea to be clastogenic.177, 178 Hydroxyurea also causes transformation of rodent embryo cells to a tumorigenic phenotype.177, 178 According to the results of other studies, hydroxyurea suppressed two-stage carcinogenesis in mouse skin111, 139, 140 and was considered noncarcinogenic in 2 small studies in animals.111, 141, 142 Although the risk of carcinogenesis/leukemogenesis in humans treated with hydroxyurea currently is unknown,111, 116, 117, 118, 119, 120, 121, 122, 123, 124, 136, 144, 145, 146, 147, 152, 156, 164 it should not be discounted.111, 116, 117, 118, 119, 120, 121, 122, 123, 124, 136, 144, 145, 146, 147, 152, 156, 164, 172, 177, 178
The most extensive, well-documented clinical evidence of the leukemogenic potential of the drug is inconclusive.111, 116, 117, 118, 119, 120, 122, 123, 136, 143, 147, 152, 156, 164 Data from the Polycythemia Vera Study Group revealed a 5.9% incidence of acute leukemia after a medical follow-up in 51 patients with polycythemia vera who were treated with hydroxyurea117, 119, 120, 136, 143, 164 doses somewhat greater than those used to treat sickle cell anemia.118, 164 The corresponding incidence of acute leukemia in a historical control group of 134 patients with polycythemia vera treated with phlebotomy alone was 1.5%.117, 119, 120, 143, 152, 164 The 3.9-fold increased incidence was not statistically significant,111, 116, 117, 118, 119, 120, 123, 136, 143, 164 but the sample size was relatively small;111, 117, 119, 136, 143, 164 the median observation period was 8.6 years.117, 143 An update on patients enrolled in the Polycythemia Vera Study Group reported an additional patient treated with hydroxyurea who had developed acute leukemia and a fifth patient who had died of a myeloproliferative syndrome.120, 152, 164 Recalculation that includes these additional cases as well as 2 additional cases that occurred in patients treated with phlebotomy alone results in an incidence of acute leukemia in hydroxyurea-treated polycythemia vera patients of 7.8%,152, 164 which was not significantly different from the 3% rate in the phlebotomy group,164 but the sample size still is relatively small and the possibility of a leukemogenic effect cannot be excluded.152, 164 In 3 smaller studies involving patients with polycythemia vera who were treated with hydroxyurea as the sole myelosuppressive agent, the reported median incidence of acute leukemia was 10.5%.120, 144, 145, 146 Non-Hodgkin's lymphoma, a complication of chlorambucil treatment in patients with polycythemia vera, has been reported in at least one patient with polycythemia vera treated with hydroxyurea.120, 147 The relevance of cancer incidence data in patients with polycythemia vera who received hydroxyurea to that of patients receiving the drug for sickle cell anemia has been questioned, 117, 119, 120 since polycythemia vera, unlike sickle cell anemia, is a myeloproliferative stem-cell disorder117, 123 that has a tendency to evolve into acute leukemia.117 However, both diseases are characterized by an intense erythroid turnover.120
No cases of secondary leukemia or malignancies were observed in 64 hydroxyurea-treated patients with erythrocytosis secondary to inoperable cyanotic congenital heart disease.117, 119, 148 These patients received hydroxyurea dosages of 9-21 mg/kg daily for 2-15 years;117 mean duration of treatment was 5.7 years.117, 119, 148
Skin cancer has been reported in patients receiving long-term therapy with hydroxyurea.177, 178
Hydroxyurea is a mutagen.123, 128, 129, 130, 177, 178 The drug also is a clastogen and reportedly a strong inducer of chromosomal breaks in vitro;111, 123, 128, 137, 156, 158, 178 however, hydroxyurea exhibited only weak activity in inducing sister chromatid exchange.111, 137 Chromosomal abnormalities have been noted in patients with lung cancer120, 129, 138 or polycythemia vera120, 145 who were treated with hydroxyurea, and in cultured cells treated with the drug.120, 138 Abnormal karyotypes have been observed in lymphocytes from patients with psoriasis who were treated with hydroxyurea, but no control studies were performed in untreated patients with psoriasis.111 Hydroxyurea's ability to induce chromosomal abnormalities was considered minor in some preliminary studies,111, 122 but longer follow-up of additional patients receiving the drug for sickle cell anemia or polycythemia vera will be required to assess the risk.122, 165
Pregnancy, Fertility, and Lactation
Hydroxyurea can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.177, 178, 214, 215 Hydroxyurea crosses the placenta and has been shown to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys, when administered in doses within onefold of the human dose based on body surface area.127, 128, 129, 131, 133, 134, 135, 177, 178 Administration of 180 mg/kg daily (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) or 30 mg/kg daily (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) of the drug resulted in fetal malformations (including partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae) in rats or rabbits, respectively.177, 178 Embryotoxicity, manifested as decreased fetal viability, reduced live litter sizes, and developmental delays, also was observed.177, 178 Single doses of 375 mg/kg (approximately 1.7 times the maximum recommended human daily dose on a mg/m2 basis) in rats resulted in growth retardation and impaired learning ability.177, 178 In other studies in rats, the teratogenic properties of hydroxyurea were demonstrated at dosages 10- to 20-fold greater than those administered in patients with sickle cell disease,123, 131, 135 and aspirin was equally teratogenic at comparable dosages.111, 123, 131
There are no adequate and well-controlled studies to date using hydroxyurea in pregnant women.177, 178 Hydroxyurea should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.214 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.177, 178 Women of childbearing potential should be advised to avoid becoming pregnant during therapy with hydroxyurea.177, 178
Children born to patients entered in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and treated with hydroxyurea have shown no evidence of birth defects or developmental abnormalities to date.117, 183 Women with chronic myelogenous leukemia receiving hydroxyurea therapy have also borne normal children,117, 123, 124, 153, 154 and there currently are no reports of hydroxyurea-treated males with chronic myelogenous leukemia having fathered a child with genetic abnormalities,123 but it has not been established whether risks exist to a fetus whose father was being treated with the drug at the time of conception.124, 156 There currently are no reports establishing hydroxyurea as causing any teratogenic or mutagenic effects in humans;117, 165 however, because hydroxyurea affects DNA synthesis, its potential as a mutagenic agent should be considered in male or female patients who may contemplate conception.177, 178 In addition, although the long-term risks of hydroxyurea (including teratogenesis, mutagenesis, leukemogenesis/carcinogenesis, and chromosomal abnormalities) are poorly documented,122, 124, 133, 135 they should not be ignored.122, 177, 178 Therefore, hydroxyurea should not be administered to pregnant women or to women of childbearing age who may become pregnant unless the potential benefit to the patient outweighs the possible risk to the fetus.177, 178 In addition, some clinicians recommend that hydroxyurea not be used for long-term therapy (e.g., sickle cell anemia) in patients likely to become pregnant,116, 156, 178 and that every effort be made to prevent conception and pregnancy in women who are patients (or partners of patients) receiving the drug chronically.111, 122, 156, 165, 178
Testicular atrophy, decreased spermatogenesis, and reduced ability to impregnate females were observed in male rats receiving hydroxyurea 60 mg/kg daily (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis).177, 178 Hydroxyurea also has been shown to induce abnormalities in sperm morphology and chromatin structure in mice.123, 130, 132 The cytologic appearance of mouse sperm was altered at hydroxyurea dosages in excess of 25 mg/kg,117, 132 but no abnormalities have been noted in offspring of male mice treated with the drug.117
Hydroxyurea is distributed into milk.177, 178 Because of the potential for serious adverse reactions to hydroxyurea in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.177, 178
Formal studies evaluating potential drug interactions with hydroxyurea have not been performed to date.177, 178 Concomitant therapy with hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse effects, and dosage adjustment may be required.177 Because hydroxyurea therapy may cause increased serum uric acid concentrations, dosage adjustment of uricosuric medication may be required.177
Acute mucocutaneous toxicity has been observed in patients receiving hydroxyurea dosages several times the recommended dose.177, 178 In addition, soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been reported.177, 178
The exact mechanism of antineoplastic activity of hydroxyurea has not been fully determined. Some studies indicate that hydroxyurea interferes with the synthesis of DNA without interfering with the synthesis of RNA or protein.177, 178 Although hydroxyurea may have multiple sites of action, it appears likely that the drug inhibits the incorporation of thymidine into DNA; in addition, it may directly damage DNA. Hydroxyurea can destroy 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. The drug is an S-phase inhibitor and may cause cells to arrest at the G1—S border, decrease the rate of cell progression into the S phase, and/or cause cells to accumulate in the S phase as a result of inhibiting DNA synthesis. Animal studies indicate that the cytotoxic effects of hydroxyurea are limited to those tissues with high rates of cellular proliferation and the effects are evident only in those cells that are actively synthesizing DNA.
Hydroxyurea can stimulate production and increase concentrations of fetal hemoglobin (Hb F);106, 107, 108, 109, 110, 111, 112, 113, 116, 117, 118, 122, 123, 124, 125, 155, 156, 157, 158, 178 however, the exact mechanisms(s) of this effect has not been elucidated.106, 109, 113, 114, 118, 122, 123, 124, 125, 126, 155, 156, 157, 158, 178 In patients with sickle cell anemia, beneficial effects have been observed at myelosuppressive dosages, and it has been suggested that hydroxyurea-induced stimulation of fetal hemoglobin production may result indirectly from induction of erythropoiesis, albeit potentially perturbed.106, 108, 110, 122, 123, 125, 155, 156, 157, 158 However, some evidence from studies with erythroid progenitors suggests that other mechanisms may be involved.106, 114, 125, 155, 158 In addition, the association between macrocytosis and response in sickle cell anemia suggests that factors controlling production of fetal hemoglobin-containing peripheral-blood red cells (F cells) may interact directly or indirectly with determinants of erythroid-volume regulation.106, 117, 124, 158, 161 Patients with sickle cell anemia and nonhuman primates with anemia who respond to hydroxyurea exhibit increases in the percentage of fetal hemoglobin-containing reticulocytes (F reticulocytes) and F cells and in the amount of fetal hemoglobin within these cells.106, 107, 108, 109, 110, 111, 112, 113 Some evidence indicates that the increase in fetal hemoglobin results principally from increased F-cell production rather than from increased concentrations per cell, although the latter contributes to the increase.106
The polymerization of deoxyhemoglobin S (deoxy Hb S) into a viscous gel of aggregated protein is responsible for the sickling of red blood cells and the vaso-occulsive crises that are characteristic of sickle cell anemia.106, 113, 116, 117, 118, 123, 124, 125, 126, 159, 160 Hydroxyurea, through its induction of fetal hemoglobin synthesis, may interfere with the polymerization of hemoglobin S (Hb S) and diminish some of the manifestations of the disease.106, 107, 116, 117, 118, 123, 124, 125, 126 After releasing oxygen to tissues, there is a finite lag or delay time before deoxygenated Hb S polymerizes within red blood cells.123, 126, 159 Biophysical evidence suggests that this delay time is inversely proportional to the intracellular concentration of Hb S.122, 123, 125, 126, 159 Small decreases in Hb S concentration have an exponentially large effect on the delay time;126 therefore, decreasing the Hb S concentration within red blood cells is a strategy for the treatment of the disease and a proposed mechanism by which increasing Hb F concentrations may provide therapeutic benefit in the treatment of sickle cell disease.118, 126 It also has been suggested that hydroxyurea's ability to increase water content117, 161, 162, 178 and secondarily increase deformability of red blood cells,117, 124, 162, 178 to alter the permeability of vascular endothelial cells and decrease adhesion of red blood cells to these cells,117, 163 and to alter properties of red blood cell membranes may contribute to the beneficial effect of the drug in sickle cell anemia.178
Hydroxyurea also may have antiviral effects.115 Because it blocks the cellular enzyme ribonucleotide reductase and decreases the amount of intracellular deoxynucleotides, hydroxyurea inhibits DNA synthesis by human immunodeficiency virus-type 1 (HIV-1) in activated peripheral blood lymphocytes.115, 184 The drug has been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and activated) and macrophages as well as in blood cells infected in vivo obtained from individuals with acquired immunodeficiency syndrome (AIDS).115
The combination of hydroxyurea with didanosine exhibits a synergistic inhibitory effect on HIV-1.115 The mechanism of the synergistic effect between hydroxyurea and nucleoside reverse transcriptase inhibitors is not fully understood.186 One postulated mechanism is that hydroxyurea, a potent inhibitor of the cellular enzyme ribonuclease reductase, depletes intracellular deoxynucleotide triphosphate (dNTP) pools and reduces competition between reverse transcriptase inhibitors and endogenous dNTPs for binding sites on HIV reverse transcriptase, which reduces the rate of HIV-1 DNA synthesis and results in inhibition of HIV replication.184, 185, 186 Depletion of the dNTP pool results in arrest of the cell cycle in the G1 phase prior to DNA synthesis; in HIV-infected cells, incomplete reverse transcription of the viral genome also results from depletion of the dNTP pool.187 Hydroxyurea preferentially depletes intracellular purine and therefore enhances the antiretroviral activity of didanosine and stavudine.187 The observation that hydroxyurea particularly reduces deoxyadenosine triphosphate (dATP) concentrations provided the rationale for study of the drug as an adjunct to didanosine, a nucleoside reverse transcriptase inhibitor that is a synthetic analog of dATP.186, 191 Hydroxyurea also may enhance the activation of nucleoside reverse transcriptase inhibitors by blocking cells in the S phase of the cell cycle, when thymidine kinase, the cellular enzyme responsible for phosphorylation of nucleoside reverse transcriptase inhibitors, is present in the highest concentrations.186
Hydroxyurea is readily absorbed from the GI tract.177, 178 Peak serum concentrations are attained within 1-4 hours following oral administration.177, 178 Blood concentrations decline rapidly and there is no cumulative effect with repeated administration. For this reason, higher blood concentrations are attained if the regular dosage is given in a large, single oral dose than if it is administered in divided doses. Disproportionate increases in peak plasma concentrations and areas under the concentration-time curve (AUCs) result when drug dosage is increased.177, 178 The effect of food on the absorption of hydroxyurea has not been determined.177, 178
Hydroxyurea distributes rapidly throughout the body and concentrates in leukocytes and erythrocytes.177, 178 The estimated volume of distribution of the drug approximates total body water.177, 178 Hydroxyurea crosses the blood-brain barrier; peak hydroxyurea CSF concentrations are attained within 3 hours following oral administration. The drug distributes into ascites fluid, resulting in drug concentrations in ascites fluid of 2-7.5 times less than plasma drug concentrations.177, 178 The drug also is distributed in milk.177, 178
Studies indicate that up to 50% of an orally administered dose of hydroxyurea is metabolized in the liver; however, the precise metabolic pathways have not been determined.177, 178 A minor metabolic pathway may involve degradation of the drug by urease, an enzyme produced by intestinal bacteria.177, 178 Acetohydroxamic acid, possibly resulting from the breakdown of hydroxyurea by urease, was detected in the serum of 3 patients with leukemia treated with hydroxyurea.177, 178
Hydroxyurea undergoes nonlinear excretion via 2 separate routes: a saturable pathway most likely involving hepatic metabolism, and a linear pathway comprised of first-order renal excretion.177, 178 Mean cumulative urinary excretion of 62% of the administered dose at 8 hours was reported in adults with sickle cell anemia.177, 178
The pharmacokinetics of hydroxyurea have not been evaluated separately by age, gender, or race.177, 178 The effects of renal and/or hepatic impairment on the disposition of hydroxyurea have not been fully evaluated.177, 178 Elimination of hydroxyurea may be impaired in patients with renal and/or hepatic dysfunction.177, 178
Studies using14C-labeled hydroxyurea indicate that about one-half an orally administered dose is degraded in the liver and is excreted as respiratory carbon dioxide and in urine as urea. The remaining portion of the drug is excreted intact in urine.
Hydroxyurea is the first clinically available derivative of urea to show antineoplastic activity. The drug is structurally similar to urea and acetohydroxamic acid100, 101, 102 and is also a urease inhibitor.101, 102 Hydroxyurea differs structurally from acetohydroxamic acid by the presence of an amino rather than a methyl group;100, 101 the N -hydroxyformamide (formohydroxamic acid) moiety appears to be responsible for urease inhibition.102
Hydroxyurea occurs as a moisture labile, white, crystalline powder and is freely soluble in water and slightly soluble in alcohol.
Hydroxyurea capsules should be stored in tight containers at 25°C; the manufacturer states that brief exposure to temperatures within the range of 15-30°C is acceptable.177, 178
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 200 mg | ||
250 mg* | Hydroxyurea Capsules | |||
300 mg | Droxia® | Bristol-Myers Squibb | ||
400 mg | Droxia® | Bristol-Myers Squibb | ||
500 mg* | Droxia® | Bristol-Myers Squibb | ||
Bristol-Myers Squibb | ||||
Hydroxyurea Capsules | ||||
Tablets | 1 g* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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. [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. [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. [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. [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. [PubMed 7715639]
118. Schechter AN, Rodgers GP. Sickle cell anemia: basic research reaches the clinic. N Engl J Med . 1995; 332:1372-4. [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. [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. [PubMed 1707463]
126. Eaton WA, Hofrichter J. The biophysics of sickle cell anemia hydroxyurea therapy. Science . 1995; 268:1142-3. [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. [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. [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. [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. [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. [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. [PubMed 3824016]
176. Sharon R, Tatarsky I, Ben-Arieh Y. Treatment of polycythemia vera with hydroxyurea. Cancer . 1986; 57:718-20. [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. [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. [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. [PubMed 9424978]
182. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med . 1997; 337:762-9. [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. [PubMed 10478997]
186. Romanelli F, Pomeroy C, Smith KM. Hydroxyurea to inhibit human immunodeficiency virus-1 replication. Pharmacotherapy . 1999; 19:196-204. [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). Updates may be available at HIV.gov website. [Web]
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. [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. [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. [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. [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. [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. [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. [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. [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. [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. [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. [PubMed 10334517]
205. Thomas GM. Improved treatment for cervical cancer\m/concurrent chemotherapy and radiotherapy. N Engl J Med . 1999; 340:1198-1200. [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 ([Web]).
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. [Fulltext MMWR][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. [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. [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. [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. [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. [Web]
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.
231. Heeney MM, Whorton MR, Howard TA et al. Chemical and functional analysis of hydroxyurea oral solutions. J Pediatr Hematol Oncol. 2004 Mar;26(3):179-84. doi: 10.1097/00043426-200403000-00007. PMID: 15125610.
252. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]