Hydroxyurea is an antimetabolite antineoplastic agent and exhibits beneficial effects against sickle cell anemia.1, 2, 177, 178
Hydroxyurea is used in the treatment of resistant chronic myeloid leukemia (CML).177
In a landmark randomized trial, patients with chronic-phase CML receiving hydroxyurea experienced prolonged median survival and less toxicity compared with those receiving busulfan.167 An individual patient data meta-analysis of 3 randomized trials confirmed that hydroxyurea is superior to busulfan in terms of 4-year survival in patients with Philadelphia chromosome (Ph)-positive CML.213 In 690 patients with Ph-positive CML, survival at 4 years was 53.6% with hydroxyurea therapy compared with 45.1% with busulfan therapy.213 Additionally, a randomized trial (CML-study II) comparing interferon alfa plus hydroxyurea versus hydroxyurea monotherapy found that the combination therapy was associated with an increased median survival time compared with hydroxyurea monotherapy in patients with newly diagnosed chronic-phase CML, suggesting that hydroxyurea augmented interferon efficacy.168
These findings, however, reflect the pre-tyrosine kinase inhibitor (TKI) era, and the therapeutic role of hydroxyurea in CML has become substantially more limited following the introduction of TKIs.32 Nevertheless, hydroxyurea continues to be used by clinicians as a temporary cytoreductive therapy while awaiting definitive diagnostic confirmation, with the aim of reducing leukocyte counts and alleviating symptoms associated with hyperleukocytosis.32 However, the clinical benefit of early cytoreduction with hydroxyurea remains uncertain, particularly in patients who do not present with symptomatic hyperleukocytosis.32
In most patients with CML, the first-line treatment is a TKI.33, 34 According to the National Cancer Institute, hydroxyurea is used primarily for the stabilization of patients with hyperleukocytosis and as palliative therapy in patients with CML who have not responded to other treatment modalities.33 Previous guidelines by the European LeukemiaNet (ELN) suggest that a short course of hydroxyurea may be administered to patients with symptomatic leukocytosis or thrombocytosis while awaiting molecular and cytogenetic confirmation of the diagnosis of CML.34
Hydroxyurea is used to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises.1, 2, 177 Hydroxyurea tablets (Siklos®) are indicated for use in adults and pediatric patients ≥2 years of age, hydroxyurea oral solution (Xromi®) is indicated for use in pediatric patients ≥6 months of age, and hydroxyurea capsules (Droxia®) are indicated for use in adults.1, 2, 178 Hydroxyurea is designated an orphan drug by FDA for this use in pediatric patients.35
Clinical efficacy of hydroxyurea in ameliorating manifestations of sickle cell anemia has been established to date principally by the landmark 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 hydroxyurea-treated 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
In patients with sickle cell anemia treated with hydroxyurea, fetal hemoglobin (HbF) increases 4-12 weeks following the start of treatment; 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 trial, the dose-related cytoreductive effect of hydroxyurea (particularly on neutrophils) correlated strongly with reduced crisis frequency.178, 179, 182, 183
A 2022 Cochrane review of 9 randomized controlled trials, including the MSH trial, evaluated use of hydroxyurea in patients with sickle cell disease (hemoglobin SS [HbSS], hemoglobin SC [HbSC], hemoglobin Sβ0thalassemia [HbSβ0thal] genotypes).40 Overall, evidence suggested that hydroxyurea may be effective in reducing the frequency of vaso-occlusive pain episodes and other acute complications in both adults and children with sickle cell anemia of the HbSS or HbSβ0thal genotypes.40 Evidence was insufficient on the long-term benefits of hydroxyurea, especially in the prevention of the chronic complications of sickle cell disease.40 Evidence was also limited on the effects of hydroxyurea in patients with the HbSC genotype.40
The European Sickle Cell Disease Cohort study (ESCORT‑HU) is a phase 4, prospective, multicenter, observational cohort study evaluating the long-term safety and efficacy of hydroxyurea therapy in patients with sickle cell disease.1, 41 In ESCORT‑HU, 1077 adults with sickle cell disease (including 436 hydroxyurea‑naïve patients; 370 evaluable for ≥12 months) demonstrated improvements after initiation of hydroxyurea.1 Median fetal hemoglobin increased from 5.2% at baseline to 14.2% by at least 6 months after treatment initiation.1 Clinically, the proportion of patients with ≥1 vaso‑occlusive episode decreased (from 63.8% pre‑treatment to 38.4% after 12 months of treatment), as did the proportion of patients with ≥1 acute chest syndrome (from 25.2% pre-treatment to 7.4% after 12 months of treatment), ≥1 hospitalization related to sickle cell disease (from 58.5% pre-treatment to 31.1% after 12 months of treatment), and ≥1 transfusion (from 43.3% pre-treatment to 18.9% after 12 months of treatment), with median event counts generally declining to 0 over 12 months.1
Pediatric data have also demonstrated benefits with hydroxyurea therapy in infants, children, and adolescents with sickle cell anemia.2, 36, 37, 38 According to the manufacturer, the effectiveness of hydroxyurea oral solution in pediatric patients ≥6 months of age with sickle cell anemia is based on an adequate and well-controlled study of hydroxyurea capsules in adults with recurrent moderate to severe pain crises, and additional pharmacokinetic data from a single-arm, open-label study of hydroxyurea oral solution in pediatric patients 10 months to <18 years of age with sickle cell anemia, who were treatment naïve or had not received hydroxyurea within the 6 months preceding enrollment.2
The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was a landmark, multicenter, double-blind, placebo-controlled trial that randomized 193 infants (9-18 months of age) with HbSS or HbSβ0thal to hydroxyurea 20 mg/kg per day or placebo.37 Infants were enrolled irrespective of clinical severity.37 Although the coprimary endpoints of spleen and kidney function preservation were not statistically significantly different, hydroxyurea substantially reduced pain episodes and dactylitis, with trends for decreased acute chest syndrome, hospitalization, and transfusion.37 More recently, a network meta-analysis evaluated pharmacological interventions for sickle cell disease complications in children and adolescents, and found that that hydroxyurea at higher dosages had the most favorable surface under the cumulative ranking curve (SUCRA) profile across efficacy outcomes including prevention of vaso-occlusive crisis, acute chest syndrome (ACS), and transfusion needs.38
In ESCORT‑HU, findings in 405 pediatric patients (2-18 years of a 141 hydroxyurea‑naïve) showed similar hematologic and clinical benefits.1 Median HbF increased from 5.6% at baseline to 12.8% by at least 6 months after initiation of hydroxyurea, with modest hemoglobin increases over 6-12 months.1 Among previously untreated children with ≥12 months follow‑up, hydroxyurea reduced disease complications.1 After 12 months of hydroxyurea treatment, the proportion of patients with ≥1 vaso‑occlusive episode decreased from 69 to 42.5%, the proportion of patients with ≥1 episode of ACS decreased from 24 to 6%, the proportion of patients with ≥1 hospitalization related to sickle cell disease decreased from 75 to 42%, and the proportion of patients with ≥1 transfusion decreased from 46 to 23%; reductions in median episode counts and hospitalization days also were observed.1
The National Heart, Lung, and Blood Institute (NHLBI) provides recommendations for the use of hydroxyurea in patients with sickle cell anemia.36 Hydroxyurea therapy is strongly recommended in adults with sickle cell anemia who have ≥3 sickle cell-associated moderate to severe pain crises within a 12-month period or have sickle cell-associated pain that interferes with daily activities and quality of life.36 The drug is also strongly recommended in adults with sickle cell anemia who have a history of severe and/or recurrent acute chest syndrome (ACS) and in adults with sickle cell anemia who have severe symptomatic chronic anemia that interferes with daily activities or quality of life.36 In infants ≥9 months of age, children, and adolescents with sickle cell anemia, treatment with hydroxyurea should be offered regardless of clinical severity to reduce complications related to sickle cell disease (e.g., pain, dactylitis, ACS, anemia).36 In adults and children with sickle cell disease who have chronic kidney disease and are receiving erythropoietin, hydroxyurea therapy can be added to improve anemia, but this is based on low-quality evidence.36 Hydroxyurea therapy should be discontinued in pregnant and breast-feeding women based on low quality evidence.36
The NHBLI emphasizes that all patients with sickle cell anemia and their families should be educated regarding hydroxyurea therapy.36 A clinical response to treatment with hydroxyurea may take 3-6 months; therefore, a 6-month trial on the maximum tolerated dosage is necessary prior to consideration of discontinuation.36 For patients with a clinical response, long-term hydroxyurea therapy is indicated.36
The American Academy of Pediatrics (AAP) recommends hydroxyurea as the first-line disease-modifying agent for children and adolescents with sickle cell disease.39 Hydroxyurea increases total and fetal hemoglobin levels while reducing vaso-occlusive complications, including painful crises, acute chest syndrome, hospitalizations, and transfusion requirements.39 Hydroxyurea use has a positive impact on health-related quality of life in patients with HbSS or Sβ0-thalassemia.39
Hydroxyurea is used in combination with chemoradiation for locally advanced squamous cell carcinomas of the head and neck, excluding the lip.177
The evidence supporting hydroxyurea for locally advanced head and neck squamous cell carcinoma is primarily derived from mostly older, phase 1/2 trials.30 In particular, 3 consecutive multicenter, phase 2 trials demonstrated that combination regimens incorporating 5‑fluorouracil and hydroxyurea with either cisplatin or paclitaxel, delivered alongside alternating-week, twice‑daily radiation therapy, achieved high response rates, with locoregional control approaching 90% and 3‑year overall survival of approximately 60% in patients with stage IV disease.30
Although hydroxyurea is approved for use in head and neck malignancies, its use in contemporary practice is limited, and it is not routinely incorporated into standard treatment paradigms.30, 31 The American Head and Neck Society lists 5-fluorouracil/hydroxyurea as one of the alternative radiosensitizing chemotherapeutic combinations recommended for treatment of unresectable disease.31
Hydroxyurea is used in the treatment of polycythemia vera† in high-risk patients (i.e., with history of thrombosis or >60 years of age).3, 4, 5, 6
Some experts recommend hydroxyurea and pegylated interferon as first-line cytoreductive drugs of choice in high-risk polycythemia vera.3 Hydroxyurea is recommended as the first-line cytoreductive drug of choice in older (>60 years of age) high-risk patients with polycythemia vera, while pegylated interferon is preferred for younger patients and women of reproductive age.3 Importantly, neither prospective nor well-designed retrospective studies implicate hydroxyurea as amplifying the risk of leukemic transformation in polycythemia vera.3 The 2021 ELN recommendations also consider hydroxyurea as the mainstay cytoreductive drug for patients >60 years of age with polycythemia vera.6
Hydroxyurea has been used in the treatment of myelofibrosis†.7, 8 While Janus kinase (JAK) inhibitors are the pharmacological standard of care for patients with myelofibrosis, traditional therapies include hydroxyurea.7, 9 According to some experts, in patients with myelofibrosis who do not present with anemia or constitutional symptoms, hydroxyurea is considered the preferred first-line therapy for the management of myelofibrosis-associated splenomegaly, leukocytosis, or thrombocytosis.8 Hydroxyurea has been shown to reduce spleen size by approximately half in nearly 40% of treated patients, and the therapeutic response is typically sustained for about 1 year.8 However, treatment may be associated with adverse effects, including myelosuppression and painful mucocutaneous ulcerations.8
Hydroxyurea has been used in the treatment of hypereosinophilic syndrome (HES)†.10, 11 According to the World Health Organization and International Consensus Classification of eosinophilic disorders, hydroxyurea has demonstrated efficacy as initial treatment in conjunction with corticosteroids or in steroid-refractory cases of HES.10
Hydroxyurea is used in the treatment of essential thrombocythemia†.12, 13, 14, 15 In a pivotal randomized trial of 114 patients at higher risk for thrombosis (e.g., >60 years of age or a prior thrombotic event), cytoreduction with hydroxyurea substantially lowered the risk of arterial or venous thrombotic events compared with no cytoreductive therapy (3.6% versus 24%) over a median follow-up of 27 months.15 Hydroxyurea is one of the first-line cytoreductive agents for high-risk essential thrombocythemia (i.e., thrombosis history or >60 years of age with JAK2 mutation).12, 14 Cytoreductive therapy is recommended for patients at high risk for thrombosis, and is considered optional for those at intermediate risk (i.e., >60 years of age, no thrombosis history, JAK2 wild-type).13, 14
Although hydroxyurea has demonstrated efficacy in reducing the risk of thrombotic events, there is no evidence that it modifies the natural course of essential thrombocythemia or prevents disease progression.12 Specifically, it has not been shown to substantially affect clonal evolution or decrease the underlying mutation burden; consequently, patients remain susceptible to progression to myelofibrosis or transformation to acute leukemia over time.12
Hydroxyurea is used as adjunctive treatment for differentiation syndrome†, specifically for managing concomitant leukocytosis.16, 17 For management of differentiation syndrome with targeted acute myeloid leukemia (AML) therapies, some experts state that prompt intervention with corticosteroids (e.g., dexamethasone) until resolution of symptoms is essential, along with hydroxyurea, when concomitant leukocytosis is observed.16
Chronic Myelomonocytic Leukemia
Hydroxyurea is used in the management of myeloproliferative chronic myelomonocytic leukemia (CMML)†.18, 19, 20 Hydroxyurea is considered the standard of care for the management of patients with myeloproliferative features.20 Evidence from a randomized phase 3 trial (DACOTA) comparing decitabine with hydroxyurea supports the use of hydroxyurea in patients with advanced myeloproliferative CMML who are ineligible for hematopoietic stem cell transplantation.18 Overall survival was similar between hydroxyurea and decitabine, despite response rates being higher for decitabine.18 In a previous randomized clinical trial, hydroxyurea demonstrated superior response rates and survival compared to oral etoposide in patients with advanced myeloproliferative CMML.19
Hydroxyurea is used in the management of acute myeloid leukemia (AML)†.21, 22 The ELN recommendations address hydroxyurea in the context of management of hyperleukocytosis (WBC >100,000 cells/mm3).21 Urgent cytoreduction with hydroxyurea is used for pre-chemotherapy cytoreduction in patients presenting with hyperleukocytosis.21 The ELN also recognizes hydroxyurea as a component of best supportive care for patients who are not candidates for anti-leukemic therapy.21
Hydroxyurea has been used in the treatment of psoriasis†, although use is diminishing.23 Joint guidelines by the Joint American Academy of Dermatology and National Psoriasis Foundation lists hydroxyurea among “other treatments” for psoriasis, alongside systemic immunosuppressants and antimetabolites such as mycophenolate mofetil, azathioprine, leflunomide, tacrolimus, and thioguanine.23 Although these agents are rarely required for the management of psoriasis, the guidelines acknowledge that they may be of therapeutic value in selected clinical circumstances.23
Dispensing and Administration Precautions
Hydroxyurea is administered orally.1, 2, 177, 178 The effect of food on the absorption of hydroxyurea is not known.1, 2, 177, 178 While hydroxyurea can be taken without regard to meals, an attempt should be made to standardize the time of administration each day.2
Hydroxyurea is available as oral capsules (Droxia®, Hydrea®), oral solution (Xromi®), and film-coated tablets (Siklos®).1, 2, 177, 178
Because hydroxyurea is a cytotoxic drug, capsules (Droxia®, Hydrea®) should be swallowed whole and not opened, broken, or chewed.177, 178 Patients and caregivers must follow applicable handling and drug administration precautions.177, 178
Hydroxyurea capsules should be stored in tight containers at 20‒25°C; the manufacturer states that brief exposure to temperatures within the range of 15-30°C is acceptable.177, 178 Store hydroxyurea capsules out of reach of children and pets.177
Commercially available hydroxyurea oral solution is supplied with 3 mL and 10 mL oral syringes; the smaller 3 mL syringe should be used for doses ≤3 mL, and the larger syringe is for doses greater than 3 mL.2
An extemporaneously compounded oral solution of hydroxyurea has been prepared using the commercially available capsules and a flavored syrup.231
Commercially available hydroxyurea oral solution should be stored at 2-8°C; excursions are permitted to 25°C for up to 72 hours.2 Bottles of oral solution should be kept tightly closed and should not be frozen.2 After the bottle is opened, the oral solution should be used within 12 weeks.2 Discard any remaining hydroxyurea oral solution 12 weeks after opening.2
Hydroxyurea film-coated tablets should be taken at the same time each day with a glass of water.1 For patients unable to swallow tablets, the tablets may be dispersed immediately before use in a small quantity of water in a teaspoon.1 The film-coated tablets are scored and can be split; the 100 mg tablets have 1 score line and can be split into 2 equal parts (50 mg each), while the 1 g tablets have 3 score lines and can be split into 4 equal parts (250 mg each).1
Hydroxyurea tablets should be stored in tight containers at 20-25°C; the manufacturer states that exposure to temperatures within the range of 15-30°C is acceptable.1 Broken tablets must be stored in the bottle and used within 3 months.1
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 should be based on actual or ideal body weight, whichever is less.1, 177, 178
Hydroxyurea Capsules (Hydrea®): For the treatment of resistant chronic myeloid leukemia in adults with creatinine clearance ≥60 mL/min, an initial hydroxyurea dosage of 15 mg/kg administered as a single dose once daily is recommended.177 Treatment should be individualized based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.177
Locally Advanced Squamous Cell Carcinomas of the Head and Neck (Excluding the Lip)
Hydroxyurea Capsules (Hydrea®): For the treatment of head and neck (excluding lip) cancer during concomitant radiation therapy in adults with creatinine clearance ≥60 mL/min, the recommended initial dosage of hydroxyurea is 15 mg/kg administered as a single dose once daily.177 Treatment should be individualized based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.177
Hydroxyurea Capsules (Droxia® ): For the treatment of sickle cell anemia in adults with recurrent moderate to severe painful crises, 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 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 dosage of 2.5 mg/kg/day less than the dosage that resulted in toxicity.178 Titration may then be resumed by increasing or decreasing the daily dosage in increments of 2.5 mg/kg/day 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 Discontinue treatment permanently if a patient develops hematologic toxicity twice.178 Fetal hemoglobin (HbF) levels can be used to evaluate the clinical efficacy of hydroxyurea for sickle cell anemia and should be obtained every 3-4 months.178 Monitor for an increase in HbF levels of at least 2-fold over the baseline value.178
Hydroxyurea Tablets (Siklos®): For the treatment of sickle cell anemia in adults with recurrent moderate to severe painful crises, the recommended initial dosage of hydroxyurea is 15 mg/kg (based on the patient's actual or ideal weight, whichever is less) once daily.1 Some patients receiving the recommended initial dosage of hydroxyurea have experienced severe or life-threatening myelosuppression requiring interruption of therapy and subsequent dosage reduction.1 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.1 If blood cell counts are in an acceptable range (i.e., neutrophil count at least 2000 cells/mm3, platelet count at least 80,000/mm3, hemoglobin concentration exceeding 5.3 g/dL, and reticulocyte count at least 80,000/mm3 if hemoglobin concentration is less than 9 g/dL), the dosage of hydroxyurea tablets may be increased in increments of 5 mg/kg daily once every 8 weeks or if a painful crisis occurs to a maximum tolerated dosage of up to 35 mg/kg daily; the maximum tolerated dosage is defined as the highest daily dose that produces mild myelosuppression (i.e., neutrophil count of 2000-4000 cells/mm3).1 If a patient's blood cell count is in the toxic range (i.e., neutrophil count less than 2000 cells/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 less than 9 g/dL), hydroxyurea should be discontinued until hematologic recovery occurs; some younger patients with lower baseline neutrophil counts may safely tolerate neutrophil counts as low as 1250 cells/mm3.1 Upon hematologic recovery, treatment may then be resumed at a reduced daily dosage of 5 mg/kg/day less than the dosage that resulted in toxicity.1 Titration may then be resumed by increasing or decreasing the daily dosage in increments of 5 mg/kg/day once every 8 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.1 Further attempts should not be made to titrate to a dosage level that resulted in hematologic toxicity during 2 separate periods of dosage adjustment.1 HbF levels can be used to evaluate the clinical efficacy of hydroxyurea for sickle cell anemia and should be obtained every 3-4 months.1 Monitor for an increase in HbF levels of at least 2-fold over the baseline value.1
Some experts recommend a starting dosage of 500 mg twice daily in older patients (>60 years of age) with high-risk polycythemia vera.3 The dosage is titrated to keep platelet count in the normal range.3
For the treatment of hypereosinophilic syndrome (HES), a typical starting dosage of hydroxyurea (used in conjunction with corticosteroids or in steroid non-responders) is 500-1000 mg daily.10, 11
When used for the treatment of essential thrombocythemia, some experts recommend an initial hydroxyurea dosage of 500 mg once or twice daily;12, 13 the dosage is titrated to maintain platelet counts below 400,000/mm3.12
In patients with differentiation syndrome, some experts recommend administration of hydroxyurea at a dosage of 2-4 g/day, with titration as needed, in addition to corticosteroids.16
In patients with acute myeloid leukemia, hydroxyurea at a dosage of up to 50-60 mg/kg per day is commonly used to lower the WBC <25,000/mm3, particularly before the commencement of hypomethylating- or venetoclax-based treatments.21
If used in the management of psoriasis, some experts recommend an initial hydroxyurea dosage of 500 mg twice daily, increasing to 1.5 g/day as tolerated.23
Hydroxyurea Oral Solution (Xromi®): For the treatment of sickle cell anemia in pediatric patients 6 months of age and older with recurrent moderate to severe painful crises, the recommended initial dosage of hydroxyurea oral solution (Xromi®) is 15 mg/kg (based on actual body weight), rounded to the nearest 10 mg and administered as a single dose once daily.2 Some patients receiving the recommended initial dosage of hydroxyurea have experienced severe or life-threatening myelosuppression requiring interruption of therapy and subsequent dosage reduction.2 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.2 If blood cell counts are in an acceptable range (i.e., neutrophil count at least 1000-3000 cells/mm3 and platelet count at least 80,000/mm3), the dosage of hydroxyurea oral solution may be increased in increments of 5 mg/kg daily once every 8-12 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 during 24 consecutive weeks of therapy.2 Dosage should only be increased if blood cell counts are within the acceptable range.2 If a patient's blood cell count is in the toxic range (i.e., neutrophil count less than 1000 cells/mm3, platelets less than 80,000/mm3 , hemoglobin decreased by 20% from baseline or hemoglobin level less than 4.5 g/dL, or reticulocytes less than 80,000/mm3 with a hemoglobin level less than 9 g/dL), hydroxyurea should be discontinued until hematologic recovery occurs; treatment may then be resumed at the same daily dosage if hematologic toxicity resolves within 1 week.2 If hematologic recovery takes more than 1 week or occurs twice in a 3-month period, treatment may then be resumed at a reduced daily dosage of 5 mg/kg less than the dosage that resulted in toxicity.2 Once a stable dosage of hydroxyurea is established, monitor CBC with differential and reticulocyte counts every month for 2 months and then as clinically indicated.2 HbF levels can be used to evaluate the clinical efficacy of hydroxyurea for sickle cell anemia and should be obtained every 3-4 months.2 Monitor for an increase in HbF levels of at least 2-fold over the baseline value.2
Hydroxyurea Tablets (Siklos®) : For the treatment of sickle cell anemia in pediatric patients 2 years of age and older with recurrent moderate to severe painful crises, the recommended initial dosage of hydroxyurea tablets (Siklos®) is 20 mg/kg once daily (based on the patient's actual or ideal weight, whichever is less).1 Some patients receiving the recommended initial dosage of hydroxyurea have experienced severe or life-threatening myelosuppression requiring interruption of therapy and subsequent dosage reduction.1 Following initiation of hydroxyurea therapy, dosage should be adjusted according to the patient's blood cell count, which should be monitored every 2 weeks.1 If blood cell counts are in an acceptable range (i.e., neutrophil count at least 2000 cells/mm3, platelet count at least 80,000/mm3, hemoglobin concentration exceeding 5.3 g/dL, and reticulocyte count at least 80,000/mm3 if hemoglobin concentration is less than 9 g/dL), the dosage of hydroxyurea tablets may be increased in increments of 5 mg/kg daily once every 8 weeks or if a painful crisis occurs to a maximum tolerated dosage of up to 35 mg/kg daily; the maximum tolerated dosage is defined as the highest daily dosage that produces mild myelosuppression (i.e., neutrophil count of 2000-4000 cells/mm3).1 If blood cell counts are in the toxic range, the dosage should not be increased.1 If a patient's blood cell count is in the toxic range (i.e., neutrophil count less than 2000 cells/mm3, platelet count less than 80,000/mm3, hemoglobin less than 4.5 g/dL, or reticulocyte count less than 80,000/mm3 if the hemoglobin concentration is less than 9 g/dL), hydroxyurea should be discontinued until hematologic recovery occurs; some younger patients with lower baseline neutrophil counts may safely tolerate neutrophil counts as low as 1250 cells/mm3.1 Upon hematologic recovery, treatment may then be resumed at a reduced daily dose of 5 mg/kg/day less than the dose that resulted in toxicity.1 Titration of the dosage of hydroxyurea may then be resumed by increasing or decreasing the daily dosage in increments of 5 mg/kg daily once every 8 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.1 Discontinue treatment permanently if a patient develops hematologic toxicity twice.1 HbF levels can be used to evaluate the clinical efficacy of hydroxyurea for sickle cell anemia and should be obtained every 3-4 months.1 Monitor for an increase in HbF levels of at least 2-fold over the baseline value.1
Dosage Modifications for Toxicity
Hydroxyurea Capsules (Droxia®): In adults receiving hydroxyurea for sickle cell anemia, withhold therapy if neutrophil count <2000/mm3, platelet count <80,000/mm3, hemoglobin concentration <4.5 g/dL, or reticulocyte count <80,000/mm3 with a hemoglobin concentration of <9 g/dL.178 Following hematologic recovery, resume therapy at a reduced daily dosage of 2.5 mg/kg less than the dosage that resulted in toxicity.178 Resume titration by increasing or decreasing the daily dosage 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 Discontinue treatment permanently if patient experiences hematologic toxicity twice.178
Hydroxyurea Oral Solution (Xromi®): In pediatric patients receiving hydroxyurea for sickle cell anemia, withhold therapy if neutrophil count <1000/mm3, platelet count <80,000/mm3, the hemoglobin concentration has decreased by 20% from baseline or is <4.5 g/dL, or reticulocyte count <80,000/mm3 with a hemoglobin concentration of <9 g/dL.2 Following hematologic recovery, may resume hydroxyurea at the same daily dosage if the toxicity resolves within 1 week.2 If hematologic recovery takes more than 1 week or occurs twice in a 3-month period, treatment may then be resumed at a reduced daily dosage of 5 mg/kg/day less than the dosage that resulted in toxicity.2 Resume titration by increasing the daily dosage in increments of 5 mg/kg once every 8-12 weeks to a maximum tolerated dosage of up to 35 mg/kg daily; maximum tolerated dosage is defined as the highest daily dose that does not produce hematologic toxicity during 24 consecutive weeks of therapy.2
Hydroxyurea Tablets (Siklos®): In patients receiving hydroxyurea for sickle cell anemia, withhold therapy if neutrophil count <2000/mm3, platelet count <80,000/mm3, hemoglobin concentration <4.5 g/dL, or reticulocyte count <80,000/mm3 with a hemoglobin concentration of <9 g/dL.1 Some younger patients with lower baseline neutrophil counts may safely tolerate neutrophil counts as low as 1250 cells/mm3.1 Following hematologic recovery, resume therapy at a reduced daily dosage of 5 mg/kg/day less than the dosage that resulted in toxicity.1 Resume titration by increasing or decreasing the daily dosage in increments of 5 mg/kg/day once every 8 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.1 Discontinue treatment permanently if patient experiences hematologic toxicity twice.1
If cutaneous vasculitic toxicity such as vasculitic ulcerations or gangrene develops in patients with myeloproliferative disorders, hydroxyurea therapy should be discontinued.177, 178 Vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy.177, 178
The effect of hepatic impairment on the elimination of hydroxyurea has not been fully evaluated.1, 2, 177, 178 Specific dosage recommendations for patients with hepatic impairment are not available; however, the manufacturers recommend close monitoring of hematologic parameters in such patients.1, 2, 177, 178
In adult and pediatric patients with a creatinine clearance less than 60 mL/minute, the manufacturers recommend reducing the initial hydroxyurea dosage by 50% and closely monitoring hematologic parameters.1, 2, 177, 178
In patients with end-stage renal disease (ESRD) undergoing hemodialysis, the daily dose of hydroxyurea should be administered following the hemodialysis session.1, 2, 177, 178
Because geriatric patients may be particularly sensitive to the effects of hydroxyurea, they may require a lower dosage of the drug.177, 178 Geriatric patients also may be more likely to have renal impairment and are therefore at greater risk of adverse reactions; dosage should be carefully selected and renal function monitoring may be helpful in such patients.177, 178
A boxed warning is included in the prescribing information of hydroxyurea about the risk of severe myelosuppression.1, 2, 178 Hydroxyurea should not be initiated in patients with marked bone marrow depression.1, 2, 177, 178 Leukopenia is usually the first and most common manifestation of bone marrow toxicity.1, 2, 177, 178 Thrombocytopenia and anemia occur less often and are usually preceded by leukopenia.1, 2, 177, 178 Recovery from bone marrow depression is usually rapid when hydroxyurea therapy is interrupted.1, 2, 177, 178 Even at the recommended initial dosage of 15 mg/kg daily in adults or 20 mg/kg daily in pediatric patients, severe or life-threatening myelosuppression has been reported.1, 2, 177, 178 Pediatric patients are at an increased risk of myelosuppression at the time of dosage adjustment due to changes in body weight that require adjustment of the daily dosage.1 Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic antineoplastic agents; hydroxyurea should be used with caution in such patients.177
Hematologic status must be carefully monitored in patients receiving hydroxyurea.1, 2, 177, 178 The manufacturers of hydroxyurea tablets and oral solution recommend monitoring hematologic status (CBC, reticulocyte count) prior to initiating hydroxyurea, and every 2 weeks during dosage escalation.1, 2 Once a stable dosage of hydroxyurea has been attained, hematologic status can be monitored every 4 weeks.1, 2 Supportive care and dosage modification or discontinuation of hydroxyurea should be provided if hematologic toxicity occurs.1, 2, 177, 178
A boxed warning is included in the prescribing information of hydroxyurea about the risk of malignancies.1, 2, 178 Hydroxyurea is a human carcinogen.1, 2, 177, 178 Secondary leukemia has been reported in patients receiving long-term therapy with hydroxyurea for myeloproliferative disorders and sickle cell anemia.1, 2, 177, 178 Leukemia has also been reported in patients with sickle cell disease and no previous history of treatment with hydroxyurea.1, 2, 178 All patients receiving hydroxyurea should have blood counts regularly assessed on a long-term basis to monitor for leukemia.2, 178 Skin cancer has been reported in patients receiving long-term therapy with hydroxyurea.1, 2, 177, 178 Advise patients to avoid sun exposure and monitor for the development of secondary malignancies.1, 2, 177, 178
Other Warnings and Precautions
Hemolytic anemia has been reported in patients receiving hydroxyurea for myeloproliferative disorders.1, 2, 177, 178 Patients who develop acute jaundice or hematuria in the presence of persistent or worsening anemia should have laboratory tests evaluated for hemolysis (e.g., serum lactate dehydrogenase levels, haptoglobin, reticulocytes, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests).1, 2, 177, 178 In the absence of other causes, hydroxyurea should be discontinued if hemolytic anemia is confirmed.1, 2, 177, 178
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and animal studies, hydroxyurea can cause fetal harm when administered during pregnancy.1, 2, 177, 178 Hydroxyurea crosses the placenta and has been shown to be a potent teratogen in a wide variety of animal models.1, 2, 177, 178 Fetal malformations and embryotoxicity have been observed in animals.1, 2, 177, 178 Preterm birth and early termination of pregnancy have been described in postmarketing human data.1
Verify pregnancy status before initiating hydroxyurea.1, 2, 177, 178 Advise females of reproductive potential to use effective contraception while receiving and for at least 6 months following hydroxyurea therapy.1, 2, 177, 178 The manufacturers of Droxia®, Hydrea®, and Xromi® recommend that males of reproductive potential use effective contraception during and for at least 12 months following therapy.2, 177, 178 The manufacturer of Siklos® recommends that males of reproductive potential use effective contraception during and for at least 6 months following therapy.1
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients receiving hydroxyurea for myeloproliferative disorders, particularly in patients who have received or are currently receiving interferon therapy.1, 2, 177, 178 If cutaneous vasculitic ulcers occur, discontinue hydroxyurea and institute appropriate treatment.2, 177, 178
The manufacturer of hydroxyurea tablets states that if cutaneous vasculitic ulcerations occur, use of the drug should be discontinued and/or the dosage reduced; use of the drug should be avoided in patients with preexisting leg wounds (leg ulcers).1 Rarely, ulcers are caused by leukocytoclastic vasculitis.1
Since concomitant use of hydroxyurea could potentiate viral replication and/or increase adverse reactions from the vaccine due to immunosuppression, live vaccines should be avoided in patients receiving hydroxyurea.1, 2, 177, 178 Administration of live vaccines during therapy with hydroxyurea could result in severe infection.1, 2, 177, 178 The development of antibodies following vaccine administration may be diminished in patients receiving hydroxyurea.1, 2, 177, 178
Risks with Concomitant Antiretroviral Drugs
Pancreatitis, hepatotoxicity, and peripheral neuropathy have been reported when hydroxyurea has been administered with antiretroviral drugs, including didanosine and stavudine.1, 2, 177, 178
Use of hydroxyurea in combination with didanosine and stavudine should be avoided.1, 2, 177, 178 If concomitant use cannot be avoided, closely monitor patients for clinical manifestations of pancreatitis.1, 2, 177, 178 Permanently discontinue hydroxyurea if signs and symptoms of pancreatitis occur.1, 2, 177, 178
Hydroxyurea may cause macrocytosis, which is self-limiting and often seen early in the course of treatment.1, 2, 177, 178 The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency.1, 2, 177, 178 This may mask the diagnosis of pernicious anemia.1, 2, 177, 178 Prophylactic administration of folic acid is recommended in patients receiving the drug.1, 2, 177, 178
Interstitial lung disease, including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases), have occurred in patients receiving hydroxyurea for myeloproliferative neoplasms.2, 177, 178
Monitor patients who develop pyrexia, cough, dyspnea, or other respiratory symptoms frequently and investigate and treat promptly.2, 177, 178 If these signs or symptoms occur, discontinue hydroxyurea and manage patients with corticosteroids.2, 177, 178
False elevations in results of uric acid, urea, or lactic acid assays can occur during therapy with hydroxyurea.1, 2, 177, 178
Hydroxyurea may falsely elevate sensor glucose readings from certain continuous glucose monitoring (CGM) systems, which could lead to hypoglycemia if insulin dosing is dependent on glucose readings.1, 2, 177, 178 If a patient using a CGM device is to be started on hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.1, 2, 177, 178
Exacerbation of post-irradiation erythema can occur in patients who have previously received radiation therapy.177 Monitor for skin erythema in patients who have received prior radiation and manage symptoms if skin erythema occurs.177
Based on animal studies and the drug's mechanism of action, hydroxyurea can cause fetal harm when administered to pregnant women.1, 2, 177, 178 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.1, 2, 177, 178 Administration of 180 mg/kg daily (about 0.8 times the maximum recommended human daily dosage on a mg/m2 basis) or 30 mg/kg daily (about 0.3 times the maximum recommended human daily dosage 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.1, 2, 177, 178 Embryotoxicity, manifested as decreased fetal viability, reduced live litter sizes, and developmental delays, also was observed.1, 2, 177, 178 Single doses of ≥375 mg/kg (approximately 1.7 times the maximum recommended human daily dosage on a mg/m2 basis) in rats resulted in growth retardation and impaired learning ability.1, 2, 177, 178
In a retrospective analysis of a cohort of 123 adult patients treated with hydroxyurea, 61% of 23 reported pregnancies had no adverse developmental outcomes.1 In other cases with known evaluation, pregnancy had been interrupted voluntarily or upon medical advice.1
Postmarketing data from 3 reported pregnancies when the father was being treated and 16 pregnancies when 15 mothers were being treated with hydroxyurea show that out of 13 cases with known evolution, 5 pregnancies had no adverse developmental outcomes, 4 led to preterm birth, and 4 were terminated early.1 Verify pregnancy status before initiating hydroxyurea.1, 2, 177, 178
Hydroxyurea is distributed into human milk.177, 178 Because of the potential for serious adverse reactions to hydroxyurea (including carcinogenicity) in nursing infants, avoid breast-feeding during treatment with hydroxyurea.1, 2, 177, 178
Females and Males of Reproductive Potential
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 dosage on a mg/m2 basis).177, 178
Verify pregnancy status before initiating hydroxyurea.1, 2, 177, 178 Advise females of reproductive potential to use effective contraception while receiving and for at least 6 months following hydroxyurea therapy.1, 2, 177, 178 The manufacturers of Droxia®, Hydrea®, and Xromi®recommend that males of reproductive potential use effective contraception during and for at least 12 months following therapy.2, 177, 178 The manufacturer of Siklos® recommends that males of reproductive potential use effective contraception during and for at least 6 months following therapy.1
Based on findings in animals and humans, male fertility may be impaired by hydroxyurea treatment.1, 2, 177, 178 Azoospermia and oligospermia, which are sometimes reversible, have been observed in men.1, 2, 177, 178 Male patients should be informed about the possibility of sperm conservation before starting hydroxyurea therapy.1, 2, 177, 178
Safety and efficacy of hydroxyurea tablets (Siklos®) have been established in pediatric patients 2<18 years of age with sickle cell anemia and recurrent moderate to severe painful crises.1 Use of hydroxyurea tablets in this age group is supported by data from a cohort study of 405 pediatric patients aged 2 to <18 years; of the 405 pediatric patients, 274 were 2<11 years of age and 108 pediatric patients were 12<16 years of age.1 Pediatric patients 2<16 years of age had a higher incidence of neutropenia compared to older patients.1
Safety and efficacy of hydroxyurea oral solution (Xromi®) have been established in pediatric patients 6 months of age and older with sickle cell anemia and recurrent moderate to severe painful crises.2 Use of Xromi® in this age group is based on a pharmacokinetic, efficacy, and safety study in which 32 pediatric patients 6 months to <18 years of age were enrolled.2
Safety and efficacy of hydroxyurea capsules (Droxia® and Hydrea®) have not been established in pediatric patients.177, 178
The pharmacokinetics of hydroxyurea are similar in pediatric patients 4<17 years of age and adults.1
Continuous follow-up of growth is recommended in pediatric patients who receive hydroxyurea.1, 2
Because geriatric patients may be particularly sensitive to the effects of hydroxyurea, they may require a lower dosage of the drug.177
More frequent monitoring of hematologic parameters is recommended in patients with hepatic impairment.1, 2, 177, 178
In patients with sickle cell anemia who were administered hydroxyurea, patients with impaired renal function (creatinine clearance of less than 60 mL/minute or with end-stage renal disease) had a 64% higher exposure (mean AUC) compared to patients with normal renal function (creatinine clearance above 60 mL/minute).2
Adverse effects reported with hydroxyurea capsules in at least 30% of adult patients with sickle cell anemia include hematological, GI symptoms, and anorexia.177, 178
Adverse effects reported in more than 10% of patients receiving hydroxyurea tablets include infections and neutropenia in pediatric patients and infections, headache, and dry skin in adults.1
Adverse effects reported in more than 5% of pediatric patients with sickle cell anemia receiving hydroxyurea oral solution include neutropenia, thrombocytopenia, and papular rash.2
Formal studies evaluating potential drug interactions with hydroxyurea have not been performed to date.177, 178
Pancreatitis (fatal and nonfatal), hepatotoxicity (including hepatic failure resulting in death), and peripheral neuropathy (severe in some cases) have been reported when hydroxyurea has been administered with antiretroviral drugs, including didanosine and stavudine.1, 2, 177, 178
Avoid concomitant use of hydroxyurea with didanosine and stavudine.1, 2, 177, 178 If concomitant use of hydroxyurea with didanosine and/or stavudine cannot be avoided, closely monitor patients for clinical manifestations of pancreatitis.1, 2, 177, 178 Permanently discontinue hydroxyurea if signs and symptoms of pancreatitis occur.1, 2, 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
Concomitant use of hydroxyurea could potentiate viral replication and/or increase adverse reactions from the vaccine virus; severe infections may result.1, 2, 177, 178 The patient's antibody response to vaccines may be decreased during hydroxyurea therapy.1, 2, 177, 178 Use of live vaccines should be avoided in patients receiving hydroxyurea.1, 2, 177, 178 Concomitant immunization with live virus vaccines should only occur if benefits clearly outweigh potential risks; consider consultation with a specialist.1, 2, 177, 178
False elevations in results of uric acid, urea, or lactic acid assays can occur during therapy with hydroxyurea.1, 2, 177, 178
Hydroxyurea may also falsely elevate sensor glucose readings from certain continuous glucose monitoring (CGM) systems, which could lead to hypoglycemia, if insulin dosing is dependent on glucose readings.1, 2, 177, 178 If a patient using a CGM device is to be started on hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.1, 2, 177, 178
The exact mechanism of antineoplastic activity of hydroxyurea has not been fully determined.1, 2, 177, 178 Some studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting like a ribonucleotide reductase inhibitor without interfering with the synthesis of RNA or protein.1, 2, 177, 178
The mechanisms by which hydroxyurea exert its beneficial effects in patients with sickle cell anemia are unclear; however, known pharmacologic effects that may contribute to its beneficial effects include increasing fetal hemoglobin (HbF) levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing the deformability of RBCs, and altering the adhesion of RBCs to endothelium.1, 2, 178
Hydroxyurea is readily absorbed from the GI tract.177, 178 Hydroxyurea oral bioavailability is 85<100%.1 Peak serum concentrations are attained within 1-4 hours following oral administration of hydroxyurea capsules and tablets.1, 2, 177, 178 Following administration of hydroxyurea oral solution, peak serum concentrations occur within 0-2 hours.2 Disproportionate increases in peak plasma concentrations and AUCs result when drug dosage is increased.1, 2, 177, 178 The effect of food on the absorption of hydroxyurea has not been determined.1, 2, 177, 178 Hydroxyurea distributes throughout the body and concentrates in leukocytes and erythrocytes.1, 2, 177, 178 Hydroxyurea distributes into milk.177, 178 Up to 60% of an orally administered dose of hydroxyurea is metabolized in the liver or undergoes degradation by urease found in intestinal bacteria.1, 2, 177, 178 Mean cumulative urinary excretion of approximately 40% of the administered dose was reported in patients with sickle cell anemia.1, 2, 177, 178 The elimination half-life of hydroxyurea is 2<4 hours.1
The pharmacokinetics of hydroxyurea tablets are similar between children 4<17 years of age and adults.1 Model estimated steady state exposure (AUC) in pediatric patients receiving a daily dosage of 15 mg/kg of hydroxyurea oral solution is lower in patients 6 months to <2 years and 2 to <6 years of age by 40 and 28%, respectively, compared to adults at the same dosage (Xromi® not approved for use in adults).2 Following administration of hydroxyurea oral solution, exposure to hydroxyurea is similar between patients 6 to <18 years of age and adults.2
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 | H2 Pharma | |
300 mg | Droxia® | H2 Pharma | ||
400 mg | Droxia® | H2 Pharma | ||
500 mg* | H2 Pharma | |||
Hydroxyurea Capsules | ||||
Solution | 100 mg/mL | Xromi® (supplied in a 148 mL multi-dose bottle) | Rare Disease Therapeutics | |
Tablets | 100 mg | Siklos® | Medunik | |
1000 mg | Siklos® | Medunik |
* 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.
1. Medunik USA. Siklos® (hydroxyurea) film-coated tablets prescribing information. Princeton, NJ; 2023 Nov.
2. Rare Disease Therapeutics, Inc. Xromi® (hydroxyurea) oral solution prescribing information. Franklin, TN; 2025 Dec.
3. Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(9):1465-1487.
4. Ferrari A, Carobbio A, Masciulli A, et al. Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis. Haematologica. 2019;104(12):2391-2399.
5. Tremblay D, Kremyanskaya M, Mascarenhas J, Hoffman R. Diagnosis and Treatment of Polycythemia Vera: A Review. JAMA. 2025;333(2):153-160.
6. Marchetti M, Vannucchi AM, Griesshammer M, et al. Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. Lancet Haematol. 2022;9(4):e301-e311.
7. Saqib M, Ijaz H, Zubair MM, et al. JAK inhibitors vs traditional therapy for myelofibrosis: a meta-analysis of randomized clinical trials. J Clin Oncol. 2026;44(16_suppl):e18603.
8. Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(5):801-821.
9. Martino M, Pitea M, Sgarlata A, et al. Treatment Strategies Used in Treating Myelofibrosis: State of the Art. Hematol Rep. 2024;16(4):698-713. Published 2024 Oct 30.
10. Shomali W, Gotlib J. World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management. Am J Hematol. 2024;99(5):946-968.
11. Helbig G, Czachor K. Clinical Management of Persistent Hypereosinophilia. Eur J Haematol. 2025;114(5):763-774.
12. Rouf R, Tremblay D. Pharmacologic management of ET: established therapies and emerging agents. Expert Opin Pharmacother. 2025;26(16):1741-1750.
13. Tefferi A, Gangat N, Loscocco GG, et al. Essential Thrombocythemia: A Review. JAMA. 2025;333(8):701-714.
14. Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management. Am J Hematol. 2024;99(4):697-718.
15. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995;332(17):1132-1136.
16. Fathi AT, Stein EM, DiNardo CD, Levis MJ, Montesinos P, de Botton S. Differentiation syndrome with lower-intensity treatments for acute myeloid leukemia. Am J Hematol. 2021;96(6):735-746.
17. Woods AC, Norsworthy KJ. Differentiation Syndrome in Acute Leukemia: APL and Beyond. Cancers (Basel). 2023;15(19):4767. Published 2023 Sep 28.
18. Itzykson R, Santini V, Thepot S, et al. Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network. J Clin Oncol. 2023;41(10):1888-1897.
19. Wattel E, Guerci A, Hecquet B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group. Blood. 1996;88(7):2480-2487.
20. Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management. Am J Hematol. 2024;99(6):1142-1165.
21. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377.
22. Bewersdorf JP, Giri S, Tallman MS, Zeidan AM, Stahl M. Leukapheresis for the management of hyperleukocytosis in acute myeloid leukemia-A systematic review and meta-analysis. Transfusion. 2020;60(10):2360-2369.
23. Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445-1486.
30. Argiris A, Haraf DJ, Kies MS, Vokes EE. Intensive concurrent chemoradiotherapy for head and neck cancer with 5-Fluorouracil- and hydroxyurea-based regimens: reversing a pattern of failure. Oncologist. 2003;8(4):350-360.
31. Fulcher CD, Haigentz M Jr, Ow TJ; Education Committee of the American Head and Neck Society (AHNS). AHNS Series: Do you know your guidelines? Principles of treatment for locally advanced or unresectable head and neck squamous cell carcinoma. Head Neck. 2018;40(4):676-686.
32. Kockerols CCB, Geelen I, Levin MD, et al. The use of hydroxyurea pretreatment in chronic myeloid leukemia in the current tyrosine kinase inhibitor era. Haematologica. 2022;107(8):1940-1943. Published 2022 Aug 1.
33. PDQ® Adult Treatment Editorial Board. PDQ Chronic Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated March 13, 2025. [Web]
34. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-984.
35. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2026 Jun 29. [Web]
36. National Heart, Lung, and Blood Institute. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. Bethesda, MD: National Institutes of Health; 2014.
37. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377(9778):1663-1672.
38. Tonin FS, Ginete C, Ferreira J, et al. Efficacy and safety of pharmacological interventions for managing sickle cell disease complications in children and adolescents: Systematic review with network meta-analysis. Pediatr Blood Cancer. 2023;70(6):e30294.
39. Yates AM, Aygun B, Nuss R, Rogers ZR; Section on Hematology/Oncology ; AMERICAN SOCIETY OF PEDIATRIC HEMATOLOGY/ONCOLOGY . Health Supervision for Children and Adolescents With Sickle Cell Disease: Clinical Report. Pediatrics. 2024;154(2):e2024066842.
40. Rankine-Mullings AE, Nevitt SJ. Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database Syst Rev. 2022;9(9):CD002202. Published 2022 Sep 1.
41. de Montalembert M, Voskaridou E, Oevermann L, et al. Real-Life experience with hydroxyurea in patients with sickle cell disease: Results from the prospective ESCORT-HU cohort study. Am J Hematol. 2021;96(10):1223-1231.
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.
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.
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. Hehlmann R, Berger U, Pfirrmann M, et al. Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea. Leukemia. 2003;17(8):1529-1537.
177. H2-Pharma, LLC. Hydrea® (hydroxyurea) capsules prescribing information. Montgomery, AL; 2023 Dec.
178. H2-Pharma, LLC. Droxia® (hydroxyurea) capsules prescribing information. Montgomery, AL; 2023 Dec.
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]
182. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997; 337:762-9
183. Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Semin Hematol. 1997; 34:15-21
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]
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 2025 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
555. Institute for Safe Medication Practices (ISMP). ISMP List of Confused Drug Names. ISMP; 2024.
602. Centers for Disease Control and Prevention National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2024. From CDC website.