PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Other Antimetabolites Antineoplastic Agents
    Sickle Cell Disease Agents

    BOXED WARNING

    Anemia, bone marrow suppression, leukopenia, neutropenia, thrombocytopenia

    Hydroxyurea may cause severe bone marrow suppression/myelosuppression (e.g., leukopenia, anemia, neutropenia, and thrombocytopenia). Evaluate hematologic status before and during treatment (weekly for cancer and every 2 weeks for sickle cell disease). Do not initiate therapy if bone marrow function is markedly depressed. Provide supportive care and modify or discontinue treatment as necessary. Advise patients to report any signs and symptoms of infection (e.g., fever, chills, sore throat, cough) or unusual bleeding or bruising immediately. Recovery from myelosuppression is usually observed within 15 days of therapy interruption; resume therapy at a lower dose. Some patients, treated at the recommended initial dose for sickle cell anemia, have experienced severe or life-threatening myelosuppression. Pediatric patients have an increased risk of myelosuppression at the time of dosage adjustment due to the change in body weight requiring modification of daily dose. Use caution in patients with a history of receiving prior chemotherapy or radiation, which may increase the risk for bone marrow suppression. Correct anemia prior to Hydrea therapy. Leukopenia is generally the first and most common manifestation of bone marrow suppression from hydroxyurea. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia.

    New primary malignancy, radiation therapy, sunlight (UV) exposure, vasculitis

    Hydroxyurea is carcinogenic in humans; new primary malignancy (e.g., leukemia and skin cancer) has been reported in patients receiving long-term hydroxyurea for both myeloproliferative disorders and sickle cell disease. Monitor blood counts regularly and on a long-term basis in all patients using hydroxyurea. Advise protection from sunlight (UV) exposure. Patients with myeloproliferative disorders such as polycythemia vera and thrombocythemia who receive hydroxyurea may be at increased risk of developing leukemia. Consider the risk of secondary malignancy compared with the benefit of hydroxyurea therapy. Cutaneous vasculitis, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue or reduce the dose of hydroxyurea. Avoid the use of hydroxyurea in patients with leg wounds/ulcers. Radiation recall reaction has also been reported with hydroxyurea use; monitor for skin erythema in patients who previously received radiation therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antimetabolite
    Used for resistant chronic myelogenous leukemia, locally advanced squamous cell carcinomas of head and neck, and to reduce frequency of painful crises and blood transfusions in sickle cell anemia
    Associated with severe myelosuppression

    COMMON BRAND NAMES

    Droxia, Hydrea, Siklos

    HOW SUPPLIED

    Droxia/Hydrea/Hydroxyurea Oral Cap: 200mg, 300mg, 400mg, 500mg
    Siklos Oral Tab: 100mg, 1000mg

    DOSAGE & INDICATIONS

    For the treatment of resistant chronic myelogenous leukemia (CML).
    Oral dosage
    Adults

    20 to 30 mg/kg orally once daily as a single dose. Continue therapy if a response is observed after 6 weeks of therapy. Interrupt hydroxyurea therapy for white blood cell (WBC) counts less than 2500 cells/mm3 or platelet counts less than 100,000 cells/mm3; re-evaluate after 3 days and resume therapy if these blood counts increase to acceptable levels. Hydroxyurea has been administered as single-agent therapy or as part of combination therapy;various hydroxyurea dosage regimens have been studied. Use actual or ideal body weight (whichever is less) for dosing. Prophylactic administration of folic acid is recommended. Overall survival was improved with hydroxyurea compared with busulfan at 4 years (53.6% vs. 45.1%; absolute difference = 8.5%; 95% CI, 0.1 to 16.9; p = 0.01) but not at 10 years (absolute difference = 2.3%; 95% CI, -4 to 8.7; p = 0.01) in patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in a meta-analysis of 3 randomized trials (n = 690). The initial hydroxyurea dosages in the randomized trials were as follows: 40 mg/kg per day (target WBC level: 5 to 15 x 103 cells/mm3), 1.5 to 2 grams/day (target WBC level: 4 to 20 x 103 cells/mm3), and 30 mg/kg per day (target WBC level: 10 to 20 x 103 cells/mm3).

    For the treatment of locally advanced squamous cell head and neck cancer (excluding the lip) in combination with chemoradiation therapy.
    Oral dosage
    Adults

    80 mg/kg orally every third day in combination with chemoradiation therapy ; various hydroxyurea dosages and chemoradiation therapy regimens have been studied. Use actual or ideal body weight (whichever is less) for dosing. Prophylactic administration of folic acid is recommended. A multicenter, randomized, phase II study evaluated 3 chemotherapy regimens administered with concurrent radiation (70 Grey in 35 fractions) in previously untreated patients with stage III or IV (M0) squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx. The 3 treatment regimens consisted of weekly cisplatin and fluorouracil (n = 78), hydroxyurea (1 gram PO every 12 hours for 11 doses/cycle) and fluorouracil (800 mg/m2 as continuous IV infusion daily delivered with each fraction of radiation) every other week for a total of 13 weeks (n = 76), and weekly paclitaxel and cisplatin (n = 77). At a follow-up of 0.34 to 4 years, the estimated 2-year disease-free survival rates were 38.2%, 48.6%, and 69.4% in the cisplatin/fluorouracil, hydroxyurea/fluorouracil, and paclitaxel/cisplatin arms, respectively; additionally, the estimated 2-year overall survival rates were 57.4%, 69.4%, and 66.6%, respectively.

    For the treatment of sickle cell disease to reduce the frequency of painful crises and need for blood transfusions in persons with recurrent moderate to severe painful crises.
    NOTE: The FDA has designated hydroxyurea as an orphan drug for the treatment of sickle cell anemia.
    Oral dosage (Droxia only)
    Adults

    15 mg/kg/dose PO once daily, initially. Dose based on actual or ideal body weight (whichever is less). If blood counts are within an acceptable range, increase dose by 5 mg/kg/day every 12 weeks to the highest dose that does not produce toxic blood counts over 24 consecutive weeks. Max: 35 mg/kg/day. Blood counts within an acceptable range are defined as neutrophil count at least 2,500 cells/mm3, platelet count at least 95,000 cells/mm3, hemoglobin concentration higher than 5.3 g/dL, and a reticulocyte count at least 95,000 cells/mm3 if the hemoglobin concentration is less than 9 g/dL. If the blood counts are considered toxic, discontinue hydroxyurea therapy until hematologic recovery then resume therapy at a reduced dosage. Obtain fetal hemoglobin (HbF) concentrations every 3 to 4 months; monitor for an increase in HbF of at least 2-fold over baseline. Prophylactic administration of folic acid is recommended.

    Oral dosage (Siklos only)
    Children and Adolescents 2 to 17 years

    20 mg/kg/dose PO once daily, initially. Dose based on actual or ideal body weight (whichever is less) and calculate the rounded dose to the nearest 50- or 100-mg strength. If blood counts are within an acceptable range, increase dose by 5 mg/kg/day every 8 weeks or if a painful crisis occurs until mild myelosuppression (absolute neutrophil count 2,000 to 4,000 cells/microliter) is achieved. Max: 35 mg/kg/day. Blood counts within an acceptable range are defined as neutrophil count at least 2,000 cells/mm3, platelet count at least 80,000 cells/mm3, hemoglobin concentration more than 5.3 g/dL, and a reticulocyte count at least 80,000 cells/mm3 if the hemoglobin concentration is less than 9 g/dL. If the blood counts are considered toxic, discontinue treatment until hematologic recovery then resume therapy at a reduced dosage. Obtain fetal hemoglobin (HbF) concentrations every 3 to 4 months; monitor for an increase in HbF of at least 2-fold over baseline. Prophylactic administration of folic acid is recommended. Guidelines suggest that hydroxyurea can be considered as a substitute for regular blood transfusions in children with sickle cell disease with abnormal transcranial Doppler ultrasound (TCD) results and 1) without vasculopathy or silent cerebral infarcts who have received at least 1 year of transfusions and 2) in those with hemoglobin SS, hemoglobin S beta-thalassemia, or compound heterozygous sickle cell disease and living in low-to-middle income settings where regular blood transfusion and chelation therapy are not available or affordable.

    For the treatment of acute myelogenous leukemia (AML)†.
    In elderly patients not fit for intensive treatment†.
    Oral dosage
    Adults aged 60 years and older

    The use of hydroxyurea for the treatment of AML in geriatric patients has not been established. Hydroxyurea PO (dose titrated to a white blood cell count of less than 10 X 109/L) was compared to cytarabine 20 mg subcutaneous twice daily for 10 days repeated every 4 to 6 weeks in a randomized trial in 212 patients not considered fit for intensive treatment. Patients were also randomized to receive treatment with tretinoin 45 mg/m2/day for 60 days or no tretinoin therapy. Most patients (n = 208) were aged 60 years or older and all patients also received supportive care. This trial was closed early when a significant benefit in OS was demonstrated in patients who received low-dose cytarabine compared with patients who received hydroxyurea (0.6; 95% CI, 0.44-0.81; p = 0.0009). Additionally, treatment with tretinoin did not improve OS in either the low-dose cytarabine or hydroxyurea arm.

    To lower peripheral blast blood counts prior to induction therapy†.
    Oral dosage
    Adults

    50 to 100 mg/kg (Max dose: 6 g) PO daily until the blast cell count decreased to less than 100,000/mm3 was studied in 9 adult patients with acute leukemia, including 7 patients with acute myeloid leukemia. Induction chemotherapy was started at the same time as hydroxyurea or soon after; additionally, most patients also received allopurinol and some patients received IV fluids and urine alkalinization. In all 10 episodes treated with hydroxyurea, the mean peripheral blast count was decreased below 100,000/mm3 within 72 hours with 1 or 2 doses. Following 1 dose of hydroxyurea, the mean blast count decreased by 50% (mean decrease of 83,000/mm3; range, 43,900 to 139,000/mm3). No patient developed intracerebral hemorrhage or leukostasis.

    For the treatment of advanced non-small cell lung cancer (NSCLC)†, in combination with chemotherapy.
    Oral dosage
    Adults

    The dosage of hydroxyurea in combination with chemotherapy for the treatment of non-small cell lung cancer has not been established. Second-line therapy with hydroxyurea 500 mg PO on Monday, Wednesday, and Friday (starting 1 week before paclitaxel) plus paclitaxel 135 mg/m2 IV over 1 hour every 3 weeks for up to 10 cycles resulted in 1 partial response (PR) in a nonrandomized study in 30 patients. In this study, the median overall survival (OS) time was 20 weeks and the 1-year OS rate was 19%. In a randomized study in 58 patients comparing combination therapy with hydroxyurea 20 mg/kg orally from days 4 to 7 plus cyclophosphamide, 5-fluorouracil, and methotrexate repeated every 10 days as tolerated to single-agent cyclophosphamide, 1 patient in each treatment arm experienced a PR. The OS time was 26 weeks with combination therapy and 24 weeks with single-agent cyclophosphamide.

    For the treatment of polycythemia vera†.
    Oral dosage
    Adults

    1000 to 2000 mg PO per day divided into 1 to 3 doses initially. The dose is adjusted as needed to normalize the blood counts of red cells, neutrophils, and platelets.

    For the prevention of thrombosis in patients with essential thrombocytosis†.
    Oral dosage
    Adults

    In one study, 114 elderly patients with a platelet count of 1,500,000/mm3 or less and a history of thrombosis were randomly assigned to receive hydroxyurea or no treatment. Both groups were followed for a median of 27 months. The starting dose of hydroxyurea was 15 mg/kg/day PO and was adjusted to maintain the platelet count below 600,000/mm3 without causing a WBC count less than 4000/mm3. Patients were allowed to continue taking aspirin or ticlopidine. All patients assigned to receive hydroxyurea demonstrated a platelet count less than 600,000/mm3 within 2 to 8 weeks and this value was maintained for the duration of therapy. Two patients in the hydroxyurea group and 14 patients in the control group had thrombotic episodes.

    For the treatment of psoriasis†.
    Oral dosage
    Adults

    Limited data suggests 1000 to 1500 mg/day PO increasing up to 3000 mg/day PO as tolerated. Alternatively, 3000 to 4500 mg/week PO has been used. Maximal clinical response occurs 6 to 8 weeks after initiation of therapy. In a study of 85 patients with extensive chronic plaque psoriasis unresponsive to conventional topical therapy, treatment with hydroxyurea 500 to 1500 mg/day PO (mean duration of 16 months) resulted in complete or near complete clearing of psoriasis in 60% of patients. In a study of 31 patients with recalcitrant psoriasis treated with hydroxyurea 1000 to 1500 mg/day PO, 75% of patients had >= 35% reduction in psoriasis area and severity index (PASI) score and 55% had >= 70% reduction in PASI score. Hydroxyurea administered in doses of 3000 to 4500 mg/week PO was compared to methotrexate 15 to 20 mg/week PO in a study of 30 patients with moderate to severe chronic plaque psoriasis. After 12 weeks of therapy, the mean reduction in PASI score was 49% in the hydroxyurea group vs. 77% in the methotrexate group; however, there was an increased incidence of adverse effects in the methotrexate group. The authors concluded that hydroxyurea may represent an alternative to methotrexate in patients who experience intolerable side effects or who have reached the recommended cumulative dose of methotrexate.

    For the adjuvant treatment of high-grade malignant glioma†, as part of the 8-in-1 regimen.
    Oral dosage
    Children aged greater than 23 months, Adolescents, and Adults 19 years and younger

    3000 mg/m2 PO as part of the 8-in-1 regimen has been studied. Hydroxyurea as part of the 8-in-1 regimen (vincristine 1.5 mg/m2 IV, lomustine 100 mg/m2 IV, procarbazine 75 mg/m2 PO, cisplatin 90 mg/m2 IV, cytarabine 300 mg/m2 IV, dacarbazine 150 mg/m2 IV and methylprednisolone 300 mg/m2 IV) for 3 doses/day on day 1 repeated every 6 weeks for 8 cycles following induction then postoperative radiotherapy (RT) did not significantly improve progression-free survival (PFS) (14 months in both arms) or overall survival (OS) (31 vs. 25 months) compared with vincristine, lomustine , and prednisone plus induction therapy with RT in 172 pediatric patients in a randomized, phase III trial; additionally, the 5-year PFS (33% vs. 26%) and OS (39% vs. 29%) rates were not significantly different between the 2 treatment arms. All patients received postoperative RT with 54 Gy delivered in 30 fractions (1.8 Gy/fraction) over 6 weeks. Patients treated in the 8-in-1 arm experienced more myelosuppression and hearing loss.

    Infants and Children aged 23 months and younger

    3000 mg/m2 PO as part of the 8-in-1 regimen has been studied. Hydroxyurea as part of the 8-in1 regimen (vincristine 1.5 mg/m2 IV, lomustine 70 mg/m2 PO, procarbazine 100 mg/m2 PO, cisplatin 90 mg/m2 IV, cytarabine 300 mg/m2 IV, dacarbazine 150 mg/m2 IV, and prednisone 300 mg/m2 PO) for 3 doses/day on day 1 starting within 6 weeks from surgery repeated once after 2 weeks and then given every 4—6 weeks for 8 additional cycles led to 3-year progression-free survival and overall survival rates of 36% and 51%, respectively, in 39 pediatric patients aged 1—23 months who were nonrandomly assigned to receive 8-in-1 chemotherapy in a clinical trial. The 8-in-1 regimen doses were calculated per kilogram in patients with body surface area of 0.45 m2 or less and radiotherapy (RT) was scheduled following the 10 cycles of 8-in-1 therapy; however, only 2 patients received RT. Bone morrow suppression was frequently reported; additionally, 7 children had hearing loss within the speech range contributing to the omission of cisplatin in 22% of maintenance cycles. No chemotherapy-related deaths were reported.

    For the adjuvant treatment of medulloblastoma†, in combination with radiotherapy and following procarbazine.
    Oral dosage
    Children, Adolescents, and Adults

    250 mg/m2 PO 4 times daily on Mondays, Wednesdays, and Fridays was given during reduced-dose radiotherapy (RT) (whole brain and spinal axis, 25 Gy; posterior fossa, 54 Gy) following surgery and procarbazine (100 mg/m2/day PO for 14 days starting 2—4 weeks after surgery) in 39 patients with medulloblastoma of the posterior fossa in a clinical study. An additional 26 patients received high-dose RT only (whole brain, 40—50 Gy; spinal axis, 30—40 Gy [median, 36 Gy]; posterior fossa, 54 Gy). Of the 65 patients included in this study (age range, 1—56 years), 51 patients were 18 years of age or younger. At a median follow-up of 51 months (range, 24—228 months), the 5-year disease-free survival (DFS) rates were 56% and 78% in patients who received chemotherapy plus reduced-dose RT and high-dose RT only, respectively; additionally, the 5-year overall survival (OS) rates were 68% and 79%, respectively. In high-risk patients who received chemotherapy plus reduced-dose RT (n = 24) and high-dose RT (n = 14), the 5-year DFS rates were 39% and 78%, respectively, and the 5-year OS rates were 58% and 69%, respectively. Myelotoxicity was reported in 38% of patients who received chemotherapy.

    For the adjuvant treatment of primitive neuroectodermal tumor†, as part of the 8-in-1 chemotherapy regimen.
    Oral dosage
    Infants >= 5 months, Children, Adolescents, and Adults < 20 years

    1500 mg/m2 PO as part of the 8-in-1 regimen (vincristine 1.5 mg/m2 IV, lomustine 75 mg/m2 PO [or carmustine 75 mg/m2 PO], procarbazine 75 mg/m2 PO, cisplatin 60 mg/m2 IV [with mannitol and hydration], cytarabine 300 mg/m2 IV, cyclophosphamide 300 mg/m2 IV, and methylprednisolone 300 mg/m2 IV) with each drug given for 3 doses/day on day 1 given every 4 or 6 weeks for 6 or 8 cycles following an induction period with 2 cycles of 8-in-1 (14 days apart) has been studied in pediatric patients with primitive neuroectodermal tumors (PNT) in clinical trials. Patients older than 18 months of age received radiotherapy (RT) after the 2 cycles of induction therapy. 8-in-1 therapy given every 6 weeks for 8 cycles following an induction period prior to postoperative radiotherapy (RT) was compared to vincristine, lomustine, and prednisone following an induction period with RT and vincristine in 25 pediatric patients (aged 0.4—19.6 years) with PNT arising in the pineal region in a randomized trial. All 8 infants (l< 18 months of age) nonrandomly assigned to receive the 8-in-1 regimen (2 induction courses of the 8-in-1 regimen given 14 days apart followed by 8 cycles repeated monthly) without RT had progressive disease in 3—14 months (median time to progression, 4 months). Of the 17 patients older than 18 months who received postoperative RT (administered to the primary tumor site and craniospinal axis) and chemotherapy, the 3-year progression-free survival (PFS) rate was 61% and the 3-year overall survival (OS) rate was 73%; additionally, there was no difference in treatment effect between the 2 regimens. 8-in-1 therapy starting within 6 weeks from surgery repeated once after 2 weeks and then given monthly for a total of 8 cycles was studied in 96 pediatric patients aged less than 18 months with PNT. RT to the involved site was scheduled following the first 2 cycles of 8-in-1 therapy or as craniospinal RT given at the completion of therapy; however, RT was only given to 9 patients prior to relapse and 4 patients at relapse. The 3-year PFS and OS rates were 23% and 33%, respectively. At a median follow-up of 49 months, 19 of 24 patients who completed chemotherapy without disease progression had PFS greater than 18 months. Serious toxicities included infection and grade 3—4 neutropenia and thrombocytopenia. Chemotherapy-related deaths occurred in 5 patients, with 3 deaths attributed to pulmonary failure.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    80 mg/kg PO.

    Geriatric

    80 mg/kg PO.

    Adolescents

    35 mg/kg/day PO for sickle cell disease. Safety and efficacy have not been established for other indications; doses up to 3,000 mg/m2 PO have been given off-label for malignant glioma.

    Children

    2 to 12 years: 35 mg/kg/day PO for sickle cell disease. Safety and efficacy have not been established for other indications; doses up to 3,000 mg/m2 PO have been given off-label for malignant glioma.
    1 year: Safety and efficacy have not been established; doses up to 3,000 mg/m2 PO have been given off-label for malignant glioma.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidance for dosage adjustment is not available; monitor hematologic parameters closely.

    Renal Impairment

    Obtain creatinine clearance (CrCl) using a 24-hour urine collection.
    CrCl 60 mL/minute or more: No dosage adjustment.
    CrCl less than 60 mL/minute: Reduce the initial dosage by 50%.
    Patients receiving hemodialysis: Reduce the initial hydroxyurea dosage by 50%; administer after dialysis on dialysis days.

    ADMINISTRATION

     
    Observe and exercise usual precautions for handling, preparing, and administering cytotoxic drugs. If the powder from hydroxyurea capsules or broken tablets is spilled, immediately wipe it up with a damp disposable towel and discard the used towels and empty capsules in a closed container, such as a plastic bag. Clean the spill areas 3 times using a detergent solution followed by clean water.

    Oral Administration
    Oral Solid Formulations

    Capsules
    May be taken with or without food; the affect of food on hydroxyurea absorption has not been studied.
    Swallow capsules whole; do not cut or crush capsules.
     
    Tablets
    Available in 100 mg and 1,000 mg tablet strengths. Do NOT split the 100 mg tablets into smaller parts. The 1,000 mg tablets have 3 score lines and can be split into 4 parts (each 250 mg). Round doses to the nearest 50- or 100-mg strength, as appropriate, based on the prescriber's clinical judgement.
    Take the dose once daily with a glass of water. For patients not able to swallow whole tablets, the dose can be dispersed immediately prior to use in a small quantity of water in a teaspoon.
    Storage: Broken 1,000 mg tablets must be stored in the bottle and used within 3 months.

    STORAGE

    Droxia:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Hydrea:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Siklos:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Hydroxyurea is contraindicated in patients who have a hypersensitivity to hydroxyurea or any other component of its formulation.

    Anemia, bone marrow suppression, leukopenia, neutropenia, thrombocytopenia

    Hydroxyurea may cause severe bone marrow suppression/myelosuppression (e.g., leukopenia, anemia, neutropenia, and thrombocytopenia). Evaluate hematologic status before and during treatment (weekly for cancer and every 2 weeks for sickle cell disease). Do not initiate therapy if bone marrow function is markedly depressed. Provide supportive care and modify or discontinue treatment as necessary. Advise patients to report any signs and symptoms of infection (e.g., fever, chills, sore throat, cough) or unusual bleeding or bruising immediately. Recovery from myelosuppression is usually observed within 15 days of therapy interruption; resume therapy at a lower dose. Some patients, treated at the recommended initial dose for sickle cell anemia, have experienced severe or life-threatening myelosuppression. Pediatric patients have an increased risk of myelosuppression at the time of dosage adjustment due to the change in body weight requiring modification of daily dose. Use caution in patients with a history of receiving prior chemotherapy or radiation, which may increase the risk for bone marrow suppression. Correct anemia prior to Hydrea therapy. Leukopenia is generally the first and most common manifestation of bone marrow suppression from hydroxyurea. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia.

    New primary malignancy, radiation therapy, sunlight (UV) exposure, vasculitis

    Hydroxyurea is carcinogenic in humans; new primary malignancy (e.g., leukemia and skin cancer) has been reported in patients receiving long-term hydroxyurea for both myeloproliferative disorders and sickle cell disease. Monitor blood counts regularly and on a long-term basis in all patients using hydroxyurea. Advise protection from sunlight (UV) exposure. Patients with myeloproliferative disorders such as polycythemia vera and thrombocythemia who receive hydroxyurea may be at increased risk of developing leukemia. Consider the risk of secondary malignancy compared with the benefit of hydroxyurea therapy. Cutaneous vasculitis, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue or reduce the dose of hydroxyurea. Avoid the use of hydroxyurea in patients with leg wounds/ulcers. Radiation recall reaction has also been reported with hydroxyurea use; monitor for skin erythema in patients who previously received radiation therapy.

    Geriatric, hepatic disease, renal disease, renal impairment

    Reduce the dosage of hydroxyurea and closely monitor hematologic parameters in patients with renal impairment (CrCl less than 60 mL/minute or end stage renal disease). Close monitoring of hematologic parameters is also advised in patients with hepatic disease. Geriatric patients have a greater risk of impaired renal function due to age; therefore, consider monitoring renal function in these patients.

    Human immunodeficiency virus (HIV) infection

    Pancreatitis, hepatotoxicity, and peripheral neuropathy have been reported in patients with human immunodeficiency virus (HIV) infection who were receiving antiretroviral agents and hydroxyurea. Avoid the concomitant use of hydroxyurea with stavudine and didanosine; fatal hepatotoxicity has been reported in with this drug combination. If hydroxyurea is used in HIV-patients who are also taking didanosine and/or stavudine, monitor patients closely for signs and symptoms of pancreatitis; discontinue hydroxyurea in patients who develop pancreatitis. Patients with HIV infection should contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy during hydroxyurea treatment.

    Vaccination

    Avoid vaccination with live virus vaccines during hydroxyurea therapy. The concomitant use of hydroxyurea and a live virus vaccine may increase the risk of a patient developing a severe infection. Additionally, patients may have a decreased antibody response to the vaccine due to immunosuppression caused by hydroxyurea. Consider consultation with a specialist.

    Pernicious anemia

    Hydroxyurea may mask a diagnosis of pernicious anemia; all patients should receive folic acid supplementation. Self-limiting macrocytosis may occur early in the course of hydroxyurea treatment and may look like pernicious anemia; macrocytosis is not related to vitamin B12 or folic acid deficiency.

    Laboratory test interference

    Hydroxyurea administration may cause laboratory test interference of urea, uric acid, and lactic acid assays resulting in falsely elevated results.

    Intrauterine fetal death, pregnancy

    Hydroxyurea is genotoxic and may cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy; apprise women of the potential hazard to the fetus. Although data from a limited number of exposed pregnancies indicate no adverse effects on pregnancy or the health of the fetus/newborn, careful follow-up with adequate clinical, biological, and ultrasonographic examinations should be considered if a pregnant female is exposed to hydroxyurea through self-therapy or via their male partner treated with hydroxyurea. In a retrospective analysis of 123 adults treated with hydroxyurea, 23 pregnancies have been reported from 15 women treated with hydroxyurea and partners of 3 men treated with hydroxyurea. Most (61%) had no adverse developmental outcomes. In other cases with known evolution, pregnancy was interrupted voluntarily or upon medical advice. In retrospective cohorts of 352 children and adolescents with sickle cell disease treated with hydroxyurea for up to 12 years, 3 pregnancies under hydroxyurea with no adverse developmental outcomes were reported. From postmarketing data in sickle cell treatment, 3 pregnancies have been reported while the father was treated with hydroxyurea and 16 pregnancies have been reported in 15 hydroxyurea-treated females. Among the 13 cases with known evolution, 5 had no adverse developmental outcomes, 4 led to premature birth, and 4 were early terminated. There are many reports in the literature describing the use of hydroxyurea in pregnant women with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease. Several women electively terminated their pregnancies; one developed eclampsia and delivered a phenotypically normal still-born infant (intrauterine fetal death). All others delivered live, healthy infants without congenital anomalies. However, further studies and longer follow-up with careful assessment of fetotoxic effects are required to determine the safety of hydroxyurea during pregnancy. In animal studies, hydroxyurea crosses the placenta. Teratogenicity has been demonstrated in mice, hamsters, cats, miniature swine, dogs, and monkeys at hydroxyurea doses that were within 1-fold of the human dose (based on mg/m2 dosing). Fetal malformations (e.g., partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) and embryotoxicity (e.g., decreased fetal viability, reduced live litter sizes, developmental delays) occurred in rats and rabbits who received hydroxyurea. Growth retardation and impaired learning ability were observed in rats that received approximately 1.7-times the maximum recommended human daily dose of hydroxyurea.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel both male and female patients about the potential reproductive risk of hydroxyurea and discuss contraception requirements. Pregnancy testing should be performed prior to starting hydroxyurea in female patients of reproductive potential. These patients should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with hydroxyurea. Female patients should report pregnancy immediately. Due to the potential for male-mediated teratogenicity, males who have female partners of reproductive potential should use effective contraception during and for at least 6 months (Siklos) or 1 year (Droxia and Hydrea) after hydroxyurea treatment. Hydroxyurea may cause infertility in men. Azoospermia or oligospermia has occurred in men who received hydroxyurea. Counsel male patients to consider sperm conservation procedures before the start of therapy.

    Breast-feeding

    According to the manufacturer, hydroxyurea or breast-feeding should be discontinued because of the potential for serious adverse reactions (e.g., carcinogenicity) in nursing infants from hydroxyurea. Hydroxyurea passes into breast milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children

    Continuous follow-up of the growth of hydroxyurea-treated pediatric patients is recommended. Children and adolescents aged 2 to 16 years had a higher risk of neutropenia than older patients during clinical trials.

    ADVERSE REACTIONS

    Severe

    anemia / Delayed / 1.7-1.7
    neutropenia / Delayed / 1.0-1.0
    headache / Early / 1.0-1.0
    thrombocytopenia / Delayed / 0.5-0.5
    nausea / Early / 0.5-0.5
    fever / Early / 0.5-0.5
    leukemia / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    skin atrophy / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known

    Moderate

    infection / Delayed / 0.5-2.5
    weight gain / Delayed / 1.7-1.7
    constipation / Delayed / 1.2-1.2
    bone marrow suppression / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    stomatitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    erythema / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    hallucinations / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    infertility / Delayed / Incidence not known

    Mild

    macrocytosis / Delayed / Incidence not known
    anorexia / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    nail discoloration / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    rash / Early / Incidence not known
    chills / Rapid / Incidence not known
    dizziness / Early / Incidence not known
    drowsiness / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    amenorrhea / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Anagrelide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Anticoagulants: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Antithrombin III: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Apixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betrixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bivalirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Glycopyrrolate; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cilostazol: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Clopidogrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Colchicine; Probenecid: (Major) Hydroxyurea may raise the serum uric acid concentration, so dosage adjustment of uricosuric medications such as probenecid may be necessary.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cytarabine, ARA-C: (Minor) Hydroxyurea potentiates the activity of cytarabine, ARA-C by depleting the cell of another nucleoside, deoxycytidine triphosphate, which would otherwise compete with cytarabine for activity in the cell. Some clinicians have recommended decreasing the dose of cytarabine when it is given concurrently with hydroxyurea.
    Dabigatran: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Danaparoid: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Desirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Didanosine, ddI: (Major) While there have been reports that the combined use of hydroxyurea and didanosine may result in an increased immune response for up to 1 year, the combined use of these drugs is associated with an increased incidence of didanosine-associated adverse effects, including pancreatitis and peripheral neuropathy. Additionally, there are post-marketing reports of hepatotoxicity and hepatic failure resulting in death with a treatment regimen of hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine; this combination should be avoided. Finally, it is recommended that hydroxyurea not be used in patients with HIV; reports of hydroxyurea's improvement of viral suppression are inconsistent and hydroxyurea is associated with decreased CD4 counts.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Eptifibatide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Floxuridine: (Minor) Neurotoxicity may occur to a significant extent during concomitant administration of floxuridine and hydroxyurea.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluorouracil, 5-FU: (Minor) High levels of deoxyuridine monophosphate have been associated with resistance to fluorouracil, 5-FU. Hydroxyurea may inhibit the formation of dUMP and lead to increased efficacy of 5-FU when administered after 5-FU.
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fondaparinux: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Ganciclovir: (Moderate) Use ganciclovir and hydroxyurea together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Heparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Piroxicam: (Major) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Prasugrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Probenecid: (Major) Hydroxyurea may raise the serum uric acid concentration, so dosage adjustment of uricosuric medications such as probenecid may be necessary.
    Reteplase, r-PA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Rivaroxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Stavudine, d4T: (Major) It is recommended that hydroxyurea not be used in patients with HIV; reports of hydroxyurea's improvement of viral suppression are inconsistent and hydroxyurea is associated with decreased CD4 counts. While there have been reports that hydroxyurea may enhance the antiretroviral activity of stavudine, the overall results of these reports are inconsistent, and the combined use of these drugs is associated with an increased incidence of stavudine-associated adverse effects, including pancreatitis and peripheral neuropathy. Additionally, there are postmarketing reports of hepatotoxicity and hepatic failure resulting in death with a treatment regimen of hydroxyurea and stavudine.
    Streptokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Sulfinpyrazone: (Major) Hydroxyurea may raise the serum uric acid concentration, so dosage adjustment of uricosuric medications such as sulfinpyrazone may be necessary.
    Sulindac: (Major) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Tenecteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as hydroxyurea, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Thrombolytic Agents: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Ticagrelor: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Ticlopidine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Tirofiban: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Tolmetin: (Major) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Urokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Valganciclovir: (Moderate) Use valganciclovir and hydroxyurea together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vorapaxar: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Warfarin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Hydroxyurea is genotoxic and may cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy; apprise women of the potential hazard to the fetus. Although data from a limited number of exposed pregnancies indicate no adverse effects on pregnancy or the health of the fetus/newborn, careful follow-up with adequate clinical, biological, and ultrasonographic examinations should be considered if a pregnant female is exposed to hydroxyurea through self-therapy or via their male partner treated with hydroxyurea. In a retrospective analysis of 123 adults treated with hydroxyurea, 23 pregnancies have been reported from 15 women treated with hydroxyurea and partners of 3 men treated with hydroxyurea. Most (61%) had no adverse developmental outcomes. In other cases with known evolution, pregnancy was interrupted voluntarily or upon medical advice. In retrospective cohorts of 352 children and adolescents with sickle cell disease treated with hydroxyurea for up to 12 years, 3 pregnancies under hydroxyurea with no adverse developmental outcomes were reported. From postmarketing data in sickle cell treatment, 3 pregnancies have been reported while the father was treated with hydroxyurea and 16 pregnancies have been reported in 15 hydroxyurea-treated females. Among the 13 cases with known evolution, 5 had no adverse developmental outcomes, 4 led to premature birth, and 4 were early terminated. There are many reports in the literature describing the use of hydroxyurea in pregnant women with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease. Several women electively terminated their pregnancies; one developed eclampsia and delivered a phenotypically normal still-born infant (intrauterine fetal death). All others delivered live, healthy infants without congenital anomalies. However, further studies and longer follow-up with careful assessment of fetotoxic effects are required to determine the safety of hydroxyurea during pregnancy. In animal studies, hydroxyurea crosses the placenta. Teratogenicity has been demonstrated in mice, hamsters, cats, miniature swine, dogs, and monkeys at hydroxyurea doses that were within 1-fold of the human dose (based on mg/m2 dosing). Fetal malformations (e.g., partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) and embryotoxicity (e.g., decreased fetal viability, reduced live litter sizes, developmental delays) occurred in rats and rabbits who received hydroxyurea. Growth retardation and impaired learning ability were observed in rats that received approximately 1.7-times the maximum recommended human daily dose of hydroxyurea.

    MECHANISM OF ACTION

    Hydroxyurea blocks ribonucleotide reductase, the rate-limiting enzyme of DNA synthesis. This enzyme is responsible for converting ribonucleotides to deoxyribonucleotide triphosphates (dNTPs), which are critical to DNA synthesis and repair. Ribonucleotide reductase is composed of two subunits, M1 and M2. The M2 protein is the catalytic subunit and contains a nonheme iron complex. The cellular concentration of M2 is variable throughout the cell cycle but peaks during the S-phase. Hydroxyurea inhibits ribonucleotide reductase by binding to the M2 subunit and disrupting the iron complex. Since the effects of hydroxyurea may be partially reversed in vitro by ferrous iron and iron-chelating agents may increase cytotoxicity, a nonheme iron cofactor is necessary for this process. Hydroxyurea reduces the total amount of deoxyribonucleotides, especially purines. Hydoxyurea causes immediate inhibition of DNA synthesis but does not affect RNA or protein synthesis. In addition, hydroxyurea reduces the levels of dATP, an deoxyribonucleotide that inhibits ribonucleotide reductase activity. Hydroxyurea also decreases the binding of vitamin B12 to transcobalamin II, causing a secondary type of vitamin B12 deficiency. Hydroxyurea exerts its affects on cells in the S-phase, especially cells rapidly synthesizing DNA. Hydroxyurea causes an accumulation of cells at the G1/S-phase or the early S-phase of the cell cycle, which leads to cell death.
     
    In psoriasis, the result of hydroxyurea therapy is a slowing of basal cell-layer replication. Hydroxyurea alters the red blood cell membrane so it is unable to penetrate the capillaries of the skin. This creates a hypoxic state that slows the growth of the basal layer. In addition, the hydroxyurea-induced decrease in the neutrophil count will decrease the pustule formation characteristic of psoriasis. Finally, hydroxyurea also seems to correct the abnormal keratin formation seen in psoriasis.
     
    In the treatment of sickle cell disease, hydroxyurea induces the production of fetal hemoglobin. In sickle cell anemia, there is a defect in the beta-chain of hemoglobin resulting in hemoglobin S (HbS). Under conditions of low oxygen, the deoxygenated HbS becomes rigid and less soluble than deoxygenated adult hemoglobin (HbA). Fetal hemoglobin (HbF) is the predominant hemoglobin prior to birth. During the third trimester, HbF is replaced by HbA leaving approximately 1% HbF in healthy adults. Hemoglobin F has a protective effect on the clinical manifestations of sickle cell disease in newborns. When HbF is present within erythrocytes it does not enter the HbS polymer. In addition, as HbF concentrations increase, the concentration of HbS decreases providing a sparing effect. Hydroxyurea, by increasing the concentrations of HbF, has been shown to decrease hemolytic and vaso-occlusive crisis in some sickle cell disease patients. Hydroxyurea can not be used to treat these crises.
     
    Hydroxyurea appears to have activity in the treatment of HIV disease due to its ability to reduce deoxyribonucleotide triphosphates (dNTPs), including deoxyadenosine triphosphate (dATP), through inhibition of ribonucleotide reductase. Hydroxyurea decreases the concentration of dATP to a greater degree than other dNTPs. In HIV-infected cells, depletion of the dNTP pool results in incomplete reverse transcription of the viral genome. Endogenous dNTPs normally compete with nucleoside reverse transcriptase inhibitors (NRTIs) for binding sites on HIV reverse transcriptase. Hydroxyurea potentiates the effect of NRTIs, especially adenosine analogs such as didanosine, ddI, by reducing the competition for binding sites. In vitro hydroxyurea also induces the activity of cellular kinases that phosphorylate NRTIs, potentially further enhancing their activity. Trials are ongoing to establish whether this also occurs in vivo. In addition, by allowing cells to accumulate at the G1/S-phase or early S-phase, hydroxyurea may allow increase time for activation of NRTIs. Hydroxyurea does not appear to delay or decrease the onset of viral-resistance to NRTIs.

    PHARMACOKINETICS

    Hydroxyurea is administered orally. The volume of distribution of hydroxyurea approximates that of total body water; it is concentrated in leukocytes and erythrocytes. Oral hydroxyurea undergoes saturable hepatic metabolism (up to 60%); it is also metabolized via urease in intestinal bacteria (minor pathway). Approximately 40% of the hydroxyurea dose was recovered in the urine in patients with sickle cell anemia.

    Oral Route

    Cmax is achieved 1 to 4 hours after oral administration. Cmax and AUC values increase more than proportionally with increasing doses. There are no data on the effect of food on the absorption of hydroxyurea.