Droxia

Other Antimetabolites Antineoplastic Agents
Sickle Cell Disease Agents

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
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.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

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. The 100 mg tablets have 1 score line and can be split into 2 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, at the same time of day, 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 tablets must be stored in the bottle and used within 3 months.

Extemporaneous 100 mg/mL Oral Solution
Mix the contents of 500 mg capsules (Hydrea) with a sufficient amount of room temperature Sterile Water to achieve a concentration of 200 mg/mL.
Vigorously stir for several hours using a magnetic stirrer.
Filter to remove insoluble excipients.
Add flavored syrup (Syrpalta without color) in a sufficient quantity to produce a final concentration of 100 mg/mL.
Prepare and dispense monthly. Hydroxyurea 100 mg/mL oral solution prepared and maintained at room temperature is chemically and functionally stable for several months.
Storage: Store at room temperature in amber plastic bottles.

anemia / Delayed / 1.7-3.4
headache / Early / 1.0-2.5
infection / Delayed / 0.1-2.5
thrombocytopenia / Delayed / 0.5-1.2
neutropenia / Delayed / 0.6-1.0
skin ulcer / Delayed / 1.0-1.0
asthenia / Delayed / 0.9-0.9
dizziness / Early / 0.8-0.8
nausea / Early / 0.3-0.5
abdominal pain / Early / 0.5-0.5
alopecia / Delayed / 0.5-0.5
xerosis / Delayed / 0.5-0.5
fever / Early / 0.4-0.5
influenza / Delayed / 0.5-0.5
weight gain / Delayed / 0.4-0.4
dyspnea / Early / 0.4-0.4
cough / Delayed / 0.3-0.3
fatigue / Early / 0.2-0.2
peripheral edema / Delayed / 0.2-0.2
pharyngitis / Delayed / 0.1-0.1
leukemia / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
skin cancer / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
hypomagnesemia / Delayed / Incidence not known
peptic ulcer / 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

diarrhea / Early / 1.2-1.2
constipation / Delayed / 1.2-1.2
jaundice / Delayed / Incidence not known
bleeding / Early / Incidence not known
leukopenia / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
bone marrow suppression / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known
erythema / Early / 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
pneumonitis / Delayed / Incidence not known
interstitial lung disease / Delayed / Incidence not known
radiation recall reaction / Delayed / Incidence not known
infertility / Delayed / Incidence not known

arthralgia / Delayed / 2.4-2.4
back pain / Delayed / 1.0-1.0
macrocytosis / Delayed / Incidence not known
vomiting / Early / Incidence not known
anorexia / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
nail discoloration / Delayed / Incidence not known
rash / Early / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
chills / Rapid / Incidence not known
malaise / Early / Incidence not known
drowsiness / Early / Incidence not known
amenorrhea / Delayed / Incidence not known
oligospermia / Delayed / Incidence not known
azoospermia / Delayed / Incidence not known

Do not initiate hydroxyurea in patients with marked bone marrow suppression. Hydroxyurea can cause severe myelosuppression. Use hydroxyurea with caution in patients who have received previous radiotherapy or cytotoxic chemotherapy; myelosuppression is more common in these patients. Additionally, 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. Evaluate hematologic status before and during treatment (weekly for cancer and every 2 weeks for sickle cell disease). Provide supportive care and modify the dose or discontinue treatment as required if myelosuppression occurs. Recovery from myelosuppression is usually rapid when therapy is interrupted. In patients who develop acute jaundice or hematuria in the presence of persistent or worsening anemia, evaluate for hemolytic anemia [e.g., by measuring lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin, urinalysis, and direct and indirect antiglobulin (Coombs) tests]. Discontinue hydroxyurea if a diagnosis of hemolytic anemia is confirmed.

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.

DROXIA, HYDREA, Siklos

Rx

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

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).

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.

15 mg/kg/dose PO once daily, rounded to the nearest 500-mg increment. Increase the dose by 5 mg/kg/day every 8 weeks until mild myelosuppression (absolute neutrophil count [ANC] 2,000 to 4,000/microliter) is achieved. Max: 35 mg/kg/day. Monitor blood counts at least every 4 weeks while adjusting dose and every 2 to 3 months once a stable dose is achieved. Aim for target ANC of 2,000/microliter or more and a platelet count of 80,000/microliter or more. If neutropenia or thrombocytopenia occurs, hold hydroxyurea, monitor blood counts weekly, and restart hydroxyurea at a dose 5 mg/kg/day lower than previous dose when blood count has recovered. Clinical response to treatment may take 3 to 6 months; therefore, a 6-month trial on the maximum tolerated dose is recommended before considering discontinuation due to treatment failure. Long term therapy is indicated for those with a clinical response.

20 mg/kg/dose PO once daily. Increase the dose by 5 mg/kg/day every 8 weeks until mild myelosuppression (absolute neutrophil count [ANC] 2,000 to 4,000/microliter) is achieved. Max: 35 mg/kg/day. Monitor blood counts at least every 4 weeks while adjusting dose and every 2 to 3 months once a stable dose is achieved. Aim for target ANC of 2,000/microliter or more (younger patients with lower baseline counts may safely tolerate ANC down to 1,250/microliter) and a platelet count of 80,000/microliter or more. If neutropenia or thrombocytopenia occurs, hold hydroxyurea, monitor blood counts weekly, and restart hydroxyurea at a dose 5 mg/kg/day lower than previous dose when blood count has recovered. Clinical response to treatment may take 3 to 6 months; therefore, a 6-month trial on the maximum tolerated dose is recommended before considering discontinuation due to treatment failure. Long term therapy is indicated for those with a clinical response.

15 mg/kg/dose PO once daily initially. Base dose on actual or ideal body weight (whichever is less). If blood counts are within an acceptable range, increase the 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.

15 mg/kg/dose PO once daily initially. Base dose on actual or ideal body weight (whichever is less) and round the calculated dose to the nearest 50- or 100-mg strength. If blood counts are within an acceptable range, increase the 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.

20 mg/kg/dose PO once daily initially. Base dose on actual or ideal body weight (whichever is less) and round the calculated 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

10 to 15 mg/kg/dose PO once daily, initially. Increase the dose by 2.5 to 5 mg/kg/day gradually. Usual dose: 15 to 30 mg/kg/day. Max 35 mg/kg/day.

10 to 15 mg/kg/dose PO once daily, initially. Increase the dose by 2.5 to 5 mg/kg/day gradually. Usual dose: 15 to 30 mg/kg/day. Max 35 mg/kg/day.

†Indicates off-label use

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

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%.
 
Hemodialysis
Reduce the initial dosage by 50%; administer after dialysis on dialysis days.

Albuterol; 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.
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.
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.
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.
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; Epinephrine: (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.
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.
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.
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.
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.
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.
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.
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.
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-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-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.
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; Epinephrine: (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.
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.
Olopatadine; 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.
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.
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.
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.
Probenecid; Colchicine: (Major) Hydroxyurea may raise the serum uric acid concentration, so dosage adjustment of uricosuric medications such as probenecid may be necessary.
Ropeginterferon 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.
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.
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.
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.
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.
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.
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.
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.

DROXIA/HYDREA/Hydroxyurea Oral Cap: 200mg, 300mg, 400mg, 500mg
Siklos Oral Tab: 100mg, 1000mg

80 mg/kg PO.

80 mg/kg PO.

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.

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.

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.

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. Half-life is approximately 2 to 4 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

Oral bioavailability of hydroxyurea is 85% to 100%. 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.

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.