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Hydroxyurea (hydroxycarbamide): Drug information

Hydroxyurea (hydroxycarbamide): Drug information
(For additional information see "Hydroxyurea (hydroxycarbamide): Patient drug information" and see "Hydroxyurea (hydroxycarbamide): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Bone marrow suppression (Droxia, Siklos):

Hydroxyurea may cause severe myelosuppression. Do not give if bone marrow function is markedly depressed. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary.

Secondary malignancy (Droxia, Siklos):

Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies.

Brand Names: US
  • Droxia;
  • Hydrea;
  • Siklos
Brand Names: Canada
  • APO-Hydroxyurea;
  • Hydrea;
  • MYLAN-Hydroxyurea;
  • RIVA-Hydroxyurea
Pharmacologic Category
  • Antineoplastic Agent, Miscellaneous
Dosing: Adult

Note: Doses should be based on ideal or actual body weight, whichever is less (per manufacturer). Prophylactic administration of folic acid is recommended. Per the manufacturer’s labeling, do not initiate therapy if bone marrow function is markedly reduced; for oncologic indications, correct severe anemia prior to initiating treatment. Due to potential cutaneous vasculitic toxicity, avoid use in patients with leg ulcer wounds. If at risk for tumor lysis syndrome, hydrate adequately and initiate antihyperuricemic agents as clinically necessary.

Acute myeloid leukemia, cytoreduction

Acute myeloid leukemia, cytoreduction (off-label use): Oral: 50 to 100 mg/kg/day until WBC <100,000/mm3 (Ref) or 50 to 60 mg/kg/day until WBC <10,000 to 20,000/mm3 (Ref).

Chronic myeloid leukemia

Chronic myeloid leukemia (Hydrea): Initial: Oral: 40 mg/kg/day (reduce initial dose for thrombocytopenia); reduce dose to 20 mg/kg/day if WBC count <2,000/mm3. Further individualize dose based on WBC counts (Ref). Hydroxyurea may be used for short-term therapy of elevated WBC counts prior to initiating a TKI (Ref).

Essential thrombocythemia, high-risk

Essential thrombocythemia, high-risk (off-label use): Oral: 500 to 1,000 mg daily; adjust dose to maintain platelets <400,000/mm3 (Ref).

Head and neck cancer

Head and neck cancer (Hydrea): Individualize treatment/regimen based on tumor type, response, and current clinical practice standards. Oral: 1,000 mg every 12 hours for 11 doses per cycle, in combination with continuous infusion fluorouracil and radiation therapy (Ref).

Hypereosinophilic syndrome, refractory

Hypereosinophilic syndrome, refractory (off-label use): Oral: 1,000 mg/day (range: 500 to 2,000 mg/day) (Ref) or 1,000 to 3,000 mg/day (Ref).

Meningioma

Meningioma (off-label use): Oral: 20 mg/kg once daily (Ref).

Polycythemia vera, high-risk

Polycythemia vera, high-risk (off-label use): Patients <65 years of age: Oral: 15 to 20 mg/kg/day (Ref) or 500 mg twice daily initially, titrated based on target hematocrit and hematologic toxicity (Ref) or 25 mg/kg/day as induction therapy, followed (after remission achieved) by maintenance dosing of 10 to 15 mg/kg/day (Ref).

Sickle cell anemia

Sickle cell anemia:

Droxia: Initial: Oral: 15 mg/kg once daily. Monitor blood counts every 2 weeks; if blood counts are in an acceptable range, may increase by 5 mg/kg/day every 12 weeks until the maximum tolerated dose of 35 mg/kg/day is achieved or the dose that does not produce toxic effects over 24 consecutive weeks (do not increase dose if blood counts are between acceptable and toxic ranges). If toxicity occurs, withhold treatment until the bone marrow recovers, then restart with a dose reduction of 2.5 mg/kg/day; if no toxicity occurs over the next 12 weeks, then the subsequent dose may be increased by 2.5 mg/kg/day every 12 weeks to a maximum tolerated dose (dose that does not produce hematologic toxicity for 24 consecutive weeks). If hematologic toxicity recurs a second time at a specific dose, discontinue treatment.

Acceptable hematologic ranges: Neutrophils ≥2,500/mm3; platelets ≥95,000/mm3; hemoglobin >5.3 g/dL; and reticulocytes ≥95,000/mm3 if hemoglobin is <9 g/dL.

Toxic hematologic ranges: Neutrophils <2,000/mm3; platelets <80,000/mm3; hemoglobin <4.5 g/dL; and reticulocytes <80,000/mm3 if hemoglobin is <9 g/dL.

Siklos: Initial: Oral: 15 mg/kg once daily. Calculate rounded doses to the nearest 50 mg or 100 mg strength. Monitor blood counts every 2 weeks; if blood counts are in an acceptable range, may increase by 5 mg/kg/day every 8 weeks or if a painful crisis occurs until mild myelosuppression (ANC 2,000 to 4,000/mm3) is achieved, or up to a maximum dose of 35 mg/kg/day. If blood counts are in a toxic range, discontinue until hematologic recovery. Following hematologic recovery, restart with the dose reduced by 5 mg/kg/day; may titrate dose up or down every 8 weeks in 5 mg/kg/day increments, seeking a stable dose with no hematologic toxicity for 24 weeks. Discontinue permanently if hematologic toxicity develops twice.

Acceptable hematologic ranges: Neutrophils ≥2,000/mm3; platelets ≥80,000/mm3; hemoglobin >5.3 g/dL; and reticulocytes ≥80,000/mm3 if hemoglobin is <9 g/dL.

Toxic hematologic ranges: Neutrophils <2,000/mm3 (neutrophil limit of 1,250/mm3 may be acceptable in younger patients with lower baseline counts); platelets <80,000/mm3; hemoglobin <4.5 g/dL; and reticulocytes <80,000/mm3 if hemoglobin is <9 g/dL.

Note: A clinical response to treatment may take 3 to 6 months; a 6-month trial of the maximum tolerated dose is recommended prior to considering discontinuation due to treatment failure. Effectiveness of hydroxyurea depends upon daily dosing adherence. For patients who have a clinical response, long-term hydroxyurea therapy is indicated (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: For indications in which the anticipated use is short term (eg, cytoreduction for acute myeloid leukemia), the risks versus benefits may not favor empiric dose reduction as described below for patients with altered kidney function or on renal replacement therapies; instead, consider initiating on the low end of the normal range and adjust dose based on targeted hematologic response (eg, WBC reduction) (Ref).

Altered kidney function:

CrCl ≥60 mL/minute: No dosage adjustment necessary (Ref).

CrCl <60 mL/minute: Initial: Administer 50% of the usual indication-specific dose; titrate based on tolerance and response (Ref).

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):

Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).

Initial: No dosage adjustment necessary; titrate based on tolerability and response (expert opinion). Note: Since hydroxyurea clearance is dependent on kidney function, titration to doses that may exceed the usual recommended dose may be required in patients with ARC (Ref).

Hemodialysis, intermittent (thrice weekly): There are no data on the extent of removal by hemodialysis (has not been studied); however, based on protein binding (75% to 80%) and Vd (approximates total body water), it is likely somewhat dialyzed, although the full extent is unknown (Ref):

Initial: Administer 50% of the usual indication-specific dose; titrate based on tolerability and response. When scheduled dose falls on hemodialysis days, administer after hemodialysis (Ref).

Peritoneal dialysis: There are no data on the extent of removal by peritoneal dialysis (has not been studied); the following recommendations are empirically derived from hemodialysis patients:

Initial: Administer 50% of the usual indication-specific dose; titrate based on tolerability and response (Ref).

CRRT:

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Close monitoring of response and adverse reactions (eg, myelosuppression) due to drug accumulation is important. Although there are no data for patients on CRRT (has not been studied), some removal of hydroxyurea may be expected.

Initial: Administer 50% of the usual indication-specific dose; titrate based on tolerability and response (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration):

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions (eg, myelosuppression) due to drug accumulation is important. Although there are no data for patients on PIRRT (has not been studied), some removal of hydroxyurea may be expected.

Initial: Administer 50% of the usual indication-specific dose; titrate based on tolerability and response; when scheduled dose falls on PIRRT days, administer after PIRRT (Ref).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; closely monitor for bone marrow toxicity; however, no need for dosage adjustment is expected; monitor closely for hematologic toxicities (Ref).

Dosing: Obesity: Adult

ASCO Guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2 (solid tumors): Utilize patient's actual body weight (full weight) for calculation of BSA- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing with subsequent cycles if cause of toxicity (eg, hepatic or renal impairment) is clearly established and fully resolved (Ref). Note: The manufacturer recommends dosing based on ideal or actual body weight, whichever is less.

Dosing: Adjustment for Toxicity: Adult

Cutaneous vasculitic ulcerations: Discontinue hydroxyurea (or reduce the dose) and initiate therapy for vasculitic toxicity.

Hematologic toxicity: Provide supportive care and modify hydroxyurea dose or discontinue as clinically indicated. Do not initiate therapy if bone marrow function is markedly reduced.

Sickle cell anemia:

Droxia: Neutrophils <2,000/mm3, platelets <80,000/mm3, hemoglobin <4.5 g/dL, or reticulocytes <80,000/mm3 with hemoglobin <9 g/dL: Interrupt treatment; following recovery, may resume with a dose reduction of 2.5 mg/kg/day. Hydroxyurea may then be titrated up or down every 12 weeks in 2.5 mg/kg/day increments until the patient is at a stable dosage that does not result in hematologic toxicity for 24 weeks. If hematologic toxicity recurs a second time at a specific dose, discontinue treatment.

Siklos: Neutrophils <2,000/mm3 (neutrophil limit of 1,250/mm3 may be acceptable in younger patients with lower baseline counts), platelets <80,000/mm3, hemoglobin <4.5 g/dL, and reticulocytes <80,000/mm3 with hemoglobin <9 g/dL: Interrupt treatment; following recovery, may resume with a dose reduction of 5 mg/kg/day. Hydroxyurea may then be titrated up or down every 8 weeks in 5 mg/kg/day increments until the patient is at a stable dosage that does not result in hematologic toxicity for 24 weeks. If hematologic toxicity recurs a second time at a specific dose, discontinue treatment.

Hemolytic anemia: If hemolytic anemia diagnosis is confirmed (and no alternative etiologies are present), discontinue hydroxyurea.

Pancreatitis: Discontinue hydroxyurea permanently.

Pulmonary toxicity: Interstitial lung disease: Discontinue hydroxyurea and manage as clinically appropriate.

Dosing: Older Adult

Refer to adult dosing. May require lower doses.

Dosing: Pediatric

(For additional information see "Hydroxyurea (hydroxycarbamide): Pediatric drug information")

Note: Doses should be based on ideal or actual body weight, whichever is less (per manufacturer); calculate rounded doses to the nearest 50 mg or 100 mg strengths.

Sickle cell anemia

Sickle cell anemia:

Infants ≥6 months, Children, and Adolescents: Limited data available in infants and children <2 years:

Initial: Oral: 20 mg/kg/dose once daily; monitor blood count every 2 weeks; may increase by 5 mg/kg/day every 8 weeks or sooner if painful crisis occurs; maximum daily dose: 35 mg/kg/day; continue therapy until mild myelosuppression (ANC 2,000 to 4,000/mm3) is achieved (as long as myelosuppression acceptable) (Ref). An initial starting dose of 15 mg/kg/dose once daily has also been studied (Ref).

A clinical response to treatment may take 3 to 6 months; a 6-month trial of the maximum tolerated dose is recommended prior to considering discontinuation due to treatment failure; effectiveness of hydroxyurea depends upon daily dosing adherence. For patients who have a clinical response, long-term hydroxyurea therapy is indicated (Ref).

Acceptable hematologic ranges: Neutrophils ≥2,000/mm3 (younger patients with lower baseline counts may safely tolerate ANC down to 1,250/mm3), platelets ≥80,000/mm3, hemoglobin >5.3 g/dL, and reticulocytes ≥80,000/mm3 if hemoglobin is <9 g/dL.

Toxic hematologic ranges: Neutrophils <2,000/mm3 (younger patients with lower baseline counts may safely tolerate ANC down to 1,250/mm3), platelets <80,000/mm3, hemoglobin <4.5 g/dL, and reticulocytes <80,000/mm3 if hemoglobin is <9 g/dL.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: Infants ≥6 months, Children, and Adolescents: Oral:

Hematologic: Sickle cell disease:

Toxic myelosuppression (neutrophils <2,000/mm3 [ANC minimum limit of 1,250/mm3 may be acceptable in younger patients with lower baseline counts], platelets <80,000/mm3, hemoglobin <4.5 g/dL, or reticulocyte <80,000/mm3 if hemoglobin <9 g/dL): Hold therapy until counts recover (monitor weekly); reinitiate at a dose 5 mg/kg/day lower than the dose given prior to onset of toxic myelosuppression (Ref); some have recommended reinitiating at a dose 2.5 mg/kg/day lower (Ref). Titrate dose up or down every 8 weeks in 5 mg/kg/day increments until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. If hematologic toxicity develops again (ie, twice), permanently discontinue therapy.

Non-hematologic: The presented adjustments are based on experience in adult patients with disease states other than sickle cell disease; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.

Cutaneous vasculitic ulcerations: Discontinue.

Pancreatitis: Discontinue permanently.

Dosing: Kidney Impairment: Pediatric

Siklos: Manufacturer suggests use of a 24-hour urine collection for calculation of CrCl.

Children ≥2 years and Adolescents:

CrCl ≥60 mL/minute: No dosage adjustment (of initial dose) necessary.

CrCl <60 mL/minute: Oral: Initial dose: 10 mg/kg/day; titrate to response/avoidance of toxicity (refer to usual dosing).

End-stage renal disease: Oral: Initial dose: 10 mg/kg/day, on dialysis days, administer after hemodialysis; titrate to response/avoidance of toxicity (refer to usual dosing).

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; closely monitor for bone marrow toxicity.

Adverse Reactions (Significant): Considerations
Bone marrow suppression

Hydroxyurea may cause severe or life-threatening bone marrow depression at the recommended initial dose. Leukopenia and neutropenia commonly occur, while anemia and thrombocytopenia are less common; leukopenia/neutropenia occur first. Hematologic toxicity is usually rapidly reversible with treatment interruption.

Mechanism: Related to mechanism of action; as a derivative of urea, hydroxyurea directly inhibits DNA synthesis by inactivating ribonucleotide diphosphate reductase (Ref).

Onset: Intermediate; neutrophil nadir occurred around weeks 2 to 4 after initiation (Ref).

Risk factors:

• Previous cytotoxic chemotherapy or radiation therapy

• Pediatric patients (timing of dose adjustments due to changes in body weight)

Cutaneous vasculitic toxicities

Vasculitic skin ulceration has been reported in patients with myeloproliferative disorders (eg, polycythemia vera, thrombocythemia) during hydroxyurea treatment, most often in patients with a history of or concurrent treatment with interferon. Most common location reported in the literature is leg ulcer, especially in the malleolar area; ulcers are usually painful (Ref). Ulcers may rarely be caused by hypersensitivity angiitis (Ref). Cutaneous lesions may require therapy interruption, dose reduction, discontinuation and/or treatment, depending on severity. Upon discontinuation and appropriate treatment, complete resolution of cutaneous lesions occurred in a median of 5 months (range: 1 to 28); however, some lesions persisted or worsened with continued hydroxyurea therapy (including at reduced doses) or recurred with reintroduction of therapy (Ref).

Mechanism: Not clearly established; direct inhibition of DNA synthesis, macrocytosis, and platelet dysregulation may cause direct tissue damage, including death of keratinocytes, microthrombus formation, and impaired tissue repair (Ref). Biopsies of ulcerations have shown hypersensitivity angiitis, perivascular lymphocytic infiltration, formation of thrombus, swelling of endothelial cells, and thickening of vascular walls (Ref).

Onset: Delayed; mucocutaneous lesions occurred in a mean of 38 months (range: 10 to 74 months) after initiation (Ref).

Risk factors:

• History of or current treatment with interferon therapy

• History of arterial hypertension, diabetes mellitus, peripheral vascular disease (Ref)

• Older females (Ref)

Second primary malignancies

Hydroxyurea is carcinogenic in animal studies, but has not been well defined in the human population. Treatment of myeloproliferative disorders (eg, polycythemia vera, thrombocythemia) and sickle cell disease with long-term hydroxyurea is associated with secondary leukemia; it is unknown if this is drug-related or disease-related. Skin carcinoma has been reported with long-term hydroxyurea use.

Mechanism: Dose- and time-related, related to mechanism of action; DNA inhibition, through targeting of ribonucleotide reductase, can lead to DNA damage and impedance of TP53 gene activation (and by extension DNA repair), which creates a favorable environment for the development of gene mutations, especially involving chromosome 17. For skin cancers, hydroxyurea potentiates the effect of UV radiation and solar hypersensitivity, coupled with the inhibition of DNA repair, leading to development of skin cancer (Ref).

Onset: Delayed; ranges from 6 months to 15 years (Ref).

Risk factors:

• Higher cumulative dose (Ref)

• Longer duration of therapy (Ref)

• Excess sun exposure (Ref)

• Sequential use of busulfan therapy (Ref)

• Older age (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and adults unless otherwise indicated.

>10%:

Dermatologic: Eczema (infants and children: 13%) (Thornburg 2012), xeroderma (adults: 12%)

Hematologic & oncologic: Macrocytosis (MCV >97: 42%) (Randi 2005), neutropenia (5% to 13%; severe neutropenia: ≤1%)

Infection: Bacterial infection (children and adolescents: 16%; adults: 4%), infection (40% to 43%; serious infection: 4% to 18%)

Nervous system: Headache (children and adolescents: 7%; adults: 20%; severe headache: 1% to 3%)

1% to 10%:

Cardiovascular: Peripheral edema (adults: 3%)

Dermatologic: Alopecia (adults: 5%), dermal ulcer (adults: 7%) (Antonioli 2012), dermatological reaction (children and adolescents: 4%), leg ulcer (7%) (Hernández-Boluda 2011)

Endocrine & metabolic: Vitamin D deficiency (children and adolescents: 6%), weight gain (2% to 4%)

Gastrointestinal: Acute mucocutaneous toxicity (5%) (Hernández-Boluda 2011), constipation (children and adolescents: 3%), diarrhea (adults: 3%), nausea (3% to 6%; severe nausea: <1%), upper abdominal pain (adults: 5%)

Genitourinary: Disorder of urinary system (children and adolescents: ≤2%), urinary tract infection (adults: 4%)

Hematologic & oncologic: Anemia (4% to 10%; severe anemia: 2% to 3%), thrombocytopenia (7%; severe thrombocytopenia: ≤1%)

Infection: Influenza (adults: 4%); parvovirus B19 seroconversion (children and adolescents: 4%), viral infection (4% to 10%)

Nervous system: Asthenia (adults: 9%), dizziness (adults: 9%), fatigue (adults: 5%), severe nervous system disease (4%)

Neuromuscular & skeletal: Arthralgia (adults: 9%; severe arthralgia: <1%), back pain (adults: 5%), limb pain (adults: 3%)

Renal: Renal disease (≤2%)

Respiratory: Asthma (infants and children: 9%) (Thornburg 2012), bronchitis (adults: 4%), cough (adults: 6%), dyspnea (adults: 4%), nasopharyngitis (adults: 4%), pulmonary disease (adults: 5%)

Miscellaneous: Fever (8%)

Frequency not defined:

Dermatologic: Skin depigmentation

Hematologic & oncologic: Bone marrow depression (can be severe bone marrow depression), hemorrhage, leukopenia

Postmarketing:

Cardiovascular: Edema, vasculitic skin ulceration (patients with myeloproliferative disorders) (Antonioli 2012)

Dermatologic: Actinic keratosis (Antonioli 2012), atrophy of nail, basal cell carcinoma of skin (Antonioli 2012), cutaneous lupus erythematosus (Yanes 2017), dermatitis (Antonioli 2012), dermatomyositis-like skin changes, desquamation, dyschromia (Antonioli 2012), facial erythema, gangrene of skin and/or subcutaneous tissues (patients with myeloproliferative disorders) (Antonioli 2012), hyperkeratosis (eg, acral) (Antonioli 2012, Worley 2016), hyperpigmentation (Issaivanan 2004), maculopapular rash, nail discoloration (melanonychia) (Issaivanan 2004), nail hyperpigmentation (Issaivanan 2004), papule of skin, psoriasiform eruption (plaques) (Worley 2016), skin atrophy (Antonioli 2012), skin rash

Endocrine & metabolic: Amenorrhea, hypomagnesemia (severe), increased uric acid

Gastrointestinal: Anorexia, cholestasis, gastric distress (Antonioli 2012), gastrointestinal ulcer, mucous membrane lesion (Antonioli 2012), oral mucosa ulcer (Hernández-Boluda 2011), stomatitis, vomiting

Genitourinary: Azoospermia, dysuria, oligospermia

Hematologic & oncologic: Hemolytic anemia (Jabr 2004), leukemia (secondary) (Gavini 2021, Kissova 2014), malignant neoplasm (Wong 2014), reticulocytopenia (Wang 2011), skin carcinoma (Gavini 2021, Kissova 2014), squamous cell carcinoma (Antonioli 2012), tumor lysis syndrome

Hepatic: Hepatitis (Westerman 1998), increased liver enzymes

Hypersensitivity: Hypersensitivity angiitis (Worley 2016)

Local: Localized erythema of the extremities

Nervous system: Chills, disorientation, drowsiness, drug fever (Antonioli 2012), hallucination, malaise, seizure

Neuromuscular & skeletal: Panniculitis (Antonioli 2012, Mattessich 2017), systemic lupus erythematosus (including lupus-like syndrome [Layton 1994])

Renal: Increased blood urea nitrogen, increased serum creatinine

Respiratory: Interstitial pulmonary disease, pneumonitis (Antonioli 2012), pulmonary alveolitis (including allergic) (Antonioli 2012), pulmonary fibrosis (Antonioli 2012), pulmonary infiltrates (Antonioli 2012)

Contraindications

US labeling: Hypersensitivity to hydroxyurea or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Severe bone marrow depression (eg, leukopenia [<2,500/mm3], thrombocytopenia [<100,000/mm3], or severe anemia)

Warnings/Precautions

Disease-related issues:

• HIV-infected patients: Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered with antiretroviral medications, including didanosine and stavudine.

Special populations:

• Radiation therapy recipients: Patients with a history of radiation therapy are at risk for exacerbation of post irradiation erythema.

Other warnings/precautions:

• Immunizations: Avoid use of live vaccines during hydroxyurea therapy. Concomitant use may potentiate viral replication and may possibly increase vaccine adverse reactions due to suppression of normal defense mechanisms by hydroxyurea and result in severe infections. The antibody response to vaccines may be decreased. Consider consultation with a specialist if immunization with a live vaccine is necessary.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Droxia: 200 mg, 300 mg [contains fd&c blue #1 (brilliant blue)]

Droxia: 400 mg [contains quinoline yellow (d&c yellow #10)]

Hydrea: 500 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]

Generic: 500 mg

Tablet, Oral:

Siklos: 100 mg [DSC]

Siklos: 100 mg [scored]

Siklos: 1000 mg

Generic Equivalent Available: US

May be product dependent

Pricing: US

Capsules (Droxia Oral)

200 mg (per each): $0.91

300 mg (per each): $0.91

400 mg (per each): $0.97

Capsules (Hydrea Oral)

500 mg (per each): $1.64

Capsules (Hydroxyurea Oral)

500 mg (per each): $0.67 - $1.47

Tablets (Siklos Oral)

100 mg (per each): $7.01

1000 mg (per each): $70.10

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Hydrea: 500 mg

Generic: 500 mg

Administration: Adult

Oral: Administer at the same time each day.

Capsules (Droxia, Hydrea): Swallow whole; the manufacturer does not recommend opening, breaking, or chewing the capsules. For patients unable to swallow capsules, an oral solution may be prepared.

Tablets (Siklos): Administer with water. If unable to swallow tablets whole, may disperse immediately before use in a small amount of water in a teaspoon (add tablet to spoon, add water; tablet dissolves in ~1 minute; administer immediately); drink an additional glass of water after administering the dose. The 100 mg tablets are scored with 1 line to enable splitting into 2 parts and the 1,000 mg tablets are scored with 3 lines to enable splitting into 4 parts; wear gloves and use a damp paper towel surface to break scored tablets (properly dispose of used gloves and paper towel). Note: Prior to October 2020, the 100 mg tablets were available as a film-coated (not scored) tablet; do not split the 100 mg film-coated (not scored) tablet into smaller parts.

Impervious gloves should be worn when handling bottles containing hydroxyurea or when handling/administering intact capsules/tablets. Wash hands with soap and water before and after contact with hydroxyurea. Avoid exposure to crushed capsules/tablets or open capsules. If skin contact occurs, immediately wash the affected area thoroughly with soap and water. If eye(s) contact occurs, the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. If powder from the capsules or tablets is spilled, immediately wipe it up with a damp disposable towel and discard (along with the empty capsules) in a closed container, such as a plastic bag. The spill areas should then be cleaned using a detergent solution followed by clean water.

Administration: Pediatric

Note: Impervious gloves should be worn when handling bottles containing hydroxyurea or when handling/administering intact capsules/tablets. Wash hands with soap and water before and after contact with hydroxyurea. Avoid exposure to crushed capsules/tablets or open capsules. If skin contact occurs, immediately wash the affected area thoroughly with soap and water. If eye(s) contact occurs, the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. If powder from the capsules or tablets is spilled, immediately wipe it up with a damp disposable towel and discard (along with the empty capsules) in a closed container, such as a plastic bag. The spill areas should then be cleaned using a detergent solution followed by clean water.

Oral: Administered at the same time each day.

Capsules: Droxia, Hydrea: Swallow whole; the manufacturer does not recommend opening the capsules. Doses rounded to the nearest 100 mg when using capsules allows for dosing accuracy within ~2 mg/kg/day (Ref). For patients unable to swallow capsules, an oral solution may be prepared.

Tablets: Siklos: Administer with a glass of water. If unable to swallow tablets whole, may disperse immediately before use in a small amount of water in a teaspoon (add tablet to spoon, add water; tablet dissolves in ~1 minute; administer immediately); drink an additional glass of water after administering the dose. The 100 mg tablets are scored with 1 line to enable splitting into 2 parts and the 1,000 mg tablets are scored with 3 lines to enable splitting into 4 parts; wear gloves and use a damp paper towel surface to break scored tablets (properly dispose of used gloves and paper towel). Film-coated tablets that are not scored should not be split. Note: Prior to October 2020, the 100 mg tablets were available as a film-coated (not scored) tablet; do not split the 100 mg film-coated (not scored) tablet into smaller parts.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product and as follows, must be dispensed with this medication:

Droxia: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/016295s057lbl.pdf#page=16

Siklos: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208843s003lbl.pdf#page=18

Use: Labeled Indications

Chronic myeloid leukemia, resistant (Hydrea): Treatment of resistant chronic myeloid leukemia (CML).

Head and neck cancer (Hydrea): Management (in combination with chemoradiation therapy) of locally advanced squamous cell head and neck cancer (excluding lip cancer).

Sickle cell anemia (Droxia, Siklos): Management of sickle cell anemia (to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with recurrent moderate to severe painful crises) in adults (Droxia, Siklos) or in children ≥2 years of age, adolescents, and adults (Siklos).

Use: Off-Label: Adult

Acute myeloid leukemia, cytoreduction; Essential thrombocythemia, high-risk; Hypereosinophilic syndrome, refractory; Meningioma; Polycythemia vera, high-risk

Medication Safety Issues
Sound-alike/look-alike issues:

Hydrea may be confused with Lyrica

Hydroxyurea may be confused with hydroxychloroquine, hydrOXYzine, Ure-Na, Urea (systemic)

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

International issues:

Hydrea [US, Canada, and multiple international markets] may be confused with Hydra brand name for isoniazid [Japan]

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Betibeglogene Autotemcel: Hydroxyurea may diminish the therapeutic effect of Betibeglogene Autotemcel. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

BUPivacaine: Hydroxyurea may enhance the adverse/toxic effect of BUPivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Didanosine: Hydroxyurea may enhance the adverse/toxic effect of Didanosine. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Didanosine may enhance the adverse/toxic effect of Hydroxyurea. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Risk X: Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination

Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification

Ritlecitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy

Stavudine: Hydroxyurea may enhance the adverse/toxic effect of Stavudine. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Stavudine may enhance the adverse/toxic effect of Hydroxyurea. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Risk X: Avoid combination

Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy

Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

Evaluate pregnancy status prior to use in patients who may become pregnant.

It is recommended to discontinue hydroxyurea at least 3 months prior to conception in patients treated for sickle cell disease (SCD) (Jain 2019). Patients diagnosed with myeloproliferative neoplasms should also discontinue hydroxyurea prior to conception (with an adequate wash-out period) (Lishner 2016). According to the manufacturer, patients who may become pregnant should use effective contraception during treatment and for at least 6 months after completion of hydroxyurea therapy (regardless of indication).

Patients with partners who may become pregnant should also use effective contraception during and for at least 6 months (Siklos) or 1 year (Droxia, Hydrea) after therapy. Hydroxyurea may damage spermatozoa and testicular tissue, resulting in potential genetic abnormalities.

Patients diagnosed with SCD have impaired semen quality. This may not be further impaired by hydroxyurea (Gille 2021; Joseph 2021). Oligo or azoospermia was reversed in most patients 3 months after hydroxyurea was discontinued in one study (Sahoo 2017). Because long-term use of hydroxyurea may cause damage to spermatogonia and germinal epithelium, the European Society for Medical Oncology recommends referral to a fertility specialist for patients requiring hydroxyurea treatment who wish to preserve fertility (ESMO [Lambertini 2020]).

The effect of hydroxyurea on ovarian reserve is not well studied in patients diagnosed with SCD (Pecker 2018; Pecker 2020). SCD itself may impair fertility by various mechanisms, including effects on the ovaries (Jain 2019).

Pregnancy Considerations

Based on its mechanism of action and data from animal reproduction studies, hydroxyurea may cause fetal harm if administered during pregnancy.

Treatment of chronic myelogenous leukemia (CML) during pregnancy should be individualized (ELN [Hochhaus 2020]). Pregnancy outcomes have been described in patients treated with hydroxyurea for cancer (NTP 2013). Although use of hydroxyurea for the treatment of CML during pregnancy has been reported (Assi 2021; Madabhavi 2019), use during pregnancy is not recommended (Berman 2018).

Patients with sickle cell disease (SCD) are at an increased risk of adverse pregnancy outcomes (ACOG 2007; Jain 2019). Although available data related to use of hydroxyurea for the treatment SCD during pregnancy are reassuring (Ballas 2009; de Montalembert 2021; Montironi 2020), due to the potential risk of teratogenic effects, use of hydroxyurea should be discontinued prior to pregnancy (ACOG 2007; Jain 2019; Montironi 2020). Use of hydroxyurea during the second and third trimesters may be considered in select patients (Montironi 2020).

Breastfeeding Considerations

Hydroxyurea is present in breast milk.

Information related to the presence of hydroxyurea in breast milk is available from a lactating patient diagnosed with Philadelphia chromosome positive chronic myelogenous leukemia. Following diagnosis, treatment was started with hydroxyurea 500 mg 3 times daily. Breast milk was collected 2 hours after the last dose each day. Concentrations of hydroxyurea were 6.1 mcg/mL (day 1), 3.8 mcg/mL (day 3), and 8.4 mcg/mL (day 4); mean 6.1 mcg/mL. The patient stopped breastfeeding her child prior to beginning hydroxyurea treatment (Sylvester 1987).

Information related to the presence of hydroxyurea in breast milk is also available from a study of 16 lactating women following a single 1,000 mg hydroxyurea dose. Two women in the study were diagnosed with sickle cell disease (SCD) (not treated with hydroxyurea) and 16 were healthy volunteers. Breast milk and plasma were sampled prior to and at intervals up to 24 hours after the dose. Hydroxyurea was detected in breast milk within 30 minutes, with an average peak concentration of 10 to 15 mcg/mL occurring 1 to 3 hours after the dose. Breast milk concentrations were 80% to 90% of the plasma concentration throughout the study period. Breast milk concentrations were significantly decreased at 12 hours and no longer detected in breast milk 24 hours after the dose. Authors of the study estimated exposure to the breastfeeding infant to be 0.46 ± 0.16 mg/kg (relative infant dose [RID] 3.4%) and suggest if patients with SCD pump and discard breast milk following each dose, exposure to the breastfed infant would further decrease by 50% (Ware 2020). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends discontinuing breastfeeding during treatment with hydroxyurea. In patients treated with hydroxyurea for SCD prior to pregnancy, treatment can be restarted once breastfeeding is discontinued (Montironi 2020).

Dietary Considerations

Supplemental administration of folic acid is recommended; hydroxyurea may mask development of folic acid deficiency.

Monitoring Parameters

CBC with differential and platelets (at baseline and once weekly for antineoplastic indications; at baseline and every 2 weeks initially for sickle cell anemia), renal function and LFTs, serum uric acid; hemoglobin F levels (sickle cell disease; every 3 to 4 months). Evaluate lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin, urinalysis, and direct and indirect antiglobulin (Coombs') test for suspected hemolysis. Evaluate pregnancy status prior to therapy initiation in patients who may become pregnant. Monitor for hemolytic anemia (eg, acute jaundice or hematuria with persistent or worsening anemia), cutaneous toxicities, respiratory symptoms, and secondary malignancies. Monitor adherence.

Sickle cell disease: Monitor for toxicity every 2 weeks during dose escalation (neutrophils, platelets, hemoglobin, reticulocytes) (manufacturer's labeling) or at least every 4 weeks when adjusting the dose (CBC with WBC differential, reticulocytes) [NHLBI 2014]). Once on a stable dose, may monitor CBC with differential, reticulocyte count and platelets every 2 to 3 months (NHLBI 2014). Monitor hematologic parameters more frequently in patients with hepatic impairment. Monitor RBC, MCV (mean corpuscular volume) and HbF (fetal hemoglobin) levels for evidence of consistent or progressive laboratory response (NHLBI 2014). Monitor seminal fluid parameters every 3 months (Sahoo 2017).

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Hydroxyurea is an antimetabolite that selectively inhibits ribonucleoside diphosphate reductase, preventing the conversion of ribonucleotides to deoxyribonucleotides, halting the cell cycle at the G1/S phase and therefore has radiation sensitizing activity by maintaining cells in the G1 phase and interfering with DNA repair. In sickle cell anemia, hydroxyurea increases red blood cell (RBC) hemoglobin F levels, RBC water content, deformability of sickled cells, and alters adhesion of RBCs to endothelium.

Pharmacokinetics (Adult Data Unless Noted)

Note: In pediatric patients, large interpatient variability and phenotypic differences have been reported (Ware 2011).

Onset: Sickle cell anemia: Fetal hemoglobin increase: 4 to 12 weeks.

Absorption: Readily absorbed (≥80%); relatively rapid (Rodriguez 1998).

Distribution: Distributes widely into tissues (including into the brain); estimated volume of distribution approximates total body water (Gwilt 1998); concentrates in leukocytes and erythrocytes.

Vd: Pediatric patients: 12.09 ± 7.59 L (range: 2.5 to 52.44 L) (Ware 2011); Adults: ~20 L/m2 (Rodriguez 1998).

Metabolism: Up to 60% via hepatic metabolism and urease found in intestinal bacteria.

Bioavailability: ~100% (Rodriguez 1998); Siklos: 85% to 100%.

Protein binding: 75% to 80% bound to serum proteins (Gwilt 1998).

Half-life elimination: Pediatric patients: Sickle cell anemia: 1.7 ± 0.53 hours (range: 0.65 to 3.05 hours) (Ware 2011); Adults: 1.9 to 3.9 hours (Gwilt 1998).

Time to peak: Pediatric patients: "Fast" phenotype: 15 to 30 minutes; "Slow" phenotype: 60 to 120 minutes (Ware 2011); Adults: 1 to 4 hours.

Excretion: Urine (sickle cell anemia: pediatric patients: ~40% of administered dose).

Clearance: Pediatric patients: 6.92 ± 3.17 L/hour (range: 1.57 to 21.59) (Ware 2011); Adults: ~7.5 L/hour (Rodriguez 1998).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Exposure is higher in patients with CrCl <60 mL/minute or end-stage renal disease.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Cureaml | Hydrea;
  • (AR) Argentina: Droxiurea | Hidroxiurea delta farma | Hidroxiurea eczane | Hidroxiurea filaxis | Hidroxiurea gobbi | Hidroxiurea gp pharm | Hidroxiurea kemex | Hidroxiurea martian | Hidroxiurea microsules | Hidroxiurea rontag | Hidroxiurea Varifa | Hydrea;
  • (AT) Austria: Hydroxyurea | Hydroxyurea medac | Litalir | Siklos;
  • (AU) Australia: Hydrea;
  • (BD) Bangladesh: Mylostat;
  • (BE) Belgium: Hydrea | Siklos;
  • (BG) Bulgaria: Hydrea | Hydroxycarbamid;
  • (BR) Brazil: Hydrea | Tepev | Ureax;
  • (CH) Switzerland: Hydroxycarbamid devatis | Hydroxycarbamid labatec | Litalir;
  • (CL) Chile: Hydrea;
  • (CN) China: Hydrea;
  • (CO) Colombia: Hidroxyurea | Hydrea | Hydroxyurea | Oxiria | Syrea;
  • (CZ) Czech Republic: Biosupressin | Litalir;
  • (DE) Germany: Hydrea | Hydroxycarbamid devatis | Hydroxycarbamid Hexal | Hydroxycarbamid ribosepharm | Litalir | Siklos | Syrea;
  • (DO) Dominican Republic: Durea | Hidroxiurea varifarma;
  • (EC) Ecuador: Hidroxiurea | Hydrea;
  • (EE) Estonia: Hydrea;
  • (EG) Egypt: Cytodrox | Hydrea | Hydroxyurea | Syrea;
  • (ES) Spain: Hydrea | Siklos;
  • (ET) Ethiopia: Riborea;
  • (FI) Finland: Hydrea | Hydroxyurea medac | Oribamide;
  • (FR) France: Hydrea | Siklos;
  • (GB) United Kingdom: Hydrea | Hydroxycarbam | Siklos;
  • (GR) Greece: Hydrea | Hydreasyn | Hydroxyurea | Siklos;
  • (HK) Hong Kong: Apo-hydroxyurea | Hydrea | Hydroxyurea;
  • (HR) Croatia: Litalir;
  • (HU) Hungary: Biosupressin | Litalir;
  • (ID) Indonesia: Cytodrox | Hydrea | Hydroxyurea medac;
  • (IE) Ireland: Hydrea;
  • (IL) Israel: Hydrea;
  • (IN) India: Cytodrox | Durea | Hondrea | Hydab | Hydran | Hydrea | Hytas | Myelostat | Neodrea | Oxyrea | Riborea | Unidrea;
  • (IT) Italy: Onco carbide | Siklos;
  • (JO) Jordan: Cureaml | Cytodrox | Hydab | Hydrea;
  • (JP) Japan: Hydrea;
  • (KR) Korea, Republic of: Hydrea | Hydrine | Jeil hydroxyurea | Union hydroxyurea;
  • (KW) Kuwait: Hydrea;
  • (LB) Lebanon: Cureaml | Hydrea | Unidrea;
  • (LT) Lithuania: Biosupressin | Hydrea;
  • (LU) Luxembourg: Hydrea | Siklos;
  • (LV) Latvia: Biosupressin | Hydrea | Hydroxycarbamid | Hydroxyurea | Litalir;
  • (MA) Morocco: Hydrea;
  • (MX) Mexico: Hydrea;
  • (MY) Malaysia: Dhnp | Hydrea | Hydroxyurea medac;
  • (NG) Nigeria: Hydrine | Oxyurea;
  • (NL) Netherlands: Hydrea | Hydroxycarbamide bmodesto | Hydroxyurea eureco pharma | Hydroxyurea medac | Siklos;
  • (NO) Norway: Hydrea | Hydroxyurea;
  • (NZ) New Zealand: Hydrea;
  • (PE) Peru: Droxamida | Durea | Hidroxiurea | Hydrine;
  • (PH) Philippines: Hydab | Litalir | Mpl hi oxy;
  • (PK) Pakistan: Hdx | Hydrea | Hydrine | Hydrourea | Hydroxa;
  • (PL) Poland: Biosupressin | Hydroxycarbamid | Hydroxyurea medac;
  • (PR) Puerto Rico: Droxia | Hydrea | Hydroxyurea | Siklos;
  • (PT) Portugal: Hidroxicarbamida Hikma | Hydrea | Hydroxyurea medac | Siklos;
  • (PY) Paraguay: Hidroxiurea df | Hidroxiurea difucap eurand | Hidroxiurea farmaceutica paraguaya | Hidroxiurea libra | Hidroxiurea lkm | Hidroxiurea varifarma;
  • (RO) Romania: Hydrea;
  • (RU) Russian Federation: Hydrea | Hydroxycarbamide lens | Hydroxycarbamide medac | Hydroxycarbamide nativ | Hydroxyurea;
  • (SA) Saudi Arabia: Cureaml | Hydrea | Hydroxycarbamide medac | Siklos;
  • (SE) Sweden: Hydrea | Hydroxikarbamid orifarm | Hydroxyurea medac | Oribamide;
  • (SG) Singapore: Hydrea | Hydrine;
  • (SI) Slovenia: Litalir;
  • (SK) Slovakia: Litalir;
  • (TH) Thailand: Hydrea;
  • (TN) Tunisia: Cureaml | Hydrea;
  • (TR) Turkey: Hydmoxia | Hydrea;
  • (TW) Taiwan: Hydrea;
  • (UA) Ukraine: Apo-hydroxyurea | Hydrea | Hydroxycarbamid | Hydroxycarbamide vista | Hydroxyurea;
  • (UY) Uruguay: Hidroxiurea delta farma | Hidroxiurea filaxis | Hidroxiurea libra | Hidroxiurea martian | Hydrea;
  • (VE) Venezuela, Bolivarian Republic of: Hidrea;
  • (ZA) South Africa: Hydrea
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