Hydroxyurea

Dosage Forms

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

Capsule, Oral:

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

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

Hydrea: 500 mg

Generic: 500 mg

Tablet, Oral:

Siklos: 100 mg, 1000 mg

Pharmacology

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/Pharmacodynamics

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

V_d: 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

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)

Onset of Action

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

Time to Peak

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

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)

Protein Binding

75% to 80% bound to serum proteins (Gwilt 1998)

Use in Specific Populations

Special Populations: Renal Function Impairment

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

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) or in children ≥2 years, adolescents, and adults (Siklos)

Use: Off Label

Acute myeloid leukemia, cytoreductioncyes

Data from a nonrandomized, open-label trial in adults with acute myeloid leukemia (AML) suggest that hydroxyurea may be beneficial for cytoreduction in patients with AML Grund 1977. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

Based on the European LeukemiaNET panel recommendations, hydroxyurea is effective and recommended for cytoreduction in AML European LeukemiaNET [Dohner 2010].

Essential thrombocythemia, high-riska

Data from a randomized trial in patients with essential thrombocythemia at high risk for vascular events supports the use of hydroxyurea (in combination with low-dose aspirin) for the management of this condition Harrison 2005.

Hypereosinophilic syndromeb

Data from a retrospective study evaluating multiple therapies in patients with hypereosinophilic syndrome supports the use of hydroxyurea in the treatment of patients with this condition Parillo 1978. Clinical experience also suggests the utility of hydroxyurea in the treatment of hypereosinophilic syndrome Klion 2006. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

Meningiomac

Data from 2 open-label, nonrandomized trials in patients with recurrent or high risk meningioma or those with an unresectable or residual meningioma suggest that hydroxyurea may be beneficial for the treatment of this condition Newton 2000, Rosenthal 2002. Additional data may be necessary to further define the role of hydroxyurea in this condition.

Polycythemia vera, high-riskc

Data from a randomized trial in patients with polycythemia vera supports the use of hydroxyurea in the treatment of patients with this condition Najean 1997. Clinical experience also suggests the utility of hydroxyurea in the treatment of patients with polycythemia vera Finazzi 2007. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

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)

Dosage and Administration

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.

Chronic myeloid leukemia (Hydrea): Oral: Initial: 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 (Hehlmann 1993). Hydroxyurea may be used for short-term therapy of elevated WBC counts prior to initiating a TKI (Baccarini 2013, Cortes 2012).

Head and neck cancer (Hydrea): Oral (individualize treatment/regimen based on tumor type, response, and current clinical practice standards): 1,000 mg every 12 hours for 11 doses per cycle, in combination with continuous infusion fluorouracil and radiation therapy (Garden 2004).

Sickle cell anemia: Oral:

Droxia: Initial: 15 mg/kg/day as a single daily dose. 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: 20 mg/kg/day as a single daily dose. 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

Calculate rounded doses to the nearest 50 or 100 mg strength.

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 (NHLBI 2014).

Acute myeloid leukemia (AML), cytoreduction (off-label use): Oral: 50 to 100 mg/kg/day until WBC <100,000/mm³ (Grund 1977) or 50 to 60 mg/kg/day until WBC <10,000 to 20,000/mm³ (Dohner 2010)

Essential thrombocythemia, high-risk (off-label use): Oral: 500 to 1000 mg daily; adjust dose to maintain platelets <400,000/mm³ (Harrison 2005)

Hypereosinophilic syndrome (off-label use): Oral: 1,000 to 3,000 mg/day (Klion 2006)

Meningioma (off-label use): Oral: 20 mg/kg once daily (Newton 2000; Rosenthal 2002)

Polycythemia vera, high-risk (off-label use): Oral: 15 to 20 mg/kg/day (Finazzi 2007)

Dosing: Geriatric

Refer to adult dosing. May require lower doses.

Dosing: Pediatric

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: 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 until mild myelosuppression (ANC 2,000 to 4,000/mm³) is achieved or if painful crises occur (as long as myelosuppression acceptable); maximum daily dose: 35 mg/kg/day (Hankins 2005; NHLBI 2014; Strouse 2012; Thornburg 2009; Wang 2001; Wang 2011). An initial starting dose of 15 mg/kg/dose once daily has also been studied (Kinney 1999; Zimmerman 2004). 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 (NHLBI 2014).

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.

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 (NHLBI 2014); some have recommended reinitiating at a dose 2.5 mg/kg/day lower (Hankins 2005; Heeney 2008; Wang 2001; Wang 2011; Zimmerman 2004). 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: Adjustment for Toxicity

Cutaneous vasculitic ulcerations: Discontinue

Pancreatitis: Discontinue permanently

Hematologic toxicity: CML, head and neck cancer: 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.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer (solid tumors): Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012). Note: The manufacturer recommends dosing based on ideal or actual body weight, whichever is less.

Extemporaneously Prepared

100 mg/mL Oral Solution (ASHP Standard Concentration) (ASHP 2017)

A 100 mg/mL oral solution may be prepared with capsules. Mix the contents of twenty 500 mg capsules with enough room temperature sterile water (~50 mL) to initially result in a 200 mg/mL concentration. Stir vigorously using a magnetic stirrer for several hours, then filter to remove insoluble contents. Add 50 mL Syrpalta (flavored syrup without color, HUMCO) to filtered solution, resulting in 100 mL of a 100 mg/mL hydroxyurea solution. Stable for 1 month at room temperature in amber plastic bottle (Heeney 2004).

Heeney MM, Whorton MR, Howard TA, et al. Chemical and functional analysis of hydroxyurea oral solutions. J Pediatr Hematol Oncol. 2004;26(3):179-184.15125610

Administration

Oral: Administer at the same time each day. Swallow whole; do not break, chew, or open capsules.

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 1 g 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). Do not split the 100 mg 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.

Dietary Considerations

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

Storage

Droxia, Hydrea: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed.

Siklos: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed; use split tablets within 3 months.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

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

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

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

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

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. 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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

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

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

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. 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. 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. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). 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. Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Test Interactions

Hydroxyurea may interfere with lactic acid, urea, or uric acid assays, resulting in falsely elevated results.

Adverse Reactions

>10%:

Dermatologic: Eczema (infants and children: 13% [Thornburg 2012])

Hematologic & oncologic: Macrocytosis (MCV >97: 42% [Randi 2005]), neutropenia (13%)

Infection: Infection (40%), bacterial infection (16%)

1% to 10%:

Central nervous system: Headache (7%), severe nervous system disease (4%)

Dermatologic: Leg ulcer (7% [Hernández-Boluda 2011]), dermatological reaction (4%), dermal ulcer (3% [Antonioli 2012])

Endocrine & metabolic: Vitamin D deficiency (6%), weight gain (2%)

Gastrointestinal: Acute mucocutaneous toxicity (5% [Hernández-Boluda 2011]), constipation (3%), nausea (3%)

Hematologic & oncologic: Thrombocytopenia (7%), anemia (4%)

Infection: Viral infection (10%), parvovirus B19 seroconversion (4%)

Respiratory: Asthma (infants and children: 9% [Thornburg 2012])

Miscellaneous: Fever (8%)

Frequency not defined:

Dermatologic: Skin depigmentation

Gastrointestinal: Gastric distress (infrequent [Antonioli 2012]), gastritis, oral mucosa ulcer (infrequent [Hernández-Boluda 2011])

Genitourinary: Urinary tract abnormality

Hematologic & oncologic: Bone marrow depression (recovery: within 2 weeks), hemorrhage, leukemia, leukopenia

Neuromuscular & skeletal: Panniculitis (Antonioli 2012)

Renal: Renal disease

<1%, postmarketing, and/or case reports: Actinic keratosis (Antonioli 2012), alopecia, amenorrhea, anorexia, asthenia, atrophy of nail, azoospermia, basal cell carcinoma (Antonioli 2012), chills, cholestasis, cough, cutaneous lupus erythematosus, dermatomyositis-like skin changes, desquamation, diarrhea, disorientation, dizziness, drowsiness, dyspnea, dysuria, edema, facial erythema, gangrene of skin and/or subcutaneous tissues (patients with myeloproliferative disorders), gastrointestinal ulcer, hallucination, hepatitis, hyperkeratosis (Antonioli 2012), hyperpigmentation, hypersensitivity angiitis, hypersensitivity reaction, hypomagnesemia (severe), increased blood urea nitrogen, increased liver enzymes, increased serum creatinine, increased uric acid, interstitial pulmonary disease, lesion, localized erythema of the extremities, maculopapular rash, malaise, malignant neoplasm (Wong 2014), mucous membrane lesion (Antonioli 2012), nail discoloration (melanonychia), oligospermia, papule of skin, pneumonitis (Antonioli 2012), pulmonary alveolitis (including allergic), pulmonary fibrosis, pulmonary infiltrates, radiation recall phenomenon, reticulocytopenia (Wang 2011), seizure, skin atrophy, skin carcinoma, skin rash, squamous cell carcinoma (Antonioli 2012), stomatitis, systemic lupus erythematosus, tumor lysis syndrome, vasculitic skin ulceration (patients with myeloproliferative disorders), vomiting, xeroderma

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Hydroxyurea may cause severe myelosuppression. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary. Leukopenia and neutropenia commonly occur (thrombocytopenia and anemia are less common); leukopenia/neutropenia occur first. Severe or life-threatening myelosuppression may occur at the recommended initial dose. Hematologic toxicity is reversible (rapid) with treatment interruption; after treatment interruption, resume therapy at a lower dose. Use with caution in patients with a history of prior chemotherapy or radiation therapy; myelosuppression is more common. Correct severe anemia prior to initiating treatment. Do not initiate therapy if bone marrow function is markedly reduced. Pediatric patients are at increased risk for myelosuppression at the time of dosage adjustments due to changes in body weight.
• Cutaneous vasculitic toxicities: Vasculitic ulcerations and gangrene have been reported in patients with myeloproliferative disorders during hydroxyurea treatment, most often in patients with a history of or receiving concurrent interferon therapy. Discontinue hydroxyurea (or reduce the dose) and consider alternate cytoreductive therapy if cutaneous vasculitic toxicity develops. Ulcers may rarely be caused by leukocytoclastic vasculitis. Avoid use in patients with leg ulcer wounds.
• Hypersensitivity: Drug-induced fever has been reported (with cardiovascular, dermatologic, GI, hepatic, musculoskeletal, or pulmonary manifestations); may require hospitalization. The onset is usually within 6 weeks of treatment initiation and resolves with discontinuation. Fever usually recurred within 24 hours with re-challenge.
• Macrocytosis: Self-limiting macrocytosis may be seen early in treatment (may resemble pernicious anemia, but is unrelated to vitamin B₁₂ or folic acid deficiency). May mask diagnosis of pernicious anemia. Prophylactic folic acid supplementation is recommended.
• Pulmonary toxicity: Interstitial lung disease, including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (some cases fatal), have been reported in patients treated for myeloproliferative disorders. Monitor for respiratory symptoms; discontinue if pulmonary toxicity occurs and manage appropriately.
• Secondary malignancy: [US Boxed Warning]: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies. Treatment of myeloproliferative disorders (eg, polycythemia vera, thrombocythemia) with long-term hydroxyurea is associated with secondary leukemia; it is unknown if this is drug-related or disease-related. Skin cancer has been reported with long-term hydroxyurea use. Monitor for signs/symptoms of secondary malignancies.
• Tumor lysis syndrome: Hyperuricemia may occur with antineoplastic treatment; adequate hydration and initiation or dosage adjustment of uricosuric agents (eg, allopurinol) may be necessary.

Disease-related issues:

• HIV-infected patients: Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered with antiretroviral medications, including didanosine and stavudine.
• Renal impairment: Use with caution in patients with renal impairment; may require dose reductions.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: May be more sensitive to the effects of hydroxyurea; may require lower doses.
• Radiation therapy recipients: Patients with a history of radiation therapy are at risk for exacerbation of post irradiation erythema and myelosuppression.

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.

Monitoring Parameters

CBC with differential and platelets (once weekly for antineoplastic indications; every 2 weeks initially for sickle cell anemia), renal function and liver function tests, serum uric acid; hemoglobin F levels (sickle cell disease; every 3 to 4 months); pregnancy status prior to therapy initiation in women of reproductive potential; monitor for cutaneous toxicities

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 RBC, MCV (mean corpuscular volume) and HbF (fetal hemoglobin) levels for evidence of consistent or progressive laboratory response (NHLBI 2014).

Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on its mechanism of action, hydroxyurea may cause fetal harm if administered during pregnancy.

Women of reproductive potential should be advised to avoid becoming pregnant during treatment. Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective contraception during and for at least 6 months after completion of therapy. Hydroxyurea use may damage spermatozoa and testicular tissue resulting in possible genetic abnormalities; males with female partners of reproductive potential should use effective contraception during and for at least 6 months (Siklos) or 1 year (Droxia, Hydrea) after therapy. Hydroxyurea may also impair male fertility. Azoospermia or oligospermia (sometimes reversible) has been observed in male patients; counsel males of reproductive potential about sperm banking prior to therapy initiation.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.
• It is used to treat cancer of the head and neck.
• It is used to treat sickle cell anemia.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Hair loss
• Nausea
• Lack of appetite
• Constipation
• Diarrhea
• Weight gain
• Headache
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Mole changes
• Skin growths
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Bruising
• Bleeding
• Severe loss of strength and energy
• Skin ulcers
• Skin changes
• Nail changes
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.