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Hydroxyurea

Pronunciation

Pronunciation

(hye droks ee yoor EE a)

Index Terms

  • HU
  • Hydroxycarbamide
  • Hydurea

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

Brand Names: U.S.

  • Droxia
  • Hydrea

Pharmacologic Category

  • Antineoplastic Agent, Miscellaneous

Pharmacology

Antimetabolite which 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.

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: Children: ~12 L (range: 2.5 to 52) (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: ~40% of administered dose)

Clearance: Children: ~7 L/hour (range: 1.6 to 22) (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

Children: "Fast" phenotype: 15 to 30 minutes; "Slow" phenotype: 60 to 120 minutes (Ware 2011)

Adults: 1 to 4 hours

Half-Life Elimination

1.9 to 3.9 hours (Gwilt 1998); Children: Sickle cell anemia: 1.7 hours (range: 0.7 to 3 hours) (Ware 2011)

Protein Binding

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

Special Populations: Renal Function Impairment

Because renal excretion is a pathway of elimination for hydroxyurea, consider dosage reduction in patients with renal impairment. Mean AUC was 64% higher in patients with CrCl <60 mL/minute than in patients with healthy renal function.

Use: Labeled Indications

Chronic myeloid leukemia (Hydrea): Treatment of refractory chronic myeloid leukemia (CML)

Head and neck cancer (Hydrea): Management (with concomitant radiation therapy) of locally advanced squamous cell head and neck cancer (excluding lip cancer)

Sickle cell anemia (Droxia): 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)

Use: Unlabeled

Treatment of essential thrombocythemia, polycythemia vera, hypereosinophilic syndrome; management of hyperleukocytosis due to acute myeloid leukemia (AML); treatment of AML in poor-risk patients; treatment of meningiomas

Contraindications

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

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

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.

US labeling:

Chronic myeloid leukemia (CML), head and neck cancer: Oral: Initial: 15 mg/kg/day; individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards. May be used alone or in combination with other agents or radiation.

Sickle cell anemia: Oral:

Manufacturer’s labeling: Initial: 15 mg/kg/day as a single dose; 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). Monitor for toxicity every 2 weeks; 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 which 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 the hemoglobin concentration 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 the hemoglobin concentration is <9 g/dL

Alternate recommendations (off-label dose): Initial: 15 mg/kg/day; if dosage escalation is warranted based on clinical/laboratory findings, may increase by 5 mg/kg/day increments every 8 weeks. Monitor for toxicity at least every 4 weeks when adjusting dose; aim for a target absolute neutrophils ≥2,000/mm3 (younger patients with lower baseline counts may safely tolerate absolute neutrophils down to 1,250/mm3; maintain platelet count ≥80,000/mm3. Give until mild myelosuppression is achieved (absolute neutrophils: 2,000/mm3 to 4,000/mm3), up to a maximum dose of 35 mg/kg/day. If toxicity occurs (neutropenia or thrombocytopenia), withhold treatment until the bone marrow recovers (monitor weekly), then restart at a dose 5mg/kg/day lower than the dose given prior to onset of cytopenias (NHLBI 2014). Note: A clinical response to treatment may take 3 to 6 months; a 6 month trial on 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)

Canadian labeling:

Note: Titrate dose to patient response; if WBC count falls to <2,500/mm3, or the platelet count to <100,000/mm3, therapy should be interrupted for at least 3 days and resumed when values rise toward normal.

Chronic myeloid leukemia (resistant): Continuous therapy: Oral: 20 to 30 mg/kg once daily

Solid tumors (eg, head and neck cancer): Oral:

Intermittent therapy: 80 mg/kg as a single dose every third day

Concomitant therapy with irradiation (head and neck cancer): 80 mg/kg as a single dose every third day starting at least 7 days before initiation of irradiation

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)

Head and neck cancer (off-label dosing; with concurrent radiation therapy and fluorouracil): Oral: 1000 mg every 12 hours for 11 doses per cycle (Garden 2004)

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). Prophylactic administration of folic acid is recommended.

Sickle cell anemia (off-label use): Infants ≥ 6 months, Children, and Adolescents: Oral: 20 mg/kg/dose once daily; increase by 5 mg/kg/day every 8 weeks until mild myelosuppression (neutrophils 2,000 to 4,000/mm3) is achieved up to a maximum of 35 mg/kg/day (Hankins 2005; NHLBI 2014; Strouse 2012). If myelosuppression occurs (platelets <80,000/mm3, neutrophils <2,000/mm3; younger patients with lower baseline counts may safely tolerate ANC down to 1,250/mm3), hold therapy until counts recover (monitor weekly); reinitiate at a dose 5 mg/kg/day lower than the dose given prior to onset of cytopenias (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). Note: A clinical response to treatment may take 3 to 6 months; a 6-month trial on 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).

Dosing: Renal Impairment

US labeling: The manufacturer's labeling recommends the following adjustments:

CML, head and neck cancer:

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

CrCl <60 mL/minute: Reduce initial dose by 50% to 7.5 mg/kg/day; titrate to response/avoidance of toxicity

End-stage renal disease (ESRD): Reduce initial dose by 50% to 7.5 mg/kg/dose (administer after dialysis on dialysis days); titrate to response/avoidance of toxicity

Sickle cell anemia:

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

CrCl <60 mL/minute: Reduce initial dose by 50% to 7.5 mg/kg/day (Yan 2005); titrate to response/avoidance of toxicity (refer to usual dosing).

ESRD: Reduce initial dose by 50% to 7.5 mg/kg/dose (administer after dialysis on dialysis days); titrate to response/avoidance of toxicity.

The following adjustments have also been reported:

Aronoff 2007: Adults:

CrCl >50 mL/minute: No dosage adjustment necessary

CrCl 10 to 50 mL/minute: Administer 50% of dose.

CrCl <10 mL/minute: Administer 20% of dose.

Hemodialysis: Administer dose after dialysis on dialysis days.

Continuous renal replacement therapy (CRRT): Administer 50% of dose.

NHLBI 2014: Sickle cell anemia: Adults: Chronic kidney disease: Initial 5 to 10 mg/kg/day

Kintzel 1995:

CrCl 46 to 60 mL/minute: Administer 85% of dose.

CrCl 31 to 45 mL/minute: Administer 80% of dose.

CrCl <30 mL/minute: Administer 75% of dose.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer's labeling; however, a dose reduction should be considered. Closely monitor for bone marrow toxicity.

Dosing: Hepatic Impairment

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

Dosing: Adjustment for Toxicity

Cutaneous vasculitic ulcerations: Discontinue

Gastrointestinal toxicity (severe nausea, vomiting, severe mucositis. anorexia) (Canadian labeling): Temporarily interrupt treatment

Hepatitis and cholestasis (Canadian labeling): Discontinue

Pancreatitis: Discontinue permanently

Hematologic toxicity: CML, head and neck cancer:

US labeling: Do not initiate therapy if bone marrow function is markedly reduced. Monitor blood counts prior to and during treatment; modify dose or discontinue hydroxyurea as needed.

Canadian labeling: WBC <2,500/mm3 or platelets <100,000/mm3: Interrupt treatment (for at least 3 days), may resume when values rise toward normal. Do not initiate therapy if bone marrow function is markedly reduced. Monitor blood counts prior to and during treatment; modify dose or discontinue hydroxyurea as needed.

Sickle cell anemia:

Manufacturer’s labeling: 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.

Alternate recommendations (off-label dose): Absolute neutrophils <2,000/mm3 (younger patients with lower baseline counts may safely tolerate absolute neutrophils down to 1,250/mm3), platelets <80,000/mm3; Interrupt treatment; following recovery, may restart at a dose 5mg/kg/day lower than the dose given prior to onset of cytopenias (NHLBI 2014).

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

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

A 40 mg/mL oral suspension may be prepared with capsules and either a 1:1 mixture of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of methylcellulose 1% and simple syrup NF. Empty the contents of eight 500 mg capsules into a mortar. Add small portions of chosen vehicle and mix to a uniform paste; mix while incrementally adding the vehicle to almost 100 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 100 mL. Label "shake well" and "refrigerate". Store in plastic prescription bottles. Stable for 14 days at room temperature or refrigerated (preferred) (Nahata 2003).

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, 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):179-84. 15125610Nahata MC, Morosco RS, Boster EA, et al, "Stability of Hydroxyurea in Two Extemporaneously Prepared Oral Suspensions Stored at Two Temperatures," 2003, 38:P-161(E) [abstract from 2003 ASHP Midyear Clinical Meeting].

Administration

Administer at the same time each day.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Impervious gloves should be worn when handling bottles containing hydroxyurea or when handling/administering intact capsules (single gloves are recommended for administration of intact capsules). Wash hands with soap and water before and after contact with the bottle or capsules when handling. Avoid exposure to crushed or open capsules. If skin contact with crushed or opened capsules occurs, immediately wash the affected area thoroughly with soap and water. If eye(s) contact with crushed or opened capsules occurs, the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. If the powder from the capsule 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 3 times using a detergent solution followed by clean water.

Although the manufacturer does not recommend opening the capsules, if it is necessary to manipulate the capsules (eg, to prepare an oral suspension or solution), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Dietary Considerations

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

Storage

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed.

Drug Interactions

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

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. Avoid combination

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

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. 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

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

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

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. 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

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. Avoid combination

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

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. Avoid combination

Test Interactions

False-negative triglyceride measurement by a glycerol oxidase method. An analytical interference between hydroxyurea and enzymes (lactate dehydrogenase, urease, and uricase) may result in false elevations of lactic acid, urea, and uric acid.

Adverse Reactions

Frequency not always defined.

Cardiovascular: Edema, hypersensitivity angiitis

Central nervous system: Chills, disorientation, dizziness, drowsiness (dose-related), hallucination, headache, malaise, peripheral neuropathy (HIV-infected patients), seizure, vasculitic ulcerations

Dermatologic: Eczema (infants and children 9 to 18 months: 13% [Thornburg 2012]), leg ulcer (7% [Hernández-Boluda 2011]), dermal ulcer (3% [Antonioli 2012]), nail discoloration (2% [Randi 2005]), alopecia (infrequent, [Hernández-Boluda 2011]), changes in nails (infrequent, [Hernández-Boluda 2011]), hyperpigmentation (infrequent, [Hernández-Boluda 2011]), atrophy of nail, dermatomyositis-like skin changes, desquamation, erythema (peripheral), facial erythema, gangrene of skin or other tissue, maculopapular rash, papule (violet), skin atrophy, skin carcinoma

Endocrine & metabolic: Increased uric acid

Gastrointestinal: Acute mucocutaneous toxicity (5% [Hernández-Boluda 2011]), diarrhea (infrequent, [Antonioli 2012]), gastric distress (infrequent, [Antonioli 2012]), nausea (infrequent, [Antonioli 2012]), oral mucosa ulcer (infrequent, [Hernández-Boluda 2011]), anorexia, BSP abnormality (retention), constipation, gastrointestinal irritation (potentiated with radiation therapy), mucositis (potentiated with radiation therapy), pancreatitis (HIV-infected patients), stomatitis, vomiting

Genitourinary: Dysuria

Hematologic & oncologic: Leukemia (4% [Hernández-Boluda 2011]; secondary; long-term use), leukopenia (2% [Hernández-Boluda 2011]), bone marrow depression (neutropenia [common], thrombocytopenia; hematologic recovery: within 2 weeks); abnormal erythropoiesis (megaloblastic; self-limiting), macrocytosis (MCV >97: 42% [Randi 2005]), reticulocytopenia (infants and children 9 to 18 months [Wang 2011])

Hepatic: Hepatic failure (HIV-infected patients), hepatotoxicity, increased liver enzymes

Neuromuscular & skeletal: Panniculitis (Antonioli 2012), weakness

Renal: Increased blood urea nitrogen, increased serum creatinine, renal tubular disease

Respiratory: Asthma (infants and children 9 to 18 months: 9% [Thornburg 2012]), dyspnea, pulmonary fibrosis (rare), pulmonary infiltrates (diffuse, rare)

<1% (Limited to important or life-threatening): Actinic keratosis (Antonioli 2012), azoospermia, basal cell carcinoma (Antonioli 2012), cholestasis, hepatitis, hyperkeratosis (Antonioli 2012), lesion (dyschromic [Antonioli 2012]), malignant neoplasm (Wong 2014), mucous membrane lesion (Antonioli 2012), oligospermia, pneumonitis (Antonioli 2012), squamous cell carcinoma (Antonioli 2012), tumor lysis syndrome

ALERT: U.S. Boxed Warning

Bone marrow suppression (Droxia):

Hydroxyurea may cause severe myelosuppression. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary.

Secondary malignancy (Droxia):

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

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 dose. Hematologic toxicity is reversible (rapid) with treatment interruption. 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. Hydroxyurea should not be used in sickle cell anemia with severe bone marrow suppression (neutrophils <2000/mm3, platelets <80,000/mm3, hemoglobin <4.5 g/dL, or reticulocytes <80,000/mm3 when hemoglobin <9 g/dL per the manufacturer’s labeling).

• Cutaneous vasculitic toxicities: Vasculitic ulcerations and gangrene have been reported with hydroxyurea treatment, most often in patients with a history of or receiving concurrent interferon therapy; discontinue hydroxyurea and consider alternate cytoreductive therapy if cutaneous vasculitic toxicity develops.

• Erythrocyte abnormalities: Self-limiting macrocytosis/megaloblastic erythropoiesis may be seen early in treatment (may resemble pernicious anemia, but is unrelated to vitamin B12 or folic acid deficiency). Plasma iron clearance may be delayed and iron utilization rate (by erythrocytes) may be reduced. Prophylactic folic acid supplementation is recommended.

• 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:

• Renal impairment: Use with caution in patients with renal impairment; may require dose reductions.

• Sickle cell anemia: Droxia is not recommended if neutrophils <2,000/mm3, platelets <80,000/mm3, hemoglobin <4.5 g/dL, or reticulocytes <80,000/mm3 when hemoglobin <9 g/dL per manufacturer’s labeling. May cause macrocytosis, which can mask folic acid deficiency; prophylactic folic acid supplementation is recommended.

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. When treated concurrently with hydroxyurea and antiretroviral agents (including didanosine and stavudine), HIV-infected patients are at higher risk for potentially fatal pancreatitis, hepatotoxicity, hepatic failure, and severe peripheral neuropathy; discontinue immediately if signs of these toxicities develop.

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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). To decrease risk of exposure, wear gloves when handling and wash hands before and after contact.

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; the antibody response to vaccines may be decreased. Immunization with live vaccines may result in severe infection. 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); 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).

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies. 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 (verify pregnancy status prior to starting hydroxyurea therapy) and should use effective contraception during and for at least 6 months after completion of therapy. Hydroxyurea use may damage spermatozoa and testicular tissue; males with female partners of reproductive potential should use effective contraception during and for at least 1 year after therapy. 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience alopecia, nausea, vomiting, lack of appetite, constipation, diarrhea, dizziness, headache, or mouth irritation. Have patient report immediately to prescriber signs of infections, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), seizures, illogical thinking, urinary retention, change in amount of urine passed, pain with urination, mole changes, skin growths, loss of strength and energy, hallucinations, swelling of arms or legs, or skin or nail changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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