Hydroxyurea

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Hydroxyurea
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Black Box Warning

Warning
See full prescribing information for complete Boxed Warning.
Condition Name: Treatment of patients with Hydroxyurea may be complicated by severe, sometimes life-threatening, adverse effects. Hydroxyurea should be administered under the supervision of a physician experienced in the use of this medication for the treatment of sickle cell anemia. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and a presumed transspecies carcinogen which implies a carcinogenic risk to humans. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. The physician and patient must very carefully consider the potential benefits of Hydroxyurea relative to the undefined risk of developing secondary malignancies.

Overview

Hydroxyurea is an antimetabolite, antineoplastic agent that is FDA approved for the treatment of sicle cell anemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include myelosuppression.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Sickle Cell Anemia
  • Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea capsules. Hydroxyurea capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below.
  • Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached.
  • If blood counts are between the acceptable rangeand toxic, the dose is not increased. If blood counts are considered toxic, Hydroxyurea should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. 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 dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.

Acceptable range

Toxic

Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.

Resistant Chronic Myeloid Leukemia
  • Used as Alternative for the primary regimen of Busulfan and Interferon[1].
  • Dosage: 20-30 mg/kg administered orally as a single dose daily, for 6 weeks[2]
Head and Neck Squamous Cell Cancer, in Combination With Radiation Therapy
  • Dosage: 1 gram PO q12h, starting the day before radiation. 11 doses in total[3].
Malignant Melanoma
  • Dosage: 80 mg/kg administered orally as a single dose every third day[4].

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyurea (patient information) in adult patients.

Non–Guideline-Supported Use

Essential Thrombocythemia
  • Dosage
    • Initial dose: 15 milligrams/kilogram/day
    • Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3[5]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Sickle Cell Anemia
  • Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea capsules. Hydroxyurea capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below.
  • Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached.
  • If blood counts are between the acceptable rangeand toxic, the dose is not increased. If blood counts are considered toxic, Hydroxyurea should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. 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 dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.

Acceptable range

Toxic

Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyurea (patient information) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroxyurea (patient information) in pediatric patients.

Contraindications

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

Warnings

Warning
See full prescribing information for complete Boxed Warning.
Condition Name: Treatment of patients with Hydroxyurea may be complicated by severe, sometimes life-threatening, adverse effects. Hydroxyurea should be administered under the supervision of a physician experienced in the use of this medication for the treatment of sickle cell anemia. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and a presumed transspecies carcinogen which implies a carcinogenic risk to humans. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. The physician and patient must very carefully consider the potential benefits of Hydroxyurea relative to the undefined risk of developing secondary malignancies.
Carcinogenesis and Mutagenesis
  • Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.
  • Conventional long-term studies to evaluate the carcinogenic potential of Hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype.

Adverse Reactions

Clinical Trials Experience

Sickle Cell Anemia
Other

Postmarketing Experience

There is limited information regarding Hydroxyurea Postmarketing Experience in the drug label.

Drug Interactions

  • Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • Hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydroxyurea in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Hydroxyurea during labor and delivery.

Nursing Mothers

  • Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

  • Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

There is no FDA guidance on the use of Hydroxyurea in geriatric settings.

Gender

There is no FDA guidance on the use of Hydroxyurea with respect to specific gender populations.

Race

There is no FDA guidance on the use of Hydroxyurea with respect to specific racial populations.

Renal Impairment

  • As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study, the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. The table below describes the recommended dosage modification.
Hdrx in Renal Impairment.png

Hepatic Impairment

  • There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Hydroxyurea in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Hydroxyurea in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Hydroxyurea Administration in the drug label.

Monitoring

Close monitoring of hematologic parameters is advised in patients with renal impairment.

IV Compatibility

There is limited information regarding the compatibility of Hydroxyurea and IV administrations.

Overdosage

  • Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed.

Pharmacology

Hydroxyurea Structure.png
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Hydroxyurea
Systematic (IUPAC) name
Hydroxyurea
Identifiers
CAS number 127-07-1
ATC code L01XX05
PubChem 3657
DrugBank DB01005
Chemical data
Formula CH4N2O2 
Mol. mass 76.0547 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism Hepatic (to CO2 and urea)
Half life 2-4 hours
Excretion Renal and lungs
Therapeutic considerations
Licence data

EUUS

Pregnancy cat.

D(AU) D(US)

Legal status

Prescription Only (S4)(AU) ?(CA) POM(UK) -only(US)

Routes Oral

Mechanism of Action

  • The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.
  • The mechanisms by which Hydroxyurea produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of Hydroxyurea that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

Structure

  • Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is:
Hydroxyurea Structure.png

Pharmacodynamics

There is limited information regarding Hydroxyurea Pharmacodynamics in the drug label.

Pharmacokinetics

Absorption
  • Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea.
Distribution
  • Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.
Metabolism
  • Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea.
Excretion
  • Excretion of hydroxyurea in humans is likely a linear first-order renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.

Nonclinical Toxicology

There is limited information regarding Hydroxyurea Nonclinical Toxicology in the drug label.

Clinical Studies

  • The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia).
  • The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea.
  • Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises.
  • Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months.
Hydroxyurea Clinical Study.png
  • No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo-treated patients.
Fetal Hemoglobin
  • In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages.
  • A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency.

How Supplied

  • 200 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6335-17). The cap and body are opaque blue-green. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6335”.
  • 300 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6336-17). The cap and body are opaque purple. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6336”.
  • 400 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6337-17). The cap and body are opaque reddish-orange. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6337”.

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep Tightly closed.

Images

Drug Images

Package and Label Display Panel

FDA Label Hydrx1.png
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Patient Counseling Information

There is limited information regarding Hydroxyurea Patient Counseling Information in the drug label.

Precautions with Alcohol

  • Alcohol-Hydroxyurea (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Hydroxyurea Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK; et al. (1993). "Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group.". Blood. 82 (2): 398–407. PMID 8329700. 
  2. "Hydrea (Hydroxyurea Package Insert)" (PDF). 
  3. Haraf DJ, Kies M, Rademaker AW, Stenson K, Mittal B, Pelzer H; et al. (1999). "Radiation therapy with concomitant hydroxyurea and fluorouracil in stage II and III head and neck cancer.". J Clin Oncol. 17 (2): 638–44. PMID 10080609. 
  4. "Hydrea (Hydroxyurea Package Insert)" (PDF). 
  5. Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F; et al. (1995). "Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.". N Engl J Med. 332 (17): 1132–6. PMID 7700286. doi:10.1056/NEJM199504273321704. 

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