Hydroxyurea

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# Black Box Warning

# 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)
- 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 patients actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patients 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
- Neutrophils 2500 cells/
- Platelets 95,000/
- Hemoglobin >5.3 g/dL
- Reticulocytes 95,000/mm3 if the hemoglobin concentration <9 g/dL.
Toxic
- Neutrophils <2000 cells/mm3,
- Platelets <80,000/mm3,
- Hemoglobin <4.5 g/dL and
- Reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL.
Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.
- Used as Alternative for the primary regimen of Busulfan and Interferon.
- Dosage: 20-30 mg/kg administered orally as a single dose daily, for 6 weeks
- Dosage: 1 gram PO q12h, starting the day before radiation. 11 doses in total.
- Dosage: 80 mg/kg administered orally as a single dose every third day.

## 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.

### NonGuideline-Supported Use
- Dosage
Initial dose: 15 milligrams/kilogram/day
Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3
- Initial dose: 15 milligrams/kilogram/day
- Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- 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 patients actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patients 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
- Neutrophils 2500 cells/
- Platelets 95,000/
- Hemoglobin >5.3 g/dL
- Reticulocytes 95,000/mm3 if the hemoglobin concentration <9 g/dL.
Toxic
- Neutrophils <2000 cells/mm3,
- Platelets <80,000/mm3,
- Hemoglobin <4.5 g/dL and
- Reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL.
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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-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
- Hydroxyurea is a cytotoxic and myelosuppressive agent. Hydroxyurea should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm3; a platelet count below 80,000/mm3; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. Hydroxyurea causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.
- In HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. *Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.
- Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine.
- Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop.
- 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 patients 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
- In patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia, the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks.
- Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding, and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving Hydroxyurea for SCA.
- Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema, and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Dysuria and alopecia have been reported. Large doses may produce drowsiness. Neurological disturbances have occurred and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels. Abnormal bromsulphalein (BSP) retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported.
- The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea has been reported. Pulmonary fibrosis also has been reported.
- In HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine, fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3.

## 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  >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.

### 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

## 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:

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

## Pharmacokinetics
- 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.
- 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.
- 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 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.
- 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.
- 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 25C (77F); excursions permitted to 15-30C (59-86F). Keep Tightly closed.

# Images

## Drug Images

## Package and Label Display Panel

# 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
- Hydroxyurea
- Hydrea

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

# Drug Shortage Status

# Price