Hydroxyurea

76.05

76.05

1741548

204-821-7

X6Q56QN5QC

757072|32065

2811

DTXSID6025438

C560

Needles from alcohol|White, crystalline powder|Needles from ethanol, crystals in 2 forms

L01XX05|L - Antineoplastic and immunomodulating agents

29242100

75.4

-1.6

white powder

1.457±0.06 g/cm3(Predicted)

141 °C

Decomposes

1.4840 (estimate)

H2O: soluble

2-8°C

2.43X10-3 mm Hg at 25 deg C (est)

Henry's Law constant = 5.42X10-11 atm-cu m/mole at 25 °C (est)

Crystals in 2 forms. MP form 1: 70-72 °C (decomposes); MP form 2: 141 °C|Moisture-labile|Hydroxyl radical reaction rate constant = 2.00X10-12 cu cm/molec-sec at 25 °C (est)

Water soluble.

Alcohols and Polyols

An amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

III

6.1

2811

3

46-63-61-40

53-36/37-45-36-22

YT4900000

T,Xn

Toxic

Stable under recommended storage conditions.

P201, P202, P281, P308+P313, P405, P501

H340

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including hydroxyurea, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

NIH/NHLBI; Clinical Alert: Drug Treatment for Sickle Cell Anemia (1/30/95). The National Heart, Lung, and Blood Institute (NHLBI) ... announced a drug treatment for sickle cell anemia. Findings from a multicenter clinical trial show that daily administration of the drug hydroxyurea reduced by about 50% the frequency of painful episodes and hospital visits for those episodes. The treatment also reduced the frequency of acute chest syndrome and the number of blood transfusions for patients in the study.|Levin VA; The Place of Hydroxyurea in the Treatment of Primary Brain Tumors; Semin Oncol 19 (3 Suppl 9): 34-9 (1992).|Kennedy BJ; The Evolution of Hydroxyurea Therapy in Chronic Myelogenous Leukemia; Semin Oncol 19 (3 Suppl 9) 21-6 (1992).|Donehower RC; An Overview of the Clinical Experience with Hydroxyurea; Semin Oncol 19 (3 Suppl 9): 11-9 (1992).|DHHS/NTP; Center for the Evaluation of Risks to Human Reproduction, NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Hydroxyurea, NIH Publication No. 08-5993 (October 2008).[Available from, as of April 11, 2016: http://ntp.niehs.nih.gov/ntp/ohat/hydroxyurea/humonograph20090401.pdf]

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Warning|H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]|P264, P273, P280, P305+P351+P338, P337+P313, and P501|Aggregated GHS information provided by 6 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Danger|H340 (85.45%): May cause genetic defects [Danger Germ cell mutagenicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 55 companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H340: May cause genetic defects [Danger Germ cell mutagenicity]

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this chemical under refrigerated temperatures, and protect it from moisture. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)|Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

In a study of Swiss oncology drug administration, hydroxyurea is 30-60% excreted in urine resulting in a predicted environmental concentration of 443 ng/L without metabolism and sewage treatment plant removal, 133-266 ng/L with metabolism(1).

Oral, mouse: LD50 = 7330 mg/kg; Oral, rat: LD50 = 5760 mg/kg Teratogenicity: Teratogenic effects have occurred in experimental animals.Hydroxyurea use during a small number of human pregnancies has been reported. Adverse effects have not been observed in any of the exposed newborns. Reproductive Effects: Adverse reproductive effects have occurred in experimental animals. Mutagenicity: Mutagenic effects have occurred in experimental animals.Mutagenic effects have occurred in humans.|IDENTIFICATION AND USE: Hydroxyurea is a white, crystalline powder. It is a drug indicated for the following uses: the treatment of resistant chronic myeloid leukemia; treatment of locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation; the palliative treatment of sickle cell anemia generally in patients with recurrent moderate to severe painful crises occurring on at least 3 occasions during the preceding 12 months (designated an orphan drug by the US Food and Drug Administration for this use). HUMAN EXPOSURE AND TOXICITY: During a 2-year period, 26 patients taking hydroxyurea for more than 6 months who had consultations at the dermatology department were systematically examined regarding cutaneous side effects. All but one had cutaneous side-effects, including dryness, moderate alopecia, increased skin pigmentation, melanonychia, cutaneous atrophy, leg ulcers, plantar keratoderma, pseudodermatomyositis, lichen planus-like eruption on the dorsum of the hands actinic keratosis, squamous cell carcinomas, and mouth ulcerations. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic failure were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine (note: hydroxyurea is not indicated for the treatment of HIV infection). In one case of an 85-year-old man taking hydroxyurea for chronic myelomonocytic leukemia, severe interstitial pneumonitis was induced by the drug. Gangrene of the toes and digits is a rare but very severe complication of long-term hydroxyurea therapy. A retrospective review of four adult men who had semen analysis during hydroxyurea therapy and in three cases after its cessation, suggests that the drug generally reduces sperm counts and motility and results in abnormal morphology. Hydroxyurea induced DNA hypermethylation in normal human embryonic lung fibroblasts and their simian virus 40-transformed counterparts. While cancer has been observed in some patients receiving long-term treatment with hydroxyurea, the drug is not yet classifiable as to its carcinogenicity to humans. ANIMAL STUDIES: Symptoms of exposure in dogs have included vomiting, ataxia, methemoglobinemia, tachycardia, lethargy, and hypothermia. Groups of 50 mice of each sex were treated intraperitoneally with hydroxyurea starting at two days of age and then at weekly intervals for one year. The incidences of pulmonary tumors were 30/50 (60%) in control and 16/35 (46%) in treated mice. Hydroxyurea is a swiftly acting developmental toxicant that inhibits DNA synthesis and is teratogenic in all mammals studied. Data from a study on mice suggest that hydroxyurea compromises folliculogenesis and the ability of generated embryos to develop. A group of 27 pregnant golden hamsters received an intravenous injection of 50 mg/kg bw hydroxyurea on day 8 of pregnancy. A high rate of fetal death and malformations, especially of the central nervous system, was observed. Hydroxyurea caused cell transformation in mass cultures of embryonic cells from mice, but not in cultures derived from two other strains of mice, nor in BALB/c 3T3 cells. Hydroxyurea treatment led to hypermethylation of DNA in hamster fibrosarcoma cells. Hydroxyurea was inactive as either a frameshift or base-pair substitution mutagen in Salmonella typhimurium strains TA1537, TA1535, TA98 and TA100, and addition of an exogenous metabolic activation system did not affect these results. Hydroxyurea induced SOS repair in Escherichia coli K12 cells. In various Saccharomyces cerevisiae strains, hydroxyurea induced mitotic crossing over, mitotic gene conversion, intrachromosomal recombination and aneuploidy, but not petite mutations. It also increased the frequency of ultraviolet-induced mitotic gene conversion and induced recombination in dividing but not G1 or G2 arrested cells of the RS112 strain of yeast. In meiotic yeast cells, hydroxyurea increased the frequency of meiotic recombination. Hydroxyurea induced micronuclei in the bone marrow of non-tumor-bearing male NMRI mice but did not induce micronucleated cells in female C57BL/6 C3H/He hybrid mice, although it produced sperm abnormalities in male mice of this strain.

Serum aminotransferase and bilirubin elevations occur in a small proportion of patients on conventional doses of hydroxyurea and a greater proportion at higher doses. However, the serum enzyme elevations are rarely associated with symptoms and are generally self-limited and resolve rapidly, rarely requiring dose modification.

The purpose of this analysis is to investigate if the combination of didanosine and stauvudine, with or without hydroxyurea, has a higher incidence of neuropathy than a single drug regimen. Data were obtained from patients followed longitudinally by the Johns Hopkins AIDS Services. Incidence rates of development of neuropathy were calculated for each of five regimens: didanosine (+/- hydroxyurea), didanosine + stauvudine (+/- hydroxyurea), and stauvudine. Cox proportional hazard regression was used to compare the relative risk of neuropathy for each regimen adjusting for CD4 cell count, other drugs received, and time on therapy. A total of 1116 patients received at least one of the five regimens. There were 117 cases of neuropathy. The crude incidence rate of neuropathy ranged from 6.8 cases per 100 person-years for didanosine to 28.6 cases per 100 person-years for didanosine + stauvudine + hydroxyurea. Compared with didanosine alone, and adjusting for CD4 cell counts and other variables, the relative risk of neuropathy was 1.39 [95% confidence interval (CI): 0.84-2.32] for stauvudine alone, 2.35 (95% CI: 0.69-8.07) for didanosine + hydroxyurea, 3.50 (95% CI: 1.81-6.77) for didanosine + stauvudine, and 7.80 (95% CI: 3.92-15.5) for didanosine + stauvudine + hydroxyurea. Based on the data, the risk of neuropathy is additive or even synergistic for didanosine + stauvudine + hydroxyurea compared with didanosine or stauvudine alone. The combination of didanosine + stauvudine also increases the risk of neuropathy but less than when hydroxyurea is included.|Concomitant therapy with hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse effects, and dosage adjustment may be required.|Because hydroxyurea therapy may cause increased serum uric acid concentrations, dosage adjustment of uricosuric medication may be required.|The antitumor activity of hydroxyurea can be potentiated by the addition of iron-chelating agents and prevented by the addition of Fe2+ to the medium.|For more Interactions (Complete) data for HYDROXYUREA (7 total), please visit the HSDB record page.

Hydrea (hydroxyurea) is contraindicated in patients with marked bone marrow depression, i.e., leukopenia (< 2500 WBC/cu mm) or thrombocytopenia (< 100,000/cu mm), or severe anemia ...|Hydroxyurea can cause fetal harm when administered to a pregnant woman. 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. Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. The physician should carefully consider this possibility before administering this drug to male or female patients who may contemplate conception|Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen. Hydroxyurea is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function|... Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with sickle cell disease before completion of the National Clinical Trial.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 4,336 workers (1,343 of these are female) were potentially exposed to hydroxyurea in the US(1).

For management of melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary and Sickle-cell anemia.|Siklos is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in paediatric and adult patients suffering from symptomatic sickle-cell syndrome.|Prevention of vaso-occlusive complications of sickle cell disease in patients over 2 years of age|Drug: Hydroxyurea

Hydroxyurea is an antimetabolite that is used in the treatment of cancer and to stimulate fetal hemoglobin production in sickle cell disease. Hydroxyurea is associated with a low rate of transient serum enzyme and bilirubin elevations during therapy, and has been implicated in rare cases of clinically apparent acute liver injury with jaundice.

Antineoplastic Agents; Sickle Cell Disease Agents

Antineoplastic Agents; Antisickling Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Hydroxyurea is included in the database.|Hydroxyurea Capsules USP are indicated for the treatment of: Resistant chronic myeloid leukemia. Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation. /Included in US product label/|Hydroxyurea has been used in the treatment of psoriasis and is reportedly beneficial in the treatment of hypereosinophilic syndrome that does not respond to corticosteroid therapy. /NOT included in US product label/|For more Therapeutic Uses (Complete) data for HYDROXYUREA (12 total), please visit the HSDB record page.

Hydroxyurea is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. Hydroxyurea therapy may be complicated by severe, sometimes life-threatening or fatal, adverse effects. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents or the use of this agent for sickle cell anemia.|Hydroxyurea should be admin with caution to patients who have recently received other cytotoxic drugs or irradiation therapy, since bone marrow depression is likely in these patients. In addition, an exacerbation of post-irradiation erythema may occur.|Hepatotoxicity, in some cases resulting in fatal hepatic failure, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents. Fatal hepatotoxicity occurred most frequently in patients receiving combination therapy with hydroxyurea, didanosine, and stavudine. Elevation of serum concentrations of hepatic enzymes has been reported in patients receiving hydroxyurea.|Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients receiving hydroxyurea for myeloproliferative disorders, particularly in patients who have received or who are receiving interferon therapy.|For more Drug Warnings (Complete) data for HYDROXYUREA (37 total), please visit the HSDB record page.

Hydroxyurea has dose-dependent synergistic activity with cisplatin in vitro. In vivo Hydroxyurea showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Hydroxyurea was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to Hydroxyurea 4 hours before cisplatin produced the greatest interaction.

Agents used to prevent or reverse the pathological events leading to sickling of erythrocytes in sickle cell conditions. (See all compounds classified as Antisickling Agents.)|Compounds that inhibit cell production of DNA or RNA. (See all compounds classified as Nucleic Acid Synthesis Inhibitors.)|Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

Well absorbed from the gastrointestinal tract.|Renal excretion is a pathway of elimination.|Hydroxyurea is readily absorbed from the GI tract. Peak serum concentrations are attained within 1-4 hours following oral administration. Blood concentrations decline rapidly and there is no cumulative effect with repeated administration. For this reason, higher blood concentrations are attained if the regular dosage is given in a large, single oral dose than if it is administered in divided doses. Disproportionate increases in peak plasma concentrations and areas under the concentration-time curve (AUCs) result when drug dosage is increased. The effect of food on the absorption of hydroxyurea has not been determined.|Hydroxyurea distributes rapidly throughout the body and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of the drug approximates total body water. Hydroxyurea crosses the blood-brain barrier; peak hydroxyurea CSF concentrations are attained within 3 hours following oral administration. The drug distributes into ascites fluid, resulting in drug concentrations in ascites fluid of 2-7.5 times less than plasma drug concentrations.|Studies using(14)C-labeled hydroxyurea indicate that about one-half an orally administered dose is degraded in the liver and is excreted as respiratory carbon dioxide and in urine as urea. The remaining portion of the drug is excreted intact in urine.|About 30-60% of an orally administered dose of hydroxyurea is excreted unchanged by the kidneys, although about 35% is generally excreted.|For more Absorption, Distribution and Excretion (Complete) data for HYDROXYUREA (7 total), please visit the HSDB record page.

Hepatic.|Studies indicate that up to 50% of an orally administered dose of hydroxyurea is metabolized in the liver; however, the precise metabolic pathways have not been determined. A minor metabolic pathway may involve degradation of the drug by urease, an enzyme produced by intestinal bacteria. Acetohydroxamic acid, possibly resulting from the breakdown of hydroxyurea by urease, was detected in the serum of 3 patients with leukemia treated with hydroxyurea.

3-4 hours|The half-time of hydroxyurea is short, with an initial half-time of 0.63 hr after intravenous administration and 1.78 hr after oral administration and a terminal half-time of 3.32 hr after oral administration and 3.39 hr after intravenous administration /to humans/.|The half-time of hydroxyurea in rats given 137 mg/kg bw per day intraperitoneally on days 9-12 of gestation was 15 min in the dams and 85 min in the embryos. In rhesus monkeys given 100 mg/kg bw per day intravenously on days 23-32 of gestation, the half-time was 120 min after the last injection in the mothers and 265 min in their fetuses.

Hydroxyurea is converted to a free radical nitroxide (NO) in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replicase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea also increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia. Levels of fetal hemoglobin increase in response to activation of soluble guanylyl cyclase (sGC) by hydroxyurea-derived NO.|The exact mechanism of antineoplastic activity of hydroxyurea has not been fully determined. Some studies indicate that hydroxyurea interferes with the synthesis of DNA without interfering with the synthesis of RNA or protein. Although hydroxyurea may have multiple sites of action, it appears likely that the drug inhibits the incorporation of thymidine into DNA; in addition, it may directly damage DNA. Hydroxyurea can destroy the tyrosyl free radical that is formed as the catalytic center of ribonucleoside diphosphate reductase, the enzyme that catalyzes the reductive conversion of ribonucleotides to deoxyribonucleotides; this conversion is a critical and probably rate-limiting step in the synthesis of DNA. The drug is an S-phase inhibitor and may cause cells to arrest at the G1-S border, decrease the rate of cell progression into the S phase, and/or cause cells to accumulate in the S phase as a result of inhibiting DNA synthesis. Animal studies indicate that the cytotoxic effects of hydroxyurea are limited to those tissues with high rates of cellular proliferation and the effects are evident only in those cells that are actively synthesizing DNA.|Hydroxyurea, a drug widely used in therapy of several human diseases, inhibits deoxynucleotide synthesis and, consequently, DNA synthesis by blocking the cellular enzyme ribonucleotide reductase. Hydroxyurea inhibits human immunodeficiency virus type 1 (HIV-1) DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides, thus suggesting that this drug has an antiviral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and activated) and macrophages, as well as in blood cells infected in vivo obtained from individuals with acquired immunodeficiency syndrome (AIDS). The antiviral effect was achieved at nontoxic doses of hydroxyurea, lower than those currently used in human therapy. Combination of hydroxyurea with the nucleoside analog didanosine (2'3'-dideoxyinosine, or ddi) generated a synergistic inhibitory effect without increasing toxicity. In some instances, inhibition of HIV-1 by hydroxyurea was irreversible, even several weeks after suspension of drug treatment. The indirect inhibition of HIV-1 by hydroxyurea is not expected to generate high rates of escape mutants. Hydroxyurea therefore appears to be a possible candidate for AIDS therapy.|Hydroxyurea (HU) is effectively used in the management of beta-hemoglobinopathies by augmenting the production of fetal hemoglobin (HbF). However, the molecular mechanisms underlying HU-mediated HbF regulation remain unclear. We previously reported that overexpression of the HU-induced SAR1 gene closely mimics the known effects of HU on K562 and CD34(+) cells, including gamma-globin induction and cell-cycle regulation. Here, we show that HU stimulated nuclear factor-kB interaction with its cognate-binding site on the SAR1 promoter to regulate transcriptional expression of SAR1 in K562 and CD34(+) cells. Silencing SAR1 expression not only significantly lowered both basal and HU-elicited HbF production in K562 and CD34(+) cells, but also significantly reduced HU-mediated S-phase cell-cycle arrest and apoptosis in K562 cells. Inhibition of c-Jun N-terminal kinase (JNK)/Jun phosphorylation and silencing of Gia expression in SAR1-transfected K562 and CD34(+) cells reduced both gamma-globin expression and HbF level, indicating that activation of Gia/JNK/Jun proteins is required for SAR1-mediated HbF induction. Furthermore, reciprocal coimmunoprecipitation assays revealed an association between forcibly expressed SAR1 and Gia2 or Gia3 proteins in both K562 and nonerythroid cells. These results indicate that HU induces SAR1, which in turn activates gamma-globin expression, predominantly through the Gia/JNK/Jun pathway. Our findings identify SAR1 as an alternative therapeutic target for beta-globin disorders.|Hydroxyurea is well absorbed after oral administration, converted to a free radical nitroxide in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replitase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea renders cells sensitive to bleomycin because the quenched tyrosyl free radical no longer stabilizes the adjacent iron center, making it more susceptible to the chelating properties of bleomycin, which then produces active oxygen. Synergy has also been observed between hydroxyurea and a number of other chemotherapeutic agents, including cytarabine and etoposide. Recently, two new effects of hydroxyurea have been observed: hydroxyurea increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia, and hydroxyurea selectively reduces the level of episomal DNA and thus potentially may reduce drug resistance associated with duplicated genes retained as episomes.|Fanconi's anemia (FA) is a recessive disease; 16 genes are currently recognized in FA. FA proteins participate in the FA/BRCA pathway that plays a crucial role in the repair of DNA damage induced by crosslinking compounds. Hydroxyurea (HU) is an agent that induces replicative stress by inhibiting ribonucleotide reductase (RNR), which synthesizes deoxyribonucleotide triphosphates (dNTPs) necessary for DNA replication and repair. HU is known to activate the FA pathway; however, its clastogenic effects are not well characterized. We have investigated the effects of HU treatment alone or in sequential combination with mitomycin-C (MMC) on FA patient-derived lymphoblastoid cell lines from groups FA-A, B, C, D1/BRCA2, and E and on lymphocytes from two unclassified FA patients. All FA cells showed a significant increase (P < 0.05) in chromosomal aberrations following treatment with HU during the last 3 h before mitosis. Furthermore, when FA cells previously exposed to MMC were treated with HU, we observed an increase of MMC-induced DNA damage that was characterized by high occurrence of DNA breaks and a reduction in rejoined chromosomal aberrations. These findings show that exposure to HU during G2 induces chromosomal aberrations by a mechanism that is independent of its well-known role in replication fork stalling during S-phase and that HU interfered mainly with the rejoining process of DNA damage. We suggest that impaired oxidative stress response, lack of an adequate amount of dNTPs for DNA repair due to RNR inhibition, and interference with cell cycle control checkpoints underlie the clastogenic activity of HU in FA cells.

SYMPTOMS: Symptoms of exposure to this compound include bone marrow suppression including megaloblastic changes, pulmonary edema and neurological reactions such as headache and dizziness. Other neurological reactions include drowsiness, disorientation, hallucinations and convulsions. Impairment of renal function may occur. Other symptoms include megaloblastic anemia, leukopenia, thrombocytopenia, gastrointestinal disturbances, mild dermatological reactions, stomatitis and alopecia. Exposure may also cause maculopapular rash, facial erythema, dysuria and fever. Symptoms of exposure to this type of compound include anorexia, nausea, vomiting, allergic reactions including skin rashes, erythema and pruritus, hypotension, malaise, weakness, anaphylaxis, vesication or irritation of the skin and mucous membranes and possible thrombophlebitis (when injected). Prolonged exposure to this type of compound may cause bone marrow depression, anemia, bleeding, immunosuppression, mouth ulcers, esophagitis, abdominal pain, hemorrhage, diarrhea, intestinal ulceration and perforation, hyperuricemia, acute renal failure due to uric acid nephropathy, hyperphosphatemia, pigmentation of the skin and nails and jaundice. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits toxic fumes of NOx. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Three patients with advanced acute myeloid leukemia were treated with oral high dose hydroxyurea at a dose of 10 g daily for 8-10 days. Severe acute stomatitis developed in all three patients. In addition, two of the patients developed a peculiar acute cutaneous type of toxicity associated with soreness, violet erythema, and edema of the palms and foot soles followed by intense universal hyperpigmentation of the skin. Apparently, the pronounced acute mucocutaneous toxicity was caused by the sustained high daily dose of hydroxyurea, indicating that myelosuppression may not be the dose limiting toxicity of this drug.|/HUMAN EXPOSURE STUDIES/ Sixty-four patients ranging in age from 8 to 47 years with inoperable cyanotic congenital heart disease were included in a prospective study in a treatment center in France. The patients received hydroxyurea at an initial dose of 10 mg/kg bw per day, which was adapted according to hematological tolerance and continued over a period ranging from (two to 15 years) (mean, approximately five years). No cases of acute leukemia or other malignancies were seen.|/SIGNS AND SYMPTOMS/ When very high doses are given intravenously, dose-related mucositis is seen, but neutropenia is usually the treatment-limiting side-effect.|/SIGNS AND SYMPTOMS/ During a 2-year period, all patients taking hydroxyurea for more than 6 months who had consultations at the dermatology department were systematically examined, regarding cutaneous side effects. Twenty-six patients were examined. All but one had cutaneous side-effects, including dryness (n = 16), moderate alopecia (n = 2), increased skin pigmentation (n = 5), melanonychia, single (n = 1) or multiple (n = 7), cutaneous atrophy (n = 4), leg ulcers (n = 8), plantar keratoderma (n = 3), pseudodermatomyositis (n = 1), lichen planus-like eruption on the dorsum of the hands (n = 2), actinic keratosis (n = 8), squamous cell carcinomas (n = 2), and mouth ulcerations (n = 1). This study shows that the frequency of hydroxyurea cutaneous side-effects diagnosed in 95% of studied patients is underestimated. They are usually benign, but some of them, in particular leg ulcers and squamous cell carcinomas, lead to modification of the treatment (39% of studied patients).|For more Human Toxicity Excerpts (Complete) data for HYDROXYUREA (27 total), please visit the HSDB record page.

Hydrea

Table: Hydroxyurea Preparations [Table#6398]

Ichthammol: ACTIVE

Analyte: hydroxyurea; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: hydroxyurea; matrix: chemical purity; procedure: liquid chromatography with detection at 214 nm and comparison to standards|Analyte: hydroxyurea; matrix: pharmaceutical preparation (capsules); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|Analyte: hydroxyurea; matrix: pharmaceutical preparation (capsules); procedure: liquid chromatography with detection at 214 nm and comparison to standards (chemical purity)

Determination by high performance liquid chromatography of hydroxyurea in human plasma.

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