Hydroxycarbamid

-1.8

log Kow = -1.80

-1.6

Needles from alcohol

White, crystalline powder

Needles from ethanol, crystals in 2 forms

greater than or equal to 100 mg/mL at 70 °F (NTP, 1992)

1000000

Freely soluble in water /1.0X10+6 mg/L at 25 °C/

Freely soluble in hot alcohol

Very soluble in water... insoluble in ethanol and benzene

2.69e+02 g/L

Decomposes (NTP, 1992)

Decomposes

291 to 295 °F (decomposes) (NTP, 1992)

133-136

141 °C

MP: 133-136 °C. Somewhat hygroscopic

142 - 146 °C

Hydroxyurea appears as odorless or almost odorless white to off-white crystalline solid. Tasteless. (NTP, 1992)

Solid

Crystals in 2 forms. MP form 1: 70-72 °C (decomposes); MP form 2: 141 °C

Moisture-labile

Danger

H340 (86.2%): May cause genetic defects [Danger Germ cell mutagenicity]；H360 (13.8%): May damage fertility or the unborn child [Danger Reproductive toxicity]；H361 (82.8%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 58 reports by companies from 14 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Hazard Traits - Developmental Toxicity；Authoritative List - Prop 65；Report - regardless of intended function of ingredient in the product

Urea, hydroxy-: Does not have an individual approval but may be used under an appropriate group standard

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)

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]

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).

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)

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.

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2 - 8 °C. Moisture sensitive. Keep in a dry place.

Store at 20 deg to 25 °C (68 deg to 77 °F)

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.

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)

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.

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.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:；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 the immediate precautionary measure distance, in the downwind direction, as necessary.；FIRE: If tank, rail tank car or highway tank 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, 2024)

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).

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.

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.

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.；Cases of clinically apparent liver injury attributed to hydroxyurea have been reported, but are rare. Two clinical presentations have been described: an acute syndrome of drug fever and mild hepatitis that resolves rapidly with stopping, and a less well characterized acute hepatitis-like injury which can be severe and even fatal, arising after several months of treatment and usually in patients on other hepatotoxic medications.；Drug fever occurs in up to 1% of patients treated with hydroxyurea, typically arising within 1 to 3 weeks of starting and presenting with high fevers and mild constitutional symptoms of fatigue and nausea (Case 1 below). The fevers are typically cyclic and temperature can rise to 41oC at intervals of every 1 to 3 days as long as therapy is continued. The fevers are generally well tolerated, although they may be accompanied by nausea, diarrhea, anorexia or fatigue. Approximately one third of patients will also have some degree of serum enzyme elevations, typically increases in both aminotransferase and alkaline phosphatase levels, with minimal increases in serum bilirubin. The liver injury is usually mild and asymptomatic and the symptom of fever predominates. White blood cell and eosinophil counts are usually normal at the time of onset, but may arise if therapy is continued. Rash and other signs of hypersensitivity are uncommon. Both the fever and liver test abnormalities resolve promptly once hydroxyurea is stopped–the fever within 24 to 48 hours and the liver test elevations within 2 to 4 weeks. The fever recurs with reexposure, generally within 24 hours.；In addition, rare instances of acute hepatitis that can be severe and lead to hepatic failure and death have been described in patients taking hydroxyurea and antiretroviral therapy for HIV/AIDS. This presentation is clearly different from the hepatitis that accompanies drug fever from hydroxyurea, and resembles acute viral hepatitis with marked elevations in serum aminotransferase levels and jaundice and only mild-to-moderate elevations in alkaline phosphatase. Immunoallergic and autoimmune features are not usually present. Some cases have been fatal; others have been marked by slow, but ultimately full recovery. The cases of severe hepatitis attributed to hydroxyurea have been described largely in patients with HIV infection on antiretroviral regimens that include agents associated with hepatotoxicity, but the addition of hydroxyurea appeared to be responsible for the liver injury, these patients later tolerating resumption of antiretroviral therapy without recurrence.；Likelihood score: C (probable cause of clinically apparent liver injury).

EC50; Species: Danio rerio (Zebra Danio) 4 hr post fertlization, embryo; Conditions: freshwater, renewal, 27 °C, pH 7.4; Concentration: 31.6 mM for 48 hr (95% confidence interval: 28.3-32 mM); Effect: increased abnormal development /formulation/

LC50; Species: Danio rerio (Zebra Danio) 4 hr post fertlization, embryo; Conditions: freshwater, renewal, 27 °C, pH 7.4; Concentration: 42.6 mM for 48 hr (95% confidence interval: 40.2-43.3 mM) /formulation/

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. Hydroxyure

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.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 17, 2015: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=127-07-1]

/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.

Hydroxyurea

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 76: (2000) Some Antiviral and Antineoplastic Drugs, and Other Pharmaceutical Agents

2000

1999

3, not classifiable as to its carcinogenicity to humans. (L135)

Drug Induced Liver Injury Rank (DILIrank 2.0)

Hydroxyurea

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ The effects of leukocyte depletion on the pulmonary response to breathing 100% O2 /was measured/ in adult sheep, using two dissimilar agents. A group of eight sheep received 4.1 g/day of hydroxyurea for 4 to 6 days, and six sheep received two to four doses of 0.4 mg/kg of nitrogen mustard before exposure to 100% O2. A group of seven sheep breathed 100% O2 with no drug treatment. A group of five control sheep breathed compressed air for 96 hours. Hydroxyurea selectively reduced circulating neutrophils (602 + or - 245 neutrophils, 2,537 + or - 394 lymphocytes per cu mm), and nitrogen mustard decreased both circulating neutrophils (633 + or - 326) and lymphocytes (521 + or - 129). In untreated sheep breathing 100% O2, survival time was 92.6 + or - 3.4 hours and postmortem blood free lung water to dry lung ratio was 4.4 + or - 0.2. Hydroxyurea significantly delayed the onset of oxygen toxicity as measured by changes in lung lymph flow, PaO2, PaCO2, and time to respiratory failure (111.8 + or - 7.7 hours), although the degree of final lung injury was unchanged and postmortem lung water was elevated (5.3 + or - 0.3). Nitrogen mustard shortened the time to hypoxemia, and CO2 retention and decreased time to respiratory failure (84.0 + or - 4.3 hours). Neutrophils were markedly reduced but not absent in the lungs of both groups of leukocyte depleted sheep. It was concluded that neutrophils are not essential for the full expression of lung O2 toxicity in adult sheep. Secondary effects of hydroxyurea and nitrogen mustard appear to influence the rate of development, but not the outcome of oxygen toxicity, by effects independent of leukocyte depletion.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Antimetabolites have been shown to be carcinogenic in animals and may be associated with an increased risk of development of secondary carcinomas in humans, although the risk appears to be less than with alkylating agents.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 50 mice of each sex of the XVII/G strain were treated intraperitoneally with hydroxyurea (purity not specified) starting at two days of age and then at weekly intervals for one year. The doses per mouse were: 1 mg at two days of age, 3 mg at eight days, 5 mg at 15 days and 10 mg from 30 days to one year of age. One group of 50 mice was kept untreated as controls. The incidences of pulmonary tumors were 30/50 (60%) in control and 16/35 (46%) in treated mice. In a positive control group treated with urethane, 28/30 (93%) of mice had lung tumors

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 36-43 female Wistar rats, weighing about 200 g, were given intraperitoneal injections of hydroxyurea in 23 fractionated consecutive doses of 0.1 mg/kg bw each shortly before and during maximal urothelial cell proliferation (33-55 hr after partial cystectomy) produced by N-methyl-N-nitrosourea administered as a single intravesicular pulse dose of 5 mg/kg bw during the various cell cycle phases. Hydroxyurea inhibited N-methyl-N-nitrosourea-induced urothelial tumor development, and the degree of this inhibition depended on the cell cycle phase during which N-methyl-N-nitrosourea was instilled. The numbers of rats with urothelial bladder tumors were: 14/43 in the control group (G0 phase) and 7/37, 4/43 (p<0.02), 10/46, 10/38, 9/36 and 12/40 in groups receiving N-methyl-N-nitrosourea during the late G1, early and late S, G2+M, and early and late postmitotic phases, respectively.

For more Non-Human Toxicity Excerpts (Complete) data for HYDROXYUREA (24 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.

Hazard Traits - Developmental Toxicity；Authoritative List - Prop 65；Report - regardless of intended function of ingredient in the product

Urea, hydroxy-: Does not have an individual approval but may be used under an appropriate group standard

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.

L01XX05

L - Antineoplastic and immunomodulating agents；L01 - Antineoplastic agents；L01X - Other antineoplastic agents；L01XX - Other antineoplastic agents；L01XX05 - Hydroxycarbamide

QL - Antineoplastic and immunomodulating agents；QL01 - Antineoplastic agents；QL01X - Other antineoplastic agents；QL01XX - Other antineoplastic agents；QL01XX05 - Hydroxycarbamide

The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in rat and human tissue cultures lend support to 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. Hydroxyurea probably acts by decreasing the rate of conversion of ribonucleotides and deoxyribonucleotides. This effect is particularly apparent in cells with a high rate of proliferation. Particularly, hydroxyurea reduces the tyrosyl free radical at the active site of the M2 via a one-electron transfer reaction through the –NH2-OH moiety. Three mechanisms have been postulated for the potentiation of the therapeutic effects of irradiation by hydroxyurea on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells and holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; there is no alteration of RNA and protein syntheses. Another proposed mechanism of action of hydroxyurea is the elevation of HbF concentrations in Sickle Cell Disease patients. HbF interferes with the polymerization of HbS (sickle haemoglobin) and thus impedes the sickling of red blood cell. Recently, hydroxyurea has shown to be associated with the generation of nitric oxide, suggesting that nitric oxide stimulates cyclic guanosine monophosphates (cGMP) production, which then activates a protein kinase and increases th

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.

In adult cancer patients, hydroxyurea was eliminated with a half-life of approximately 2-3 hours. In a single-dose study in children with Sickle Cell Disease, the mean half-life was reported to be 1.7 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.

Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation to acetohydroxamic acid by urease found in intestinal bacteria.

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.

Hepatic. Route of Elimination: Renal excretion is a pathway of elimination. Half Life: 3-4 hours

X6Q56QN5QC

HYDROXYUREA

Established Pharmacologic Class [EPC] - Antimetabolite

Chemical Structure [CS] - Urea

Hydroxyurea is an Antimetabolite.

HYDROXYUREA

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Agents used to prevent or reverse the pathological events leading to sickling of erythrocytes in sickle cell conditions.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Compounds that inhibit cell production of DNA or RNA.

After oral administration hydroxyurea is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 2 hours and by 24 hours the serum concentrations are virtually zero. Bioavailability is complete or nearly complete in cancer patients. After oral administration of 20 mg/kg of hydroxyurea, a rapid absorption is observed with peak plasma levels of about 30 mg/L occurring after 0.75 and 1.2 h in children and adult patients with sickle cell syndrome, respectively. The total exposure up to 24 h post-dose is 124 mg.h/L in children and adolescents and 135 mg.h/L in adult patients. The oral bioavailability of hydroxyurea is almost complete as assessed in indications other than sickle cell syndrome. In a comparative bioavailability study in healthy adult volunteers (n=28), 500 mg of hydroxyurea oral solution was demonstrated to be bioequivalent to the reference 500 mg capsule, with respect to both the peak concentration and area under the curve. There was a statistically significant reduction in time to peak concentration with hydroxyurea oral solution compared to the reference 500 mg capsule (0.5 versus 0.75 hours, p = 0.0467), indicating a faster rate of absorption.[L47137 In a study of children with Sickle Cell Disease, liquid and capsule formulations resulted in similar area under the curve, peak concentrations, and half-life. The largest difference in the pharmacokinetic profile was a trend towards a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, p = 0.14).

A significant fraction of hydroxycarbamide is eliminated by nonrenal (mainly hepatic) mechanisms. In adults, the urinary recovery of unchanged drug is reported to be approximately 37% of the oral dose when renal function is normal. In children, the fraction of hydroxyurea excreted unchanged into the urine comprised about 50%.

Hydroxyurea distributes rapidly throughout the human body, enters the cerebrospinal fluid, appears in peritoneal fluid and ascites, and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of hydroxycarbamide approximates total body water. The volume of distribution following oral dosing of hydroxycarbamide is approximately equal to total body water: adult values of 0.48 – 0.90 L/kg have been reported, whilst in children a population estimate of 0.7 L/kg has been reported.

The total body clearance of hydroxyurea in adult patients with Sickle Cell Disease is 0.17 L/h/kg. The respective value in children was similar, 0.22 L/h/kg.

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.

MEDICATION

Antineoplastic Agents; Antisickling Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >5000；Use (kg; exact) in Germany (2009): 5996；Consumption (g per capita; approx.) in Germany (2009): 0.0611；Consumption (g per capita; exact) in Germany (2009): 0.0732；Excretion rate: 0.45；Calculated removal (%): 75.1

For management of melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary and Sickle-cell anemia.