Mechanism of Action

The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of variousstudies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by actingas a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certainconditions, hydroxyurea may induce teratogenic effects.

Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation onsquamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptibleto the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appearsthat hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasingtheir survival rate; RNA and protein syntheses have shown no alteration.

Pharmacokinetics

Special Populations

Animal Pharmacology and Toxicology

The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single dose.

In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bonemarrow hypoplasia as well as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days, then 2520 mg/kg/dayfor 40 days), testicular atrophy with absence of spermatogenesis occurred; in several animals, hepatic cell damage with fatty metamorphosis was noted.In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels(140 to 420 mg or 140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and hemosiderosisof the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen, anddegenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400 to 800 mg/kg/day for 7 to 15days), hemorrhage and congestion were found in the lungs, brain, and urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatichypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were observed in some species of laboratory animals atdoses exceeding clinical levels.

Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed (see CONTRAINDICATIONS).Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often andare seldom seen without a preceding leukopenia. However, the recovery from myelosuppression is rapid when therapy is interrupted. It should be bornein mind that bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; hydroxyureashould be used cautiously in such patients.

Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema.

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 hydroxyureaand 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 withantiretroviral agents, including didanosine, with or without stavudine.

Severe anemia must be corrected before initiating therapy with hydroxyurea.

Erythrocytic abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of hydroxyurea therapy.The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. Hydroxyurea mayalso delay plasma iron clearance and reduce the rate of iron utilization by erythrocytes, but it does not appear to alter the red blood cell survival time.

Elderly patients may be more sensitive to the effects of hydroxyurea,and may require a lower dose regimen (see PRECAUTIONS: Geriatric Use).

In patients receiving long-term hydroxyurea for myeloproliferativedisorders, such as polycythemia vera and thrombocythemia, secondary leukemiahas been reported. It is unknown whether this leukemogenic effect is secondaryto hydroxyurea or associated with the patient’s underlying disease.

Cutaneous vasculitic toxicities, including vasculitic ulcerationsand gangrene, have occurred in patients with myeloproliferative disordersduring therapy with hydroxyurea. These vasculitic toxicities were reportedmost often in patients with a history of, or currently receiving, interferontherapy. Due to potentially severe clinical outcomes for the cutaneous vasculiticulcers reported in patients with myeloproliferative disease, hydroxyurea shouldbe discontinued if cutaneous vasculitic ulcerations develop and alternativecytoreductive agents should be initiated as indicated.

Carcinogenesis and Mutagenesis

Hydroxyurea is genotoxic in a wide range of test systems and isthus presumed to be a human carcinogen. In patients receiving long-term hydroxyureafor myeloproliferative disorders, such as polycythemia vera and thrombocythemia,secondary leukemia has been reported. It is unknown whether this leukemogeniceffect is secondary to hydroxyurea or is associated with the patient’s underlyingdisease. Skin cancer has also been reported in patients receiving long-termhydroxyurea.

Conventional long-term studies to eva luate the carcinogenic potentialof hydroxyurea have not been performed. However, intraperitoneal administrationof 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommendedhuman oral daily dose on a mg/m2 basis) thriceweekly for 6 months to female rats increased the incidence of mammary tumorsin rats surviving to 18 months compared to control. Hydroxyurea is mutagenic invitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyureais 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 tumorigenicphenotype.

Pregnancy

Drugs which affect DNA synthesis, such as hydroxyurea, may be potentialmutagenic agents. The physician should carefully consider this possibilitybefore administering this drug to male or female patients who may contemplateconception.

HYDREA can cause fetal harm when administered to a pregnant woman.Hydroxyurea has been demonstrated to be a potent teratogen in a wide varietyof animal models, including mice, hamsters, cats, miniature swine, dogs, andmonkeys at doses within 1-fold of the human dose given on a mg/m2 basis.Hydroxyurea is embryotoxic and causes fetal malformations (partially ossifiedcranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae,missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommendedhuman daily dose on a mg/m2 basis) in rats andat 30 mg/kg/day (about 0.3 times the maximum recommended human daily doseon a mg/m2 basis) in rabbits. Embryotoxicity wascharacterized by decreased fetal viability, reduced live litter sizes, anddevelopmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375mg/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 areno adequate and well-controlled studies in pregnant women. If this drug isused during pregnancy or if the patient becomes pregnant while taking thisdrug, the patient should be apprised of the potential harm to the fetus. Womenof childbearing potential should be advised to avoid becoming pregnant.

General

Therapy with hydroxyurea requires close supervision. The completestatus of the blood, including bone marrow examination, if indicated, as wellas kidney function and liver function should be determined prior to, and repeatedlyduring, treatment. The determination of the hemoglobin level, total leukocytecounts, and platelet counts should be performed at least once a week throughoutthe course of hydroxyurea therapy. If the white blood cell count decreasesto less than 2500/mm3, or the platelet count toless than 100,000/mm3, therapy should be interrupteduntil the values rise significantly toward normal levels. Severe anemia, ifit occurs, should be managed without interrupting hydroxyurea therapy.

Hydroxyurea should be used with caution in patients with markedrenal dysfunction. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.)

Hydroxyurea is not indicated for the treatment of HIV infection;however, if HIV-infected patients are treated with hydroxyurea, and in particular,in combination with didanosine and/or stavudine, close monitoring for signsand symptoms of pancreatitis is recommended. Patients who develop signs andsymptoms of pancreatitis should permanently discontinue therapy with hydroxyurea.(See WARNINGS and ADVERSE REACTIONS.)

An increased risk of hepatotoxicity, which may be fatal, may occurin patients treated with hydroxyurea, and in particular, in combination withdidanosine and stavudine. This combination should be avoided.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS for Carcinogenesis and Mutagenesis information.

Impairment of Fertility: Hydroxyurea administered to male ratsat 60 mg/kg/day (about 0.3 times the maximum recommended human daily doseon a mg/m2 basis) produced testicular atrophy,decreased spermatogenesis, and significantly reduced their ability to impregnatefemales.

Pregnancy

Pregnancy Category D. (See WARNINGS.)

Nursing Mothers

Hydroxyurea is excreted in human milk.

Because of the potential for serious adverse reactions with hydroxyurea,a decision should be made whether to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Elderly patients may be more sensitive to the effects of hydroxyurea,and may require a lower dose regimen.

This drug is known to be excreted by the kidney, and the risk oftoxic reactions to this drug may be greater in patients with impaired renalfunction. Because elderly patients are more likely to have decreased renalfunction, care should be taken in dose selection, and it may be useful tomonitor renal function (see DOSAGE AND ADMINISTRATION:Renal Insufficiency).

Drug Interactions

Prospective studies on the potential for hydroxyurea to interactwith other drugs have not been performed.

Concurrent use of hydroxyurea and other myelosuppressive agentsor radiation therapy may increase the likelihood of bone marrow depressionor other adverse events. (See WARNINGS and ADVERSE REACTIONS.)

Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactic dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.

Information for Patients

HYDREA is a medication that must be handled with care. People whoare not taking HYDREA should not be exposed to it. To decrease the risk ofexposure, wear disposable gloves when handling HYDREA or bottles containingHYDREA. Anyone handling HYDREA should wash their hands before and after contactwith the bottle or capsules. If the powder from the capsule is spilled, itshould be wiped up immediately with a damp disposable towel and discardedin a closed container, such as a plastic bag. The medication should be keptaway from children and pets. Contact your doctor for instructions on how todispose of outdated capsules.

Solid Tumors

Resistant Chronic Myelocytic Leukemia

Until the intermittent therapy regimen has been eva luated, CONTINUOUStherapy (20-30 mg/kg administered orally as a single dose daily)is recommended.

An adequate trial period for determining the antineoplastic effectivenessof hydroxyurea is six weeks of therapy. When there is regression in tumorsize or arrest in tumor growth, therapy should be continued indefinitely.Therapy should be interrupted if the white blood cell count drops below 2500/mm3,or the platelet count below 100,000/mm3. In thesecases, the counts should be reeva luated after three days, and therapy resumedwhen the counts return to acceptable levels. Since the hematopoietic reboundis prompt, it is usually necessary to omit only a few doses. If prompt reboundhas not occurred during combined HYDREA and irradiation therapy, irradiationmay also be interrupted. However, the need for postponement of irradiationhas been rare; radiotherapy has usually been continued using the recommendeddosage and technique. Severe anemia, if it occurs, should be corrected withoutinterrupting hydroxyurea therapy. Because hematopoiesis may be compromisedby extensive irradiation or by other antineoplastic agents, it is recommendedthat hydroxyurea be administered cautiously to patients who have recentlyreceived extensive radiation therapy or chemotherapy with other cytotoxicdrugs.

Pain or discomfort from inflammation of the mucous membranes atthe irradiated site (mucositis) is usually controlled by measures such astopical anesthetics and orally administered analgesics. If the reaction issevere, hydroxyurea therapy may be temporarily interrupted; if it is extremelysevere, irradiation dosage may, in addition, be temporarily postponed. However,it has rarely been necessary to terminate these therapies.

Severe gastric distress, such as nausea, vomiting, and anorexia,resulting from combined therapy may usually be controlled by temporary interruptionof hydroxyurea administration.

Renal Insufficiency

As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of HYDREA in patients with renal impairment.(See PRECAUTIONS and CLINICAL PHARMACOLOGY.) Close monitoring of hematologic parameters is advised in these patients.

Hepatic Insufficiency

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.

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Keep tightly closed.