Anhydrous disodium hydrogen phosphate, anhydrous citric acid, lactose anhydrous, magnesium stearate
The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans 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. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.
Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous 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 more 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; RNA and protein synthesis have shown no alteration.
Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed.
There are no data on the effect of food on the absorption of hydroxyurea.
Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water.
Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.
Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by unease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxlamine resulting from action of the urease on hydroxyurea.
Excretion of hydroxyurea in humans is likely a linear first-order renal process.
Geriatric, Gender, Race
No information is available regarding pharmacokinetic differences due to age, gender or race.
No pharmacokinetic data are available in pediatric patients treated with hydroxyurea.
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl] > 80 ml/min), moderate (CrCl = 30-<50 ml/min), or sever (< 30ml/min) renal impairment received hydorxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, teh second prior to hemodialysis. In this study the mean exposure (AUC) in patients whose creatinine clearance was <60 ml/min or (ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. Close monitoring of hematologic parameters is adivsed in these patients.
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.
There are no data on concomitant use of hydroxyurea with other drugs in humans.
Hydroxyurea used concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.
Hydroxyurea is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.
Concurrent use of hydroxyurea and other myelosupressive agents or radiation therpay may increase the likelihood of bone marrow depression or other adverse events.
Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medications may be necessary.
Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy.
Dyrsuria and alopecia occur very rarely. Large doses may produce moderate drowsiness. Neurological disturbances have occurred extremely rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported. Fever, chills, malaise, edema, asthenia, and elevations of hepatic enzymes have also been reported.
Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (<100,000 cells/mm3) has occurred rarely and only in the presence of marked leukopenia. Hydroxyurea may potentiate some adverse reactions, usually seen with irradiation alone, such as gastric distress and mucositis.
The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea has been reported rarely. Pulmonary fibrosis also has been reported rarely.
Fatal and nonfatal pnacreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular didanosine plus stavudine. Patients treated with hydroxyurea in combination with didanosine, stavudine, and idinavir in STudy ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3.
Category D: 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.
Hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, inculding mice, hamsters, cat, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on an mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, asbence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embyotoxicity was characterized by decreased fetal viability, reduce liver litter sizes, and development delays. Hydroxyurea corsses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
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 discontinue the drug, taking into account the importance of the drug to the mother.
To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea capsules. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during upacking and insepction, transport within a facility, and dose preparation and administration.
Procedures for proper handling and disposal of antineoplastic drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Because of the rarity of melanoma, resistant chronic myelocytic leukemia, carcinoma of the ovary, and carcinomas of the head and neck in patients, dosage regiments have not been established.
All dosage should be based on the patient's actual or ideal weight, whichever is less. Concurrent use of Hydroxyurea with other myelosupressive agents may require adjustment of dosages.
80 mg/kg administered orally as a single dose every third day.
20 to 30 mg/kg administered orally as a single dose daily.
Concomitant Therapy with Irradiation
Carcinoma of the head and neck: 80 mg/kg administered orally as a single dose every third day. Administration of hydroxyurea should begin at least seven days before intiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided that the patient may be kept under adequate obervation and evidence no unusual or severe reactions.
Resistant Chronic Myelocytic Leukemia
Until the intermittent therapy regimen has been evaluated, continuous therapy (20 to 30 mg/kg administered orally as a single daily dose) is recommended.
An adequate trial period for determining the antineoplastic effectiveness of hydroxyurea is six weeks of therapy. When there is regression in tumor size or arrest in tumor growth, therapy should be continued indefintitely. Therapy should be interrupted if the white blood cell count drops below 2500/mm3, or the platelet count below 100,000/mm3. In these cases, the counts should be reevaluated after three days, and therapy resumed when the counts return to acceptable levels. Since the hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If irradiation may also be interrupted. However, the need for postponement of irradiation has been rare; radiotherapy has usually been continued using the recommended dosage and technique. Severe anemia, if it occurs, should be corrected without interrupting hydroxyurea therapy. Because the hematopoiesis may be compromised by extensive irradiation or by other antineoplastic agents, it is recommended that hydroxyurea be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic drugs.
Pain or discomfort from inflammation of the mucous membranes at the irradiated site (mucositis) is usually controlled by measures such as topical anesthetics and orally administered analgesics. If the reaction is severe, hydroxyurea therpay may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in additions, 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 interruption of hydroxyurea administration.
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. Close monitoring of hematologic parameters is advised in these patients.
There are no data thclose moat support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema.
Fatal and nonfatal pancreatitis have occurred in HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death have been reported during post-marketing surveilance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.
Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or wihtout stavudine.
Severe anemia must be corrected before initiating therapy with hydroxyurea.
Erythrocytic abnormalitis: 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 may also 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.
In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocytopenia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroyurea or associated with the patient's underlying disease.
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reproted in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaenous vaculitic ulcerations develop and alternative cytoreductive agents should be instituted as indicated.
Therapy with hydroxyurea requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, should be determined prior to, and repeatedly during, treatment. The deteremination of the hemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxyurea therapy. If the white blood cell count decreases to less than 2500/mm3, or the platelet count to less than 100,000/mm3, therapy should be interrupted until the values rise significantly toward normal levels. Severe anemia, if it occurs, should be managed without interrupting hydroxyurea therapy.
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 signs and symptoms of pancreatitis is recommended. Patients who develop signs and symptoms of pancreatitis should permanently discontinue therapy with hydroxyurea.
Kidney function should be determined prior to, and repeatedly during, treatment.
Hydroxyurea should be used with caution in patients with marked renal dysfunction.
Liver function should be determined prior to, and repeatedly during, treatment.
An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with hydroxyurea, and in particular, in combination with didanosine and stavudine. This combination should be avoided.
Safety and effectiveness in pediatric patients have not been established.
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 of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, cause should be taken in dose selection, and it may be useful to monitor renal function.
Information for Patients
Hydroxyurea is a medication that must be handled with care. People who are not taking hydroxyurea should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling hydroxyurea or bottles containing hydroxyurea. Anyone handling hydroxyurea should wash their hands before and after contact with the bottle or capsules. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules.