Hydrea

Hydrea

hydroxycarbamide

Manufacturer:

Bristol-Myers Squibb

Distributor:

DKSH
Full Prescribing Info
Contents
Hydroxyurea.
Description
Hydrea (hydroxyurea capsules, USP) is an antineoplastic agent, available for oral use as capsules providing hydroxyurea 500 mg. It also contains the following inactive ingredients: Citric acid, colorants, gelatin, lactose, magnesium stearate, sodium phosphate and titanium dioxide.
Action
Pharmacology: The precise mechanism by which hydroxyurea produces its cytotoxic effects is not known. Various studies in tissue culture of rats and man support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis without interfering with the synthesis of ribonucleic acid of ribonucleic or protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.
Three mechanisms have been postulated for the increased effectiveness of concomitant use of hydroxyurea with irradiation 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 3rd 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.
Pharmacokinetics: After oral administration in man, hydroxyurea is readily absorbed from the gastrointestinal tract. The drug reaches peak serum concentrations within 2 hrs; by 24 hrs, the concentration in the serum is essentially undetectable. Approximately 80% of an oral or IV dose of 7-30 mg/kg may be recovered in the urine within 12 hrs. Hydroxyurea crosses the blood-brain barrier.
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 bone marrow 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/day for 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 (140-420 mg or 140-1260 mg/kg/week dose over 3 or 7 days each week for 12 weeks), growth retardation, slightly increased blood glucose values and hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen and degenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400-800 mg/kg/day for 7-15 days), hemorrhage and congestion were found in the lungs, brain and urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were observed in some species of laboratory animals at doses exceeding clinical levels.
Indications/Uses
Significant tumor response to Hydrea has been demonstrated in melanoma, resistant chronic myelocytic leukemia and recurrent, metastatic or inoperable carcinoma of the ovary.
Hydrea used concomitantly with irradiation therapy is intended for use in the local of primary squamous cell (epidermoid) carcinomas of the head and neck (excluding the lip), and carcinoma of the cervix.
Dosage/Direction for Use
All Hydrea dosage regimens should be based on the patient's actual or ideal weight, whichever is less.
Concurrent use of hydroxyurea with other myelosuppressive agents may require adjustments of dosages.
Solid Tumors: Intermittent Therapy: 80 mg/kg administered orally as a single dose every 3rd day.
Continuous Therapy: 20-30 mg/kg administered orally as a single dose daily.
The intermittent dosage schedule offers the advantage of reduced toxicity (eg, bone marrow depression). Patients on this dosage regimen have rarely required complete discontinuance of therapy because of toxicity.
Concomitant Therapy with Irradiation: Carcinoma of the head, neck and cervix: 80 mg/kg administered orally as a single dose every 3rd day. Administration of hydroxyurea, should begin at least 7 days before initiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided that the patient may be kept under adequate observation and shows no unusual or severe reactions.
Irradiation should be given at the maximum dose considered appropriate for the particular therapeutic situation. Adjustment of irradiation dosage is not usually necessary when hydroxyurea is used concomitantly.
Resistant Chronic Myelocytic Leukemia: Continuous Therapy: 20-30 mg/kg administered orally as a single dose daily. An adequate trial period for determining the antineoplastic effectiveness hydroxyurea is 6 weeks of therapy. When there is significant clinical response, therapy should be continued indefinitely. Therapy should be interrupted if the white blood cell count drops <2500/mm3, or the platelet count <100,000/mm3. In these cases, the counts should be rechecked after 3 days and therapy resumed when the counts rise significantly toward normal values. Since the hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If prompt rebound has not occurred during combined hydroxyurea and irradiation therapy, 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. Anemia, if it occurs, should be corrected, without interrupting hydroxyurea therapy. Because 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, eg topical anesthetics and orally administered analgesics. If the reaction is severe, hydroxyurea therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed. However, it has rarely been necessary to terminate these therapies.
Severe gastric distress, eg nausea, vomiting and anorexia, resulting from combined therapy may usually be controlled by temporary interruption of hydroxyurea administration; rarely has the additional interruption of irradiation been necessary.
Information for Patients: Patients should be informed to maintain adequate fluid intake. The physician should be consulted regarding missed doses.
If the patient prefers, or is unable to swallow capsules, the contents of the capsules may be emptied into a glass of water and taken immediately. Some inert material used as a vehicle in the capsule may not dissolve and may float on the surface.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Overdosage
Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at a dosage several fold in excess of the usual recommended dosage. Soreness, violet erythema, edema on palms and foot soles followed by scaling of hands and feet, intense generalized hyperpigmentation of skin and severe acute stomatitis were observed.
Contraindications
Patients with marked bone marrow depression, ie leukopenia (<2500 WBC/mm3) or thrombocytopenia (<700,000/mm3).
Special Precautions
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 and are seldom seen without a preceding leukopenia. However, the recovery from myelosuppression is rapid when therapy is interrupted. It should be borne in mind that bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; hydroxyurea should be used cautiously in such patients.
Patients who have received irradiation therapy in the past may have an exacerbation of post-irradiation erythema.
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 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.
Hydroxyurea should be used with caution in patients with marked renal dysfunction.
Elderly patients may be more sensitive to the effects of hydroxyurea and may require a lower dose regimen.
When appropriate, patients should be counseled concerning the use of contraceptive measures during therapy. Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the level of bone marrow depression or other adverse reactions (see Adverse Reactions).
Laboratory Tests: Hydroxyurea therapy requires close supervision. Hematologic profile, including bone marrow examination if indicated, kidney function and liver function should be determined prior to and repeatedly during treatment. Determination of hemoglobin, leukocyte and platelet counts should be performed at least once a week throughout the course of hydroxyurea therapy. If the leukocyte count decreases to <2500/mm3 or the platelet count to <100,000/mm3, therapy should be interrupted until the values rise significantly toward normal levels. Anemia, if it occurs, should be managed without interrupting hydroxyurea therapy.
Carcinogenicity, Mutagenicity & Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential. In rats, hydroxyurea at high dosage levels produced aspermatogenesis. In dogs, reversible spermatogenic arrest was noted at high dose levels. (See Actions.) Drugs which affect DNA synthesis, eg hydroxyurea, may be potentially mutagenic and this possibility should be considered before administering the drug to male or female patients who may contemplate conception.
Use in pregnancy: Hydroxyurea can cause fetal harm when administered to a pregnant woman and is a known teratogenic agent in animals. Malformations have been observed in the offspring of rabbits and rats given doses equivalent to 1/3 to twice the maximum human dose, respectively. 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 on hydroxyurea therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Use in lactation: Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from 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.
Use in children: Safety and effectiveness in children have not been established.
Use In Pregnancy & Lactation
Use in pregnancy: Hydroxyurea can cause fetal harm when administered to a pregnant woman and is a known teratogenic agent in animals. Malformations have been observed in the offspring of rabbits and rats given doses equivalent to 1/3 to twice the maximum human dose, respectively. 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 on hydroxyurea therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Use in lactation: Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from 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.
Adverse Reactions
Hematologic: Bone marrow depression (leukopenia, anemia and occasionally thrombocytopenia). (See Precautions.)
Gastrointestinal: Stomatitis, anorexia, nausea, vomiting, diarrhea and constipation.
Dermatologic: Maculopapular rash, facial erythema and peripheral erythema. Alopecia occurs rarely. Hyperpigmentation, erythema, atrophy of skin and nails, scaling, violet papules and alopecia have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea.
Neurologic: Large doses may produce moderate drowsiness. Neurological disturbances have occurred rarely and were limited to headache, dizziness, disorientation, hallucinations and convulsions.
Renal: Occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN and creatinine levels. Dysuria occurs rarely.
Others: Fever, chills, malaise and elevation of hepatic enzymes have also been reported. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported.
Combined Hydroxyurea and Irradiation Therapy: Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea alone. These effects primarily include bone marrow depression (anemia and leukopenia) and gastric irritation. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Decreased platelet counts (<100,000 cells/mm3) has occurred rarely and only in the presence of marked leukopenia. Gastric distress has also been reported with irradiation alone and in combination with hydroxyurea therapy.
It should be borne in mind that therapeutic doses of irradiation alone produce the same adverse reactions as hydroxyurea; combined therapy may cause an increase in the incidence and severity of these side effects.
Although inflammation of the mucous membranes at the irradiated site (mucositis) is attributed to irradiation alone, some investigators believe that the more severe cases are due to combination therapy.
Drug Interactions
Live vaccines, chloramphenicol.
Storage
Store at room temperature; avoid excessive heat. Keep tightly closed.
ATC Classification
L01XX05 - hydroxycarbamide ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Cap 500 mg x 100's.
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