Hydroxyurea Information
Hydroxyurea (Hydroxyurea)
Hydroxyurea (Hydroxyurea) Description
Hydroxyurea (Hydroxyurea) Capsules USP, is an antineoplastic agent available for oral use as capsules providing 500 mg Hydroxyurea (Hydroxyurea) . Inactive ingredients: colloidal silicon dioxide, colorants (D&C Yellow No. 10, FD&C Blue No. 1 and FD&C Red No. 40), gelatin, magnesium stearate and titanium dioxide. Imprinting ink constituents: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, pharmaceutical glaze, pharmaceutical shellac, propylene glycol, polyvinylpyrrolidone, sodium hydroxide, synthetic black iron oxide and titanium dioxide.
Hydroxyurea (Hydroxyurea) is an essentially tasteless, white crystalline powder. Its structural formula is:
Hydroxyurea (Hydroxyurea) Clinical Pharmacology
The precise mechanism by which Hydroxyurea (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 (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 (Hydroxyurea) may induce teratogenic effects.
Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of Hydroxyurea (Hydroxyurea) therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. studies utilizing Chinese hamster cells suggest that Hydroxyurea (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 susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of studies of HeLa cells: it appears that Hydroxyurea (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.
Absorption
There are no data on the effect of food on the absorption of Hydroxyurea (Hydroxyurea) .
Distribution
Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea (Hydroxyurea) concentrates in leukocytes and erythrocytes.
Metabolism
Excretion
Geriatric, Gender, Race
Pediatric
Renal Insufficiency
Hepatic Insufficiency
Drug Interactions
Hydroxyurea (Hydroxyurea) Animal Pharmacology And/or Toxicology
The oral LD of Hydroxyurea (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 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 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 to 800 mg/kg/day for 7 to 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.
Hydroxyurea (Hydroxyurea) Indications And Usage
Significant tumor response to Hydroxyurea (Hydroxyurea) capsules, USP has been demonstrated in melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary.
Hydroxyurea (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 (Hydroxyurea) Contraindications
Hydroxyurea (Hydroxyurea) is contraindicated in patients with marked bone marrow depression, i.e., leukopenia (
Hydroxyurea (Hydroxyurea) is contraindicated in patients who have demonstrated a previous hypersensitivity to Hydroxyurea (Hydroxyurea) or any other component of its formulation.
Hydroxyurea (Hydroxyurea) Warnings
Treatment with Hydroxyurea (Hydroxyurea) should not be initiated if bone marrow function is markedly depressed (see ). 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 (Hydroxyurea) should 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 (Hydroxyurea) and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hepatotoxicity and hepatic failure resulting in death have been reported during post-marketing surveillance in HIV- infected patients treated with Hydroxyurea (Hydroxyurea) and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of Hydroxyurea (Hydroxyurea) , didanosine, and stavudine. This combination should be avoided.
Severe anemia must be corrected before initiating therapy with Hydroxyurea (Hydroxyurea) .
Erythrocytic abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course of Hydroxyurea (Hydroxyurea) therapy. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. Hydroxyurea (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 (Hydroxyurea) , and may require a lower dose regimen (see ).
In patients receiving long-term Hydroxyurea (Hydroxyurea) for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to Hydroxyurea (Hydroxyurea) 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 (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 reported in patients with myeloproliferative disease, Hydroxyurea (Hydroxyurea) should be discontinued if cutaneous vasculitic ulcerations develop and alternative cytoreductive agents should be initiated as indicated.
Hydroxyurea (Hydroxyurea) Precautions
Therapy with Hydroxyurea (Hydroxyurea) requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during, treatment. The determination of the hemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of Hydroxyurea (Hydroxyurea) therapy. If the white blood cell count decreases to less than 2500/mm,or the platelet count to less than 100,000/mm, therapy should be interrupted until the values rise significantly toward normal levels. Severe anemia, if it occurs, should be managed without interrupting Hydroxyurea (Hydroxyurea) therapy.
Hydroxyurea (Hydroxyurea) should be used with caution in patients with marked renal dysfunction. (See ; ).
Hydroxyurea (Hydroxyurea) is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with Hydroxyurea (Hydroxyurea) , and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis and hepatotoxicity is recommended. Patients who develop signs and symptoms of pancreatitis or hepatotoxicity should permanently discontinue therapy with Hydroxyurea (Hydroxyurea) . (See and .) An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with Hydroxyurea (Hydroxyurea) , and in particular, in combination with didanosine and stavudine. This combination should be avoided.
Hydroxyurea (Hydroxyurea) Adverse Reactions
Reported adverse reactions are bone marrow depression (leukopenia, anemia, and thrombocytopenia), gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis -like skin changes, peripheral and facial erythema. 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 (Hydroxyurea) . Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with Hydroxyurea (Hydroxyurea) . These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy (see ).Dysuria and alopecia have been reported. Large doses may produce moderate drowsiness. Neurological disturbances have occurred and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea (Hydroxyurea) capsules, USP may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels. Abnormal BSP retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported.
Adverse reactions observed with combined Hydroxyurea (Hydroxyurea) and irradiation therapy are similar to those reported with the use of Hydroxyurea (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 (Hydroxyurea) and irradiation therapy will demonstrate concurrent leukopenia. Platelet depression (
The association of Hydroxyurea (Hydroxyurea) with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported. Pulmonary fibrosis also has been reported.
In HIV-infected patients who received Hydroxyurea (Hydroxyurea) in combination with antiretroviral agents, in particular, didanosine plus stavudine, fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported. Patients treated with Hydroxyurea (Hydroxyurea) in combination with didanosine, stavudine, and indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm. (See and .)
Hydroxyurea (Hydroxyurea) Overdosage
Acute mucocutaneous toxicity has been reported in patients receiving Hydroxyurea (Hydroxyurea) at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have also been observed.
Hydroxyurea (Hydroxyurea) Dosage And Administration
Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published.
To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea (Hydroxyurea) capsules. Hydroxyurea (Hydroxyurea) capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below.
Because of the rarity of melanoma, resistant chronic myelocytic leukemia, carcinoma of the ovary, and carcinomas of the head and neck in pediatric patients, dosage regimens have not been established.
All dosage should be based on the patient's actual or ideal weight, whichever is less. Concurrent use of Hydroxyurea (Hydroxyurea) with other myelosuppresive agents may require adjustment of dosages.
Hydroxyurea (Hydroxyurea) Solid Tumors
Administration of Hydroxyurea (Hydroxyurea) should begin at least seven 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 evidences no unusual or severe reactions.
Hydroxyurea (Hydroxyurea) Resistant Chronic Myelocytic Leukemia
Until the intermittent therapy regimen has been evaluated, CONTINUOUS therapy (20 to 30 mg/kg administered orally as a ) is recommended.
An adequate trial period for determining the antineoplastic effectiveness of Hydroxyurea (Hydroxyurea) is six weeks of therapy. When there is regression in tumor size or arrest in tumor growth, therapy should be continued indefinitely. Therapy should be interrupted if the white blood cell count drops below 2500/mm or the platelet count below 100,000/mm. In these cases, the counts should be re-evaluated 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 prompt rebound has not occurred during combined Hydroxyurea (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. Severe anemia, if it occurs, should be corrected without interrupting Hydroxyurea (Hydroxyurea) therapy. Because hematopoiesis may be compromised by extensive irradiation or by other antineoplastic agents, it is recommended that Hydroxyurea (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 (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, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by temporary interruption of Hydroxyurea (Hydroxyurea) administration.
Hydroxyurea (Hydroxyurea) How Supplied
Hydroxyurea (Hydroxyurea) capsules USP 500 mg are dark green opaque (cap) printed “724” in white ink/pink opaque (body) printed “par” in black ink capsules.They are supplied in unit dose packages of 100 (10 x 10) NDC 68084-284-01.
Dispense in a tight container as defined in the USP.
Hydroxyurea (Hydroxyurea) References
Manufactured by: Spring Valley, NY 10977
Repackaged by: Columbus, Ohio 43217
8228401/0511
Hydroxyurea (Hydroxyurea) Principal Display Panel Mg Capsules
