RxMed: Pharmaceutical Information – HYDREA

HYDREA®

Squibb

Hydroxyurea

Antineoplastic Agent

Action And Clinical Pharmacology: Neoplastic Disease. 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.

Potentiation of Irradiation Therapy: 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.

Pharmacokinetics: After oral administration in humans, hydroxyurea is readily absorbed from the gastrointestinal tract. The drug reaches peak serum concentrations within 2 hours; by 24 hours the concentration in the serum is essentially undetectable. Approximately 80% of an oral or i.v. dose of 7 to 30 mg/kg may be recovered in the urine within 12 hours. Hydroxyurea crosses the blood-brain barrier.

Indications And Clinical Uses: For concomitant use with irradiation therapy in the treatment of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.

Tumor responses to hydroxyurea have been reported in melanoma and resistant chronic myelocytic leukemia.

Contra-Indications: In patients with marked bone marrow depression, i.e., leukopenia (
Manufacturers’ Warnings In Clinical States: Hydroxyurea should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

Treatment with hydroxyurea should not be initiated if bone marrow function is depressed (see Contraindications). Hydroxyurea may produce bone marrow suppression; leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without a preceding leukopenia. The recovery from myelosuppression is rapid when hydroxyurea therapy is interrupted. 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 when hydroxyurea is given.

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 that seen in 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.

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

In patients receiving long-term therapy with 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 hydroxyurea or is associated with the patients’ underlying disease.

Pregnancy : Hydroxyurea is a known teratogen in animals. Malformations have been observed in the offspring of rabbits given doses equivalent to that of the maximum human dose, and in rats given doses equivalent to 3 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. If hydroxyurea 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.

Hydroxyurea should not be used to treat males contemplating conception.

Precautions: General: Secondary leukemia has been reported in patients receiving long-term hydroxyurea for myeloproliferative disorders (see Warnings).

Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential. Drugs which affect DNA synthesis, such as hydroxyurea, may be potentially mutagenic, and this possibility should be considered before administering the drug to male or female patients who may contemplate conception. In rats, hydroxyurea at high dosage levels produced aspermatogenesis. In dogs, reversible spermatogenic arrest was noted at high dose levels.

Children: Safety and effectiveness in children have not been established.

Pregnancy : Hydroxyurea is a known teratogen in animals. Malformations have been observed in the offspring of rabbits given doses equivalent to that of the maximum human dose, and in rats given doses equivalent to 3 times that of the maximum human dose. There are no adequate and well-controlled studies in pregnant women. If hydroxyurea 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.

Lactation : Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydroxyurea, breast-feeding should be discontinued.

Drug Interactions: Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events (see Warnings and Adverse Effects).

Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.

In vitro studies have shown a significant increase in cytarabine cytotoxic activity in hydroxyurea-treated cells. Whether this interaction will lead to synergistic toxicity in the clinical setting or the need to modify cytarabine doses has not been established.

Occupational Hazards: The effect of hydroxyurea on driving and operating machinery has not been studied. Since hydroxyurea may cause drowsiness and other neurologic effects (see Adverse Effects, Neurologic), alertness may be impaired.

Information for the Patient: Patients should be informed to maintain adequate fluid intake. The physician should be consulted regarding missed doses.

Adverse Reactions: Hematologic: bone marrow depression (leukopenia, anemia, and occasionally thrombocytopenia) (see Warnings).

Gastrointestinal: Stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation.

Dermatologic: Maculopapular rash, facial erythema, peripheral erythema, and skin ulceration. 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. Skin cancer has also been reported rarely.

Neurologic: Drowsiness, rare instances of headache, dizziness, disorientation, hallucinations, and convulsions. Their relationship to hydroxyurea administration is questionable because cerebral metastatic disease was not excluded.

Renal: Elevated serum uric acid, BUN, and creatinine levels; rare instances of dysuria. Abnormal BSP retention has been reported.

Other: Fever, chills, malaise, asthenia, and elevation of hepatic enzymes; rare instances of acute pulmonary reactions (diffuse pulmonary infiltrates/fibrosis, and dyspnea).

Combined Hydroxyurea and Irradiation Therapy: Adverse reactions observed with combined hydroxyurea and irradiation therapy were similar to those reported with the use of hydroxyurea alone, primarily bone marrow depression ( leukopenia and anemia), and gastric irritation. Nearly all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will develop leukopenia. Decreased platelet counts (
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at a dosage several times the therapeutic dose. Soreness, violet erythema, edema on palms and foot soles followed by scaling of hands and feet, severe generalized hyperpigmentation of skin, and stomatitis have also been observed. tag_DosageDosage

Dosage And Administration: Because of the rarity of carcinomas of the head and neck in children, dosage regimens have not been established.

Dosage regimens in the treatment of the neoplastic diseases should be based on the patient’s actual or ideal weight, whichever is less.

Dosage Adjustment: 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 third day.

This intermittent dosage schedule may offer the advantage over daily therapy of reduced toxicity (e.g., bone marrow depression).

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 be started at least 7 days before initiation of irradiation, and continued during radiotherapy and continue indefinitely thereafter, provided the patient is kept under adequate observation and exhibits no unusual or severe toxicity.

Resistant Chronic Myelocytic Leukemia: 20 to 30 mg/kg administered orally as a single daily dose.

An adequate trial period for determining the effectiveness of hydroxyurea is 6 weeks. 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 2 500/mm or the platelet count below 100 000/mm In these cases, the counts should be re-evaluated after 3 days, and therapy resumed when the counts return to acceptable levels. Hematopoietic rebound is usually rapid. If rapid rebound has not occurred during combined hydroxyurea and irradiation therapy, irradiation may also be interrupted. Anemia, even if severe can be managed without interrupting hydroxyurea therapy.

Hydroxyurea should 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 therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed.

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

Instructions for Handling: 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 (see Precautions, Information for Patients). Some inert material used as a vehicle in the capsule may not dissolve, and float on the surface.

Patients who take the drug by emptying the contents of the capsule into water should be reminded that this is a potent medication that must be handled with care. Patients must be cautioned not to allow the powder to come in contact with the skin and mucous membranes, including avoidance of inhaling the powder when opening the capsules. If the powder is spilled, it should be immediately wiped up with a damp towel and disposed of, as should the empty capsules. The medication, particularly the open capsules, should be kept away from children and pets.

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.

Availability And Storage: Each capsule contains: hydroxyurea 500 mg. Nonmedicinal ingredients: citric acid, dibasic sodium phosphate, lactose and magnesium stearate; capsule shell: FD&C blue No. 2 and red No. 3, gelatin, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. Bottles of 100. Store at room temperature. Protect from excessive heat and moisture. (Shown in Product Recognition Section)

HYDREA® Squibb Hydroxyurea Antineoplastic Agent