Droxia (Hydroxyurea) - Warnings and Precautions

WARNINGS

DROXIA is a cytotoxic and myelosuppressive agent. DROXIA should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm³; a platelet count below 80,000/mm³; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm³ when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. (See DOSAGE AND ADMINISTRATION.) Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

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 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 without stavudine.

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 reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop.

Carcinogenesis and Mutagenesis

(See BOXED WARNING.)

Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term 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 or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.

Conventional long-term studies to evaluate the carcinogenic potential of DROXIA have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m² basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is 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 tumorigenic phenotype.

Pregnancy

DROXIA 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, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m² basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence 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. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses 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.

PRECAUTIONS

General

Therapy with DROXIA requires close supervision. Some patients treated at the recommended initial dose of 15 mg/kg/day have experienced severe or life-threatening myelosuppression, requiring interruption of treatment and dose reduction. The hematologic status of the patient, as well as kidney and liver function should be determined prior to, and repeatedly during treatment. Treatment should be interrupted if neutrophil levels fall to <2000/mm³; platelets fall to <80,000/mm³; hemoglobin declines to less than 4.5 g/dL; or if reticulocytes fall below 80,000/mm³ when the hemoglobin concentration is below 9 g/dL. Following recovery, treatment may be resumed at lower doses (see DOSAGE AND ADMINISTRATION).

Hydroxyurea should be used with caution in patients with renal dysfunction. Data from a single-dose study of the pharmacokinetics of hydroxyurea in patients with sickle cell anemia suggest that the initial dose of hydroxyurea should be reduced in patients with renal impairment. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.)

Patients must be able to follow directions regarding drug administration and their monitoring and care.

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. (See WARNINGS and ADVERSE REACTIONS.)

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS and BOXED WARNING for Carcinogenesis and Mutagenesis information.

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

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 either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Drug Interactions

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

Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate 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

(See Patient Information at end of labeling.)

Patients should be reminded that this medication must be handled with care. People who are not taking DROXIA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling DROXIA or bottles containing DROXIA. Anyone handling DROXIA 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.

The necessity of monitoring blood counts every two weeks, throughout the duration of therapy, should be emphasized. For additional information, see the accompanying Patient Information leaflet.