Information for the Patient
Hydrea
Pharmacology
Absorption: 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 area under the plasma concentration-time curve (AUC) are observed. There are no data on the effect of food on the absorption of hydroxyurea.
Distribution: 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 erthrocytes. Hydroxyurea crosses the blood-brain barrier.
Metabolism: Up to 50% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. In one minor pathway, hydroxyurea may be degraded to acetohydroxamic acid by urease found in intestinal bacteria.
Excretion: Excretion of hydroxyurea in humans is a nonlinear process occurring through 2 pathways: one is saturable, probably hepatic metabolism; the other is first-order renal excretion. In patients with malignancies, renal elimination ranged from 25 to 55% of the administered dose. The concentration in the serum at 24 hours is negligible when the usual dose is given as a single daily dose.
Special Populations: No information is available regarding pharmacokinetic differences due to age, gender, or race.
Renal Insufficiency: Since renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage in this population. In adult patients with sickle cell disease, an open-label, non-randomized, single dose, multi-center study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal (creatinine clearance (CrCl) > 80 mL/min), mild (CrCl 50-80 mL/min), or severe (CrCl < 30 mL/min) renal impairment received hydroxyurea 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, the 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. (See Precautions and Dosage.)
Hepatic Insufficiency: There are no data that support specific guidance for dosage adjustment in patients with impaired hepatic function. (See also Dosage.)
Indications
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 HYDREA have been reported in melanoma and resistant chronic myelocytic leukemia.
Precautions
Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed.
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.
The effect of HYDREA on driving and operating machinery has not been studied. Since HYDREA may cause drowsiness and other neurologic effects (see Adverse Effects, Neurologic), alertness may be impaired.
Hydroxyurea is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydroxyurea, breast-feeding should be discontinued.
Safety and effectiveness of HYDREA in children have not been established.
Patients should be informed to maintain adequate fluid intake. The physician should be consulted regarding missed doses.
Supplied
Each capsule with opaque green cap and opaque pink body, printed with BMS 303 in black ink on both body and cap, 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 (15 to 30°C). Protect from excessive heat and moisture.
Contraindications
In patients with marked bone marrow depression, i.e., leukopenia (<2500 WBC/mm3) or thrombocytopenia (<100 000/mm3), or severe anemia; or in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.
Warnings
Elderly patients may be more sensitive to the effects of HYDREA and may require a lower dose regimen.
Fatal and nonfatal pancreatitis has occurred in HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other retroviral 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 (see Adverse Effects).
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 and alternative cytoreductive agents should be initiated as indicated (see Adverse Effects, Dermatologic).
Hydroxyurea is unequivocally genotoxic and a presumed transpecies carcinogen which implies a carcinogenic risk to humans. 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. Skin cancer has also been reported in patients receiving long-term hydroxyurea.
Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, rats, hamsters, rabbits, cats, miniature swine, dogs, and monkeys. The spectrum of effects following prenatal exposure to hydroxyurea includes embryo-fetal death, numerous fetal malformations of the viscera and skeleton, growth retardation, and functional deficits.
HYDREA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If HYDREA is used during pregnancy or if the patient becomes pregnant while on HYDREA therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking HYDREA.
HYDREA should not be used to treat males contemplating conception.
Adverse Effects
Elevated serum uric acid, BUN, and creatinine levels; rare instances of dysuria. Abnormal BSP retention has been reported.
Fever, chills, malaise, asthenia, and elevation of hepatic enzymes; rare instances of acute pulmonary reactions (diffuse pulmonary infiltrates/fibrosis, and dyspnea). Fatal and nonfatal pancreatitis 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 indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3 (see Warnings).
Stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation.
Adverse reactions observed with combined hydroxyurea and irradiation therapy were similar to those reported with the use of HYDREA alone, primarily bone marrow depression (leukopenia and anemia), and gastric irritation. Nearly all patients receiving an adequate course of combined HYDREA and irradiation therapy will develop leukopenia. Decreased platelet counts (<100 000 cells/mm3) have occurred rarely and usually in the presence of marked leukopenia. HYDREA may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.
Bone marrow depression (leukopenia, anemia, and occasionally thrombocytopenia) (see Warnings).
Drowsiness, rare instances of headache, dizziness, disorientation, hallucinations, and convulsions. Their relationship to hydroxyurea administration is questionable because cerebral metastatic disease was not excluded.
Maculopapular rash, facial erythema, peripheral erythema, skin ulceration and dermatomyositis-like skin changes. 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.
Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vaxculitic toxicities were reported most often in patients with a history of or currently receiving interferon therapy (see Warnings).
Overdose
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.
Dosage
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.
Solid Tumors: Intermittent Therapy: 80 mg/kg administered orally as a single dose every third day.
This intermittent dosage schedule may offer the advantage of reduced toxicity over daily therapy (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 HYDREA 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: Continuous Therapy: 20 to 30 mg/kg administered orally as a single daily dose.
An adequate trial period for determining the effectiveness of HYDREA 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 2500/mm3, or the platelet count below 100 000/mm3. 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 HYDREA and irradiation therapy, irradiation may also be interrupted. Anemia, even if severe can be managed without interrupting HYDREA therapy.
HYDREA should be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic drugs (see Warnings and Adverse Effects).
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, HYDREA 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 interruption of HYDREA administration.
Dosage Adjustment: Concurrent use of HYDREA with other myelosuppressive agents may require adjustments of dosages.
Renal Insufficiency: There are no data that support specific guidance for dosage adjustment in patients with impaired renal function. Since renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage in this population. Close monitoring of hematologic parameters is advised.
Hepatic Insufficiency: There are no data that support specific guidance for dosage adjustment in patients with impaired hepatic function. Close monitoring of hematologic parameters is advised.
Instructions for Use, Handling and Disposal: 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 to Be Provided to the Patient). Some inert material used as a vehicle in the capsule may not dissolve and may 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. People who are not taking HYDREA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling HYDREA or bottles containing HYDREA. Anyone handling HYDREA should wash their hands before and after contact with the bottle or capsules.
If the powder is spilled, it should be immediately wiped up with a damp disposable towel and discarded in a closed container, such as a plastic bag, as should the empty capsules. Hydroxyurea should be kept away from children and pets.
To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing HYDREA capsules. This includes handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.
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.
