HYDREA (hydroxyurea) capsules
HYDREA (hydroxyurea capsules, USP) is an antimetabolite available for oral use as capsules containing 500 mg hydroxyurea. Inactive ingredients include citric acid, colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, and D&C Red No. 28), gelatin, lactose, magnesium stearate, sodium phosphate, and titanium dioxide.
Hydroxyurea is a white to off-white crystalline powder. It is hygroscopic and freely soluble in water, but practically insoluble in alcohol. The empirical formula is CH4N2O2 and it has a molecular weight of 76.05.
Indications and usage
HYDREA is indicated for the treatment of:
- Resistant chronic myeloid leukemia.
- Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation.
Mechanism of Action
The precise mechanism by which 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 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 may induce teratogenic effects.
Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or preDNA 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; RNA and protein syntheses have shown no alteration.
Absorption: Following oral administration of HYDREA, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose.
There are no data on the effect of food on the absorption of hydroxyurea.
Distribution: Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water.
Hydroxyurea concentrates in leukocytes and erythrocytes.
Metabolism: Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria.
Excretion: In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.
Capsules: 500 mg opaque green cap and opaque pink body imprinted with “HYDREA” and “830”.
HYDREA is used alone or in conjunction with other antitumor agents or radiation therapy to treat neoplastic diseases. Individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards.
Base all dosage on the patient’s actual or ideal weight, whichever is less.
HYDREA is a cytotoxic drug. Follow applicable special handling and disposal procedures
Swallow HYDREA capsules whole. Do NOT open, break, or chew capsules because HYDREA is a cytotoxic drug.
Prophylactic administration of folic acid is recommended
Monitor blood counts at least once a week during HYDREA therapy. Severe anemia must be corrected before initiating therapy with HYDREA
HYDREA is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of the formulation.
Warnings and precautions
Myelosuppression: Hydroxyurea causes severe myelosuppression. Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed. 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. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; use hydroxyurea cautiously in such patients.
Malignancies: Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, secondary leukemia has been reported. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies.
Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, HYDREA can cause fetal harm when administered to a pregnant woman. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and discontinue HYDREA.
Live Vaccinations: Avoid use of live vaccine in patients taking HYDREA. Concomitant use of HYDREA with a live virus vaccine may potentiate the replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be suppressed by HYDREA. Vacc ination with live vaccines in a patient receiving HYDREA may result in severe infection. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.
Risks with Concomitant Use of Antiretroviral Drugs: Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine.
Radiation Recall: Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema. Monitor for skin erythema in patients who previously received radiation and manage symptomatically.
Macrocytosis: HYDREA may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended.
Pulmonary Toxicity: Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported in patients treated for myeloproliferative neoplasm. Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly. Discontinue HYDREA and manage with corticosteroids.
Laboratory Test Interference: Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea.
- Vasculitic toxicities
- Risks with concomitant use of antiretroviral drugs
- Radiation recall
- Pulmonary Toxicity
Use in specific populations
Pregnancy: HYDREA can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. There are no data with HYDREA use in pregnant women to inform a drug-associated risk. Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with HYDREA.
Lactation: Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions in a breastfed infant from hydroxyurea, including carcinogenicity, discontinue breastfeeding during treatment with HYDREA.
Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating HYDREA therapy.
Contraception: Females; HYDREA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during and after treatment with HYDREA for at least 6 months after therapy. Advise females to immediately report pregnancy.
Contraception: Males; HYDREA may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with HYDREA for at least 1 year after therapy
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: Elderly patients may be more sensitive to the effects of hydroxyurea and may require a lower dose regimen. Hydroxyurea is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Renal Impairment: The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min or in patients with end-stage renal disease (ESRD). Reduce dosage and closely monitor the hematologic parameters when HYDREA is to be administered to these patients.
Hepatic Impairment: There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
Acute mucocutaneous toxicity has been reported in patients receiving 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.
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Keep tightly closed.
Handling and Disposal
HYDREA is a cytotoxic drug. Follow applicable special handling and disposal procedures.
To decrease the risk of contact, advise caregivers to wear disposable gloves when handling HYDREA or bottles containing HYDREA. Wash hands with soap and water before and after contact with the bottle or capsules when handling HYDREA. Do not open HYDREA capsules. Avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs on the skin, wash affected area immediately and thoroughly with soap and water. If contact with crushed or opened capsules occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. If the powder from the capsule is spilled, immediately wipe it up with a damp disposable towel and discard in a closed container, such as a plastic bag; as should the empty capsules. The spill areas should then be cleaned three times using a detergent solution followed by clean water. Keep the medication away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules.