COMPOSITION Each capsule contains 500 mg hydroxyurea.
PHARMACOLOGICAL CLASSIFICATION Category A 26 Cytostatic agents.
PHARMACOLOGICAL ACTION The precise mechanism by which hydroxyurea produces its antineoplastic effects is not known. Various studies in tissue culture, rats, and humans support 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 protein.
Three mechanisms have been postulated for the potentiation of the therapeutic effect of irradiation by hydroxyurea 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 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 Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached after 1-4 hours. There are no data on the effect of food on the absorption of hydroxyurea.
Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body. Hydroxyurea concentrates in leukocytes and erythrocytes. Hydroxyurea crosses the blood-brain-barrier.
Elimination of hydroxyurea in humans is a non-linear process occurring through two pathways: hepatic metabolism and renal excretion. In patients with malignancies, renal elimination ranged from 25-55% 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.
INDICATIONS HYDREA is intended for use as an antineoplastic agent in the treatment of malignant neoplastic disease, recurrent disease or metastatic disease, chronic myeloid leukaemia and tumours of the head and neck. Sarcomas responded to HYDREA in some cases.
CONTRA-INDICATIONS HYDREA is contraindicated in patients who have demonstrated a previous hypersensivity to hydroxyurea or any other component of its formulation.
Hydroxyurea is contraindicated in patients with bone marrow depression, i.e., leukopenia (<2500 WBC/mm3) or thrombocytopenia (<100,000/mm3), or severe anemia.
WARNINGS Treatment with hydroxyurea should not be initiated if bone marrow function is depressed (See CONTRAINDICATIONS). 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 should be used cautiously in such patients.
Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema.
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 pernicious anemia but is not related to vitamin B12 or folic acid deficiency. The macrocytosis may mask the incidental development of folic acid or vitamin B12 deficiency, thus prophylactic administration of folic acid and vitamin B12 may be warranted. Hydroxyurea may also delay plasma iron clearance and reduce the rate of iron utilization by erythrocytes, but it does not appear to alter the erythrocyte survival time.
Hydroxyurea should be used with caution in patients with marked renal dysfunction. (See DOSAGE AND DIRECTIONS FOR USE)
Elderly patients may be more sensitive to the effects of hydroxyurea and may require a lower dose regimen. Carcinogenesis, mutagenesis, impairment of fertility: 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 thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukomogenic effect is secondary to hydroxyurea or associated with the patients' underlying disease. Skin cancer has also been reported in patients receiving long term hydroxyurea. Pregnancy: Hydroxyurea can cause foetal harm when administered to a pregnant woman and has been demonstrated to be a potent teratogen in a wide variety of animal models. 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 on hydroxyurea therapy, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking HYDREA. Other 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. 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. Hydroxyurea is not intended for the treatment of HIVinfection; 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 and hepatotoxicity is recommended. Patients who develop signs and symptoms of pancreatitis or hepatotoxicity should permanently discontinue therapy with hydroxyurea.
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. Some inert material used as a vehicle in the capsule may not dissolve and float on the surface.
Patients who take the medicine 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 disposable towel and discarded in a closed container, such as a plastic bag as should the empty capsules. HYDREA should be kept away from children and pets.
Procedures for proper handling and disposal of anticancer agents 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.
DOSAGE AND DIRECTIONS FOR USE All hydroxyurea dosage regimens should be based on the patient's actual or ideal weight, whichever is less.
Concurrent use of hydroxyurea 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.
NOTE: 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 "INSTRUCTIONS FOR HANDLING"
Intermittent Therapy 80 mg/kg administered orally as a single dose every third day Continuous Therapy 20 to 30 mg/kg administered orally as a single dose daily
The intermittent dosage schedule offers the advantage of reduced toxicity (e.g., bone marrow depression). Patients on this dosage regimen have rarely required complete discontinuance of therapy because of toxicity. Concomitant Therapy with Irradiation
(Carcinoma of the head, neck, and cervix) 80 mg/kg administered orally as a single dose every third day
Administration of HYDREA should begin at least seven days before initiation of irradiation and be continued during radiotherapy as well as indefinitely afterwards provided that the patient is kept under adequate observation and shows no unusual or severe reactions.
Irradiation should be given at the maximum dose considered appropriate for the particular therapeutic situation; adjustment of irradiation dosage is not usually necessary when HYDREA is used concomitantly.
RESISTANT CHRONIC MYELOCYTIC LEUKEMIA
Continuous therapy 20 to 30 mg/kg administered orally as a single dose daily.
An adequate trial period for determining the antineoplastic effectiveness of HYDREA is six weeks of therapy. When there is significant clinical response, 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 rechecked after three days and therapy resumed when the counts rise significantly toward normal values. Since the hematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If prompt rebound has not occurred during combined HYDREA 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. Anemia, if it occurs, should be corrected without interrupting HYDREA therapy.
Because hematopoiesis may be compromised by extensive irradiation or by other antineoplastic agents, it is recommended that HYDREA be administered cautiously to patients who have recently received extensive radiation therapy or chemotherapy with other cytotoxic medicines. (See WARNINGS)
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. 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 interruption of HYDREA administration; rarely has the additional interruption of irradiation been necessary.
Procedures for proper handling and disposal of anticancer drugs should be considered. DOSAGE CHART
BODY MASS KG
80mg/kg every 3 days as single doses
20 -30mg/kg daily as single daily doses
SIDE EFFECTS AND SPECIAL PRECAUTIONS When appropriate, patients should be counselled concerning the use of contraceptive measures during therapy. Medicines which effect DNA synthesis, such as hydroxyurea, may be potentially mutagenic, and this possibility should be considered before administering the medicine to male or female patients who may contemplate conception.
Secondary leukemia has been reported in patients receiving long-term hydroxyurea for myeloproliferative disorders. (see WARNINGS).
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 SIDE EFFECTS AND SPECIAL PRECAUTIONS).
Patients should be informed to maintain adequate fluid intake. The physician should be consulted regarding missed doses. Haematologic Bone marrow suppression (leukopenia, anaemia and thrombocytopenia). (See WARNINGS section). Gastrointestinal Stomatitis, anorexia, nausea, vomiting, diarrhoea, and constipation. Dermatologic 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 less frequently. Neurologic Drowsiness; less frequent instances of headache, dizziness, disorientation, hallucinations, and convulsions. Renal Elevated serum uric acid, serum ureum and creatinine levels; less frequent instances of dysuria. Other Fever, chills, malaise, asthenia, elevation of hepatic enzymes, less frequent 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).
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 (anemia and leukopenia), and gastric irritation. Nearly all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will develop leukopenia. Decreased platelet counts (<100,000/mm3) have occurred less frequently and usually in the presence of marked leukopenia. Hydroxyurea may potentiate some adverse reactions usually seen with radiation alone, such as gastric distress and mucositis.
Interactions 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.
Nursing Mothers Hydroxyurea is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydroxyurea, a decision should be made whether to discontinue nursing or to discontinue HYDREA, taking into account the importance of the medication to the mother. Safety in pregnant women has not been established.
Pediatric Use Safety and effectiveness in children have not been established.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Treatment of overdosage should be symptomatic and supportive.
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.
IDENTIFICATION Size "0" gelatin capsule, green opaque cap and pink opaque body, BMS 303 is imprinted on both cap and body of capsule.
PRESENTATION Bottles of 100 capsules.
STORAGE INSTRUCTIONS Store at room temperature not exceeding 25°C.
Avoid excessive heat. Keep tightly closed.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBERS H/2753 (Act 101 of 1965)
NAME AND BUSINESS ADDRESS OF APPLICANT BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road,
DATE OF PUBLICATION OF THIS PACKAGE INSERT 8 May 2001
*Authorised user of the TM HYDREA
Updated on this site: October 2001
Current: June 2005
Source: Pharmaceutical Industry