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Capsule: 500mg; opaque green and pink marked SQUIBB 303, size 0 capsule shell.
Inactive ingredients include; citric acid, lactose, magnesium stearate, sodium phosphate and capsule colorants.
The precise mechanism by which hydroxyurea produces its cytotoxic effects cannot, at present, be described. However, the reports of various studies in tissue culture, rats and man lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis 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 utilising Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radio-resistant 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 theorised 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 synthesis have shown no alteration.
After oral administration in man, hydroxyurea is readily absorbed from the gastrointestinal tract. The drug reaches peak serum concentrations within 2 hours. Approximately 80% of an oral or intravenous dose of 7 to 30 mg/kg may be recovered in the urine within 12 hours.
Hydroxyurea crosses the blood-brain barrier.
Significant tumour response to Hydrea (hydroxyurea) has been demonstrated in melanoma, resistant chronic myelocytic leukaemia, and recurrent metastatic or inoperable carcinoma of the ovary. Hydrea used concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip, and carcinoma of the cervix.
Because of the rarity of melanoma, resistant chronic myelocytic leukaemia, carcinoma of the ovary, and carcinomas of the head and neck in children, dosage regimens have not been established. All dosage 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.
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. 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. Hydrea should be kept away from children and pets.
80 mg/kg administered orally as a single dose every third day.
20 to 30 mg/kg administered orally as a single dose daily.
The intermittent dosage schedule offers the advantage of reduced toxicity since patients on this dosage regimen have rarely required complete discontinuance of therapy because of toxicity.
80 mg/kg administered orally as a single dose every third day.
Administration of Hydrea (hydroxyurea) should be begun at least seven days before initiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided that the patient may be kept under adequate observation and evidences 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.
20 to 30 mg/kg administered orally as a single dose daily is recommended.
An adequate trial period for determining the antineoplastic effectiveness of Hydrea is six weeks of therapy. When there is regression in tumour size or arrest in tumour growth, therapy should be continued indefinitely. Therapy should be interrupted if the white blood cell count drops below 2500/mm3, or the platelet count drops 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 haematopoietic rebound is prompt, it is usually necessary to omit only a few doses. If prompt rebound has not occurred during combined hydroxyurea 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. Anaemia, if it occurs, should be corrected with whole blood replacement, without interrupting hydroxyurea therapy. Because haematopoiesis 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 drugs.
Pain or discomfort from inflammation of the mucous membranes at the irradiated site (mucositis) it usually controlled by measures such as topical anaesthetics 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. 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 temporary interruption of Hydrea (hydroxyurea) administration; rarely has the additional interruption of irradiation been necessary.
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 haematologic parameters is advised.
There are no data that support specific guidance for dosage adjustment in patients with impaired hepatic function. Close monitoring of haematologic parameters is advised.
Hydrea is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.
Hydroxyurea is contraindicated in patients with marked bone marrow depression, i.e. leukopenia (< 2500 WBC/mm3) or thrombocytopenia (< 100,000/mm3), or severe anaemia.
Treatment with hydroxyurea should not be initiated if bone marrow function is markedly depressed (see Contraindications). Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anaemia occur less often, and are seldom seen without a preceding leukopenia. However, the recovery from the 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 post-irradiation erythema.
Severe anaemia must be corrected with whole blood replacement before initiating therapy with hydroxyurea.
Since hydroxyurea may cause drowsiness and other neurologic effects, alertness may be impaired in driving and operating machinery.
Patients should be advised to maintain adequate fluid intake. Patients should consult with their physician regarding missed doses.
Megaloblastic erythropoiesis, which is self-limiting is often seen early in the course of hydroxyurea therapy. The morphological change resembles pernicious anaemia, but is not related to Vitamin B12 or folic acid deficiency. Hydroxyurea may also delay plasma iron clearance and reduce the rate of iron utilisation 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.
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 thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or associated with the patients' underlying disease.
Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. Theses 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.
Hydroxyurea can cause foetal harm when administered to a pregnant woman and is a known teratogenic agent in animals. Malformations have been observed in the offspring of rabbits and rats given doses equivalent to one-third to twice the maximum human dose, respectively. 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 of the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydroxyurea, breastfeeding is not recommended during hydroxyurea therapy.
Safety and effectiveness in children have not been established.
When appropriate, patients should be counselled concerning the use of contraceptive measures during therapy. Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the level of bone marrow depression or other adverse reactions (see Warnings and Adverse Reactions).
Patients should be informed to maintain adequate fluid intake and to consult the physician regarding missed doses.
Therapy with hydroxyurea requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during treatment. The determination of the haemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxyurea therapy. If the white blood cell count decreases to less than 2500/mm3, or the platelet count to less than 100 000/mm3, therapy should be interrupted until the values rise significantly toward normal levels. Anaemia, if it occurs, should be managed with whole blood replacement, without interrupting hydroxyurea therapy.
The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single doses.
In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bone marrow hypoplasia as well as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred. In several animals hepatic cell damage with fatty metamorphosis was noted. In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels (140 to 420mg or 140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and haemosiderosis of the liver or spleen were found, reversible spermatogenic arrest was noted. In the higher, often lethal, doses (400 to 800 mg/kg/day for 7 to 15 days), haemorrhage and congestion were found in the lungs, brain, and urinary tract. Cardiovascular effects (change in heart rate, blood pressure, orthostatic hypotension, EKG changes) and haematological changes (slight haemolysis, slight methemoglobinemia) were observed in some species of laboratory animals at doses exceeding clinical levels.
Hydroxyurea is unequivocally genotoxic and a presumed transpecies carcinogen which implies a carcinogienic risk to humans. 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 the patients' underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.
Adverse reactions have been primarily bone marrow depression (leukopenia, anaemia, and occasionally thrombocytopenia). (see Warnings)
Adverse gastrointestinal symptoms include stomatitis, anorexia, nausea, vomiting, diarrhoea, and constipation.
Dermatologic reactions include maculopapular rash, facial erythema, and peripheral erythema, skin ulceration, dermatomyositis-like skin rashes. 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.
Large doses may produce moderate drowsiness. Neurological disturbances have occurred rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions.
Hydroxyurea occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and creatinine levels. Dysuria occurs rarely.
Fever, chills, malaise, asthenia, and elevation of hepatic enzymes have also been reported.
The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fibrosis, pulmonary oedema, fever, and dyspnoea has been rarely reported.
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 (See Warnings).
Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to those reported with the use of hydroxyurea alone. These effects primarily include bone marrow depression (anaemia and leukopenia), and gastric irritation. Almost all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will demonstrate concurrent leukopenia. Decreased platelet counts (<100,000/mm3) have occurred rarely and only in the presence of marked leukopenia. Gastric distress has also been reported with irradiation alone and in combination with hydroxyurea therapy.
It should be borne in mind that therapeutic doses of irradiation alone produce the same adverse reactions as hydroxyurea; combined therapy may cause an increase in the incidence and severity of these side effects.
Although inflammation of the mucous membranes at the irradiated site (mucositis) is attributed to irradiation alone, some investigators believe that the more severe cases are due to combination therapy.
Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events (see Warning and Precautions and Adverse Events).
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 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.
Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at a dosage several fold in excess of the usual recommended dosage. Soreness, violet erythema, edema on palms and foot soles followed by scaling of hands and feet, intense generalised hyperpigmentation of skin, and severe acute stomatitis were observed.
In the case of overdosage implement immediate gastric lavage, followed by supportive cardiorespiratory therapy. Long term monitoring of the haemopoietic system is necessary.
Store below 30°C; avoid excessive heat; keep bottle tightly closed. Dispense in air-tight containers.
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.
Guidelines for proper handling and disposal of anticancer drugs
To minimize the risk of dermal exposure, always wear impervious gloves when
handling bottles containing Hydrea capsules. This includes all 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.
Prescription Medicine.
Capsule, 500mg, 100s.
Medicines Group
Simpson Grierson Building
92-96 Albert St
AUCKLAND
New Zealand
March 2006