Drug Class Description
DNA reactive cytotoxics.

Generic Name
Hydroxyurea [hydroxycarbamide]

Drug Description
Pink, opaque capsule body with green, opaque cap, printed in black with 'BMS 303' containing 500 mg of hydroxycarbamide.

Presentation
Hard Gelatin Capsule

Indications
The treatment of chronic myeloid leukaemia.The treatment of cancer of the cervix in conjunction with radiotherapy.

Adult Dosage
Treatment regimens can be continuous or intermittent. The continuous regimen is particularly suitable for chronic myeloid leukaemia, while the intermittent regimen, with its diminished effect on the bone marrow, is more satisfactory for the management of cancer of the cervix.Hydrea should be started 7 days before concurrent irradiation therapy. If Hydrea is used concomitantly with radiotherapy, adjustment of radiation dosage is not usually necessary.An adequate trial period for determining the antineoplastic effect of Hydrea is six weeks. Where there is a significant clinical response therapy may be continued indefinitely, provided that the patient is kept under adequate observation and shows no unusual or severe reactions. Therapy should be interrupted if the white cell count drops below 2.5x109L or the platelet count below 100x109/L.Continuous therapy:Hydrea 20-30mg/kg should be given daily in single doses. Dosage should be based on the patient's actual or ideal weight, whichever is the less. Therapy should be monitored by repeat blood counts.Intermittent therapy:Hydrea 80mg/kg in single doses should be given every third day. Using the intermittent regimes the likelihood of WBC depression is diminished, but if low counts are produced, 1 or more doses of Hydrea should be omitted.Concurrent use of Hydrea with other myelosuppressive agents may require adjustments of dosages.

Child Dosage
Because of the rarity of these conditions in children, dosage regimens have not been established.

Elderly Dosage
Elderly patients may be more sensitive to the effects of hydroxycarbamide, and may require a lower dosage regimen.NB: 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. The contents of capsules should not be inhaled or allowed to come into contact with the skin or mucous membranes. Spillages must be wiped immediately.

Contra Indications
Marked leucopenia (<2.5wbcx109/L), thrombocytopenia (< 100x109/L), or severe anaemia and those who have previously shown hypersensitivity to Hydrea.

Special Precautions
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 haemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxycarbamide therapy. If WBC falls below 2.5x109/L or platelet count to <100x109/L, therapy should be interrupted. Counts should be rechecked after 3 days and treatment resumed when they rise significantly towards normal.Severe anaemia must be corrected with whole blood replacement before initiating therapy with hydroxycarbamide. If, during treatment, anaemia occurs, correct without interrupting Hydrea therapy. Erythrocytic abnormalities; megaloblastic erythropoeisis, which is self-limiting, is often seen early in the course of hydroxycarbamide therapy. The morphologic change resembles pernicious anaemia, but is not related to vitamin B12 or folic acid deficiency. Hydroxycarbamide 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.Hydroxycarbamide should be used with caution in patients with marked renal dysfunction.Hydroxycarbamide is not licensed for use in combination with antiretroviral agents for HIV disease and it may cause treatment failure and toxicities (in some cases fatal) in HIV patients.In patients receiving long-term therapy with hydroxycarbamide for myeloproliferative disorders, such as polycythemia, secondary leukaemia has been reported. It is unknown whether this leukaemogenic effect is secondary to hydroxycarbamide or associated with the patient's underlying disease.Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy. The digital distribution of these vasculitic ulcerations and progressive clinical behaviour of peripheral vasculitic insufficiency leading to digital infarct or gangrene were distinctly different than the typical skin ulcers generally described with Hydroxycarbamide. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued if cutaneous vasculitic ulcerations develop and alternative cytoreductive agents should be initiated as indicated.The possibility of an increase in serum uric acid, resulting in the development of gout or, at worst, uric acid nephropathy, should be borne in mind in patients treated with hydroxycarbamide , especially when used with other cytotoxic agents. It is therefore important to monitor uric acid levels regularly and maintain a high fluid intake during treatment.

Interactions
The myelosuppressive activity may be potentiated by previous or concomitant radiotherapy or cytotoxic therapy. Fatal and non-fatal pancreatitis has occurred in HIV-infected patients during therapy with hydroxycarbamide and didanosine, with or without stavudine.Hepatotoxicity and hepatic failure resulting in death were reported during post-marketing surveillance in HIV-infected patients treated with hydroxycarbamide and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxycarbamide, didanosine and stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxycarbamide in combination with antiretroviral agents, including didanosine, with or without stavudine.

Adverse Reactions
Bone-marrow suppression is the major toxic effect of Hydrea, while leucopenia, thrombocytopenia and anaemia may occur in that order. Other side-effects are generally rare, but the following have been reported; anorexia, nausea, vomiting, diarrhoea, constipation, headache, drowsiness, dizziness, stomatitis, alopecia, skin rash, melaena, abdominal pain, disorientations, pulmonary oedema, hallucinations, convulsions, potentiation of the erythema caused by irradiation, skin ulceration, dysuria and impairment of renal tubular function accompanied by elevation in serum uric acid, blood urea nitrogen, and creatinine levels. Fever, chills, malaise, asthenia and elevation of hepatic enzymes have been reported. Acute pulmonary reactions consisting of diffuse pulmonary infiltrates/fibrosis, and dyspnoea have been rarely reported. Skin cancer has also been rarely reported.Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy.Cases of pancreatitis and hepatotoxicity (some with fatal outcomes) and severe peripheral neuropathy have been observed in HIV patients when hydroxycarbamide was administered with antiretroviral agents.In some patients, hyperpigmentation, erythema, atrophy of skin and nails, scaling, violet papules and alopecia have been observed following several years of long-term daily maintenance therapy with hydroxycarbamide.

Manufacturer
E. R. Squibb & Sons Limited

Drug Availability
(POM)

Updated
15 May 2009