Bristol-Myers Squibb Pharmaceutical Limited

Hydrea 500 mg Hard Capsules

Each capsules contains 500 mg of Hydroxycarbamide.

Excipients: Contains Lactose Monohydrate 42.2 mg

For a full list of excipients, see Section 6.1.

Capsules hard.

Size 0 hard gelatin capsule with an opaque pink body and an opaque green cap, containing a white homogeneous powder. Printed with 'BMS 303' in black ink.

In the management of malignant neoplastic disease including chronic myeloid leukaemia. It is also indicated for treatment of cancer of the cervix and other solid type tumours in conjunction with radiotherapy.

Adults:

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 solid type tumours.

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 2.5x10⁹/L 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.

Elderly:

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.

Children:

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

Marked leucopenia (<2.5WBCx10⁹/L), thrombocytopenia (<100x10⁹/L), or severe anaemia and previously shown hypersensitivity to Hydrea. Use in non-malignant disease.

Hydroxycarbamide should only be administered under the direction of a specialist oncology service having the facilities for regular monitoring of clinical biochemical and haematological effects during and after administration.

Hydroxycarbamide should be used with caution in patients with renal dysfunction.

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.

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.

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 patients' underlying disease.

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. 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, hydroxycarbamide should be discontinued if cutaneous vasculitic ulcerations develop and alternative cytoreductive agents should be initiated as indicated.

Hydroxycarbamide has been shown to be carcinogenic in animals. The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

This product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

The myelosuppressive activity may be potentiated by previous or concomitant radiotherapy or cytotoxic therapy. Fatal and non-fatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxycarbamide in combination with antiretroviral agents, in particular didanosine plus stavudine. Patients treated with hydroxycarbamide in combination with didanosine, stavudine, and indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm³.

Drugs which affect DNA synthesis, such as hydroxycarbamide, may be potent mutagenic agents. The physician should carefully consider this possibility before administering this drug to male or female patients who may contemplate conception. Since Hydrea is a cytotoxic agent it has produced a teratogenic effect in some animal species. In rats and dogs, high doses of hydroxycarbamide reduced sperm production. Hydroxycarbamide is excreted in human breast milk.

This product should not normally be administered to patients who are pregnant, or to mothers who are breast feeding, unless the potential benefits outweigh the possible hazards.

When appropriate both male and female patients should be counselled concerning the use of contraceptive measures before and during treatment with Hydrea.

Hydroxycarbamide may cause drowsiness. Patients receiving it should not drive or operate machinery unless it has been shown not to affect physical or mental ability.

The exact frequency of undesirable effects is not known.

Haemolytic disorders

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.

Respiratory disorders

Pulmonary oedema

Acute pulmonary reactions consisting of diffuse pulmonary infiltrates/fibrosis, and dyspnoea have been rarely reported.

Vascular disorders

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. These vasculitic toxicities were reported most often in patients with a history of or currently receiving interferon therapy.

Gastrointestinal disorders

Nausea, vomiting, diarrhoea, constipation, melaena, abdominal pain, stomatitis

Genitourinary disorders

Dysuria and impairment of renal tubular function accompanied by elevation in serum uric acid, BUN, and creatinine levels.

Skin and epithelial disorders

Alopecia, skin rash, skin ulceration, skin cancer has also been rarely reported.

Erythema and the potentiation of the erythema caused by irradiation.

In some patients, hyperpigmentation, atrophy of skin and nails, scaling, violet papules and alopecia have been observed following several years of long-term daily maintenance therapy with hydroxycarbamide.

Neurological disorders

Disorientations, hallucinations, dizziness,

General disorders

Anorexia, convulsions, fever, chills, headache, drowsiness, malaise, asthenia and elevation of hepatic enzymes have been reported.

Immediate treatment consists of gastric lavage, followed by supportive therapy for the cardiorespiratory systems if required. In the long term, careful monitoring of the haemopoietic system is essential and, if necessary, blood should be transfused.

Acute mucocutaneous toxicity has been reported in patients receiving hydroxycarbamide at a dosage several times greater than that recommended. Soreness, violet erythema, oedema on palms and foot soles followed by scaling of hands and feet, intense generalised hyperpigmentation of skin, and severe acute stomatitis were observed.

ATC Code L01XX05

Hydroxycarbamide is an orally active antineoplastic agent. Although the mechanism of action has not yet been clearly defined, hydroxycarbamide appears to act by interfering with synthesis of DNA.

After oral administration hydroxycarbamide is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached in 2 hours; by 24 hours the serum concentrations are virtually zero. Approximately 80% of an oral or intravenous dose of 7 to 30 mg/kg may be recovered from the urine within 12 hours. Hydroxycarbamide crosses the blood-brain barrier. Hydroxycarbamide is well distributed throughout the body.

No further relevant data.

Citric acid, anhydrous

Lactose monohydrate,

Magnesium stearate,

Sodium phosphate,

Gelatin capsules contain:

Erythrosine (E127),

Indigotine (E132),

Yellow iron oxide (E172),

Titanium dioxide (E171),

Sodium laurilsulfate,

Opacode S-1-8100.

Not applicable.

2 years

Do not store above 25°C. Keep in the outer container in order to protect from moisture.

Carton containing 100 capsules in blisters consisting of PVC/PCTFE/PVC and sealed with aluminium foil with PVC/PVDC backing

People who are not taking Hydrea should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling Hydrea. Anyone handling Hydrea should wash their hands before and after contact with the capsules.

To minimise the risk of dermal exposure, always wear impervious gloves when handling capsules containing Hydrea. 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.

Bristol-Myers Squibb Pharmaceuticals Ltd.,

Swords,

County Dublin.

PA 2/27/1

Date of first authoriation: 01 April 1979

Date of renewal: 01 April 2009

February 2010