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.

Capsule, 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.

The treatment of chronic myeloid leukaemia.

The treatment of cancer of the cervix 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 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 20-30 mg/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 80 mg/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.

Children

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

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.

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

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 (see section 4.5).

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.

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 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. (see section 4.4).

Studies have shown that there is an analytical interference of hydroxycarbamide with the enzymes (urease, uricase, and lactic dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxycarbamide.

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.

Hydrea 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.

Not applicable.

The exact frequency of undesirable effects is not known.

Haemolytic disorders are the most serious side effects of Hydroxycarbamide.

Bone-marrow suppression is the major toxic effect, while leucopenia, thrombocytopenia and anaemia may occur in that order.

The following side effects have been reported, these are generally rare.

Neurological disorders

Disorientations, hallucinations, convulsions, dizziness, headache, drowsiness, malaise and asthenia.

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.

Respiratory disorders

Pulmonary oedema

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

Gastrointestinal disorders

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

Hepatobiliary disorders

Elevation of hepatic enzymes have been reported.

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.

Genitourinary disorders

Dysuria and impairment of renal tubular function accompanied by elevation in serum uric acid, blood urea nitrogen (BUN), and creatinine levels.

General disorders

Anorexia, fever and chills.

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 (see sections 4.4 and 4.5).

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,

Titanium dioxide (E71),

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.

100 capsules may be packaged in any of the following: PVC/PVDC blisters or PVC/aluminium blisters.

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. Pregnant women should not handle Hydrea.

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. Local guidelines on handling cytotoxics should always be followed.

E.R. Squibb & Sons Limited

Uxbridge Business Park

Sanderson Road

Uxbridge

Middlesex

UB8 1DH

PL 0034/5044R

29 May 1986 / 17 December 2002

03 October 2011

POM