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1. NAME OF THE MEDICINAL PRODUCT
Hydrea 500 mg Hard Capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule
s contains 500 mg of Hydroxycarbamide.
Excipients
with known effect: Contains Lactose Monohydrate 42.2 mg
For
a the full list of excipients, see Section section 6.1.
3. PHARMACEUTICAL FORM
Capsule
s 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.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Posology
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 2.5x10
9/L or the platelet count below 100x109/L (see section 4.4).
In these cases, the counts should be reevaluated after three days and therapy resumed when the counts return to acceptable levels. Hematopoietic rebound is usually rapid. If rapid rebound has not occurred during combined Hydrea and irradiation therapy, irradiation may also be interrupted. Anaemia, even if severe, can be managed without interrupting Hydrea therapy.
Severe gastric distress, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by interruption of Hydrea administration.
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.
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.
Special Populations
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.
Renal Impairment
Since renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of Hydrea in this population.
Method of administration
For oral use.
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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Marked leucopenia (<2.5WBCx10
9/L), thrombocytopenia (<100x109/L), or severe anaemia and previously shown hypersensitivity to Hydrea. Use in non-malignant disease.
4.4 Special warnings and precautions for use
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.
If bone marrow function is depressed, treatment with Hydrea should not be initiated. 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.
Hydrea may produce bone marrow suppression; leukopenia is generally its first and most common manifestation. Thrombocytopenia and anaemia occur less often and are seldom seen without a preceding leukopenia. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer
chemotherapeutic agents; Hydrea should be used cautiously in such patients. The recovery from myelosuppression is rapid when Hydrea therapy is interrupted.
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 B
12 or folic acid deficiency. The macrocytosis may mask the incidental development of folic acid deficiency; thus, prophylactic administration of folic acid may be warranted. 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.
Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema when Hydrea is given.
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.
In patients receiving long-term
hydroxycarbamidehydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported; it is unknown whether this leukemogenic effect is secondary to hydroxycarbamidehydroxyurea or the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Patients should be advised to protect skin from sun exposure, conduct self-inspection of the skin and be screened for secondary malignancies during routine follow-up visits.
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.
4.5 Interaction with
other medicinal products and other forms of interaction
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.
This combination should be avoided. 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.
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.
4.6
Fertility, pPregnancy and lactation
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.
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 drug to the mother.
Hydrea can cause fetal harm when administered to a pregnant woman. This productHydrea
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.
4.8 Undesirable effects
The exact frequency of undesirable effects is not known.
Haemolytic disorders
Bone-marrow suppression is the major toxic effect of
hydroxycarbamideHydrea, 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. The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy.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.
Cases of fatal and non fatal pancreatitis and hepatotoxicity and severe peripheral neuropathy have been observed in HIV patients when hydroxycarbamide was administered with antiretroviral agents, in particular didanosine plus stavudine. Patients treated with hydroxycarbamide in combination with didanosine, stavudine and indinavir showed a median decline in CD4 cells of approximately 100/mm
3 (see sections 4.4 and 4.5).
Adverse reactions observed with combined Hydrea and irradiation therapy were similar to those reported with the use of Hydrea alone, primarily bone marrow depression (leukopenia and anaemia) and gastric irritation. Nearly all patients receiving an adequate course of combined Hydrea and irradiation therapy will develop leukopenia. Decreased platelet counts (<100,000/mm
3) have occurred rarely and usually in the presence of marked leukopenia. Hydrea may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.
The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100, < 1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data).
5.1 Pharmacodynamic properties
Pharmacotherapeutic group, other antineoplastic agents, 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.
5.3 Preclinical safety data
Hydroxycarbamide is unequivocally genotoxic and a presumed transpecies carcinogen which implies a carcinogenic risk to humansNo further relevant data.
6.4 Special precautions for storage
Do not store above 25°C. Keep in the outer containerStore in the original package in order to protect from moisture.
6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product
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. If the powder is spilled, it should be immediately wiped with a damp disposable towel and discarded in a closed container, such as a plastic bag, as should the empty 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. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF
THE AUTHORISATION
Date of first authorisation: 01 April 1979
Date of
latest renewal: 01 April 2009
10. DATE OF REVISION OF THE TEXT
August 2013
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