Hydrea 500 mg Hard Capsules

  • Name:

    Hydrea 500 mg Hard Capsules

  • Company:
    info
  • Active Ingredients:

    Hydroxycarbamide

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 09/01/19

files-icon(Click to Download)

XPIL

Summary of Product Characteristics last updated on medicines.ie: 9/1/2019

Click on this link to Download PDF directly

Bristol-Myers Squibb Pharmaceuticals uc

Bristol-Myers Squibb Pharmaceuticals uc

Company Products

Medicine NameActive Ingredients
Medicine Name Adcortyl Intra-articular / Intradermal Injection 10mg/ml Suspension for Injection, 1ml Active Ingredients Triamcinolone Acetonide
Medicine Name Adcortyl Intra-articular / Intradermal Injection 10mg/ml Suspension for Injection, 5ml Active Ingredients Triamcinolone Acetonide
Medicine Name Amikin Injection 100 mg / 2 ml Active Ingredients Amikacin Sulfate
Medicine Name Azactam 1g and 2g Powder for Solution for Injection or Infusion Active Ingredients Aztreonam
Medicine Name Hydrea 500 mg Hard Capsules Active Ingredients Hydroxycarbamide
1 - 0 of 5 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 9 January 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 9 January 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 23 October 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 18 October 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Updated section 4.8 of the SmPC and with consequential changes to the section 4 of the package leaflet in line with the outcome of a PRAC signal recommendation.

 

Updated on 6 December 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 6 December 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 6 December 2017 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change of name and address of MAH (Previous details: BMS Pharmaceuticals Ltd, Swords, Dublin).

Updated on 6 December 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 3 August 2017 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The following text were added:

section 4.4

Appropriate sub headings were included

section 4.8
Nail pigmentation was added to Not known ADR list under SOC-Skin and Subcutaneous Tissue Disorders, as well as the below paragraph

Hypersensitivity

Drug induced fever

High fever (>39°C) requiring hospitalisation in so[MO1] me cases has been reported concurrently with gastrointestinal, pulmonary, muscloskeletal, hepatobiliary, dermatological or cardiovascular manifestations. Onset typically occurred within 6 weeks of initiation and resolved promptly after discontinuation of hydroxycarbamide. Upon readministration fever re-occurred within 24 hours.

Updated on 31 July 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 22 June 2017 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Update of the legal entity of the MAH. i.e. deletion of Limited from the name of the MAH

Updated on 19 June 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 22 July 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

$0section4.2 - Some inert material used as a vehicle in the capsule may notdissolve and float on the surface. has been added; section4.4 - alignment of the API name in SmPC and update to the paragraph onVaccinations to further clarify the use of vaccinations whislt taking Hydrea; section4.5 - Updated with additional information; section4.6 - alignment of the API name in SmPC; section4.8 - addition of new adverse reaction Tumor lysis syndrome under Metabolismand Nutrition Disorders; section6.6 - Hydrea should be kept away from children and pets. has beenadded; section10 - Date of revision updated to July 2015 from December 2014$0$0$0$0$0

Updated on 21 July 2015 PIL

Reasons for updating

  • Change to storage instructions
  • Change to side-effects
  • Change to date of revision

Updated on 22 December 2014 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions
  • Change to information about pregnancy or lactation

Updated on 22 December 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

Type II variation to update various sections of the SmPC in line with Company Core Data Sheet (CCDS) dated March 2014.

 

Updated on 9 April 2014 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

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

 

 

 

 

 

Updated on 13 March 2014 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions
  • Change to date of revision
  • Change to improve clarity and readability
  • Correction of spelling/typing errors
  • Improved electronic presentation

Updated on 24 October 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 8 - MA number
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

 



4.2 Posology and method of administration

Posology


....................................

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.


...................................................

Special Populations

Elderly:


..................................................

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.


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

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.

 


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).

 

**(MedDRA table inserted)**


 

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.

 



8. MARKETING AUTHORISATION NUMBER

PA

0002/027/001

 




Updated on 23 October 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to instructions about overdose
  • Change to storage instructions
  • Change to side-effects
  • Change to information about pregnancy or lactation
  • Change to information about driving or using machinery
  • Change to further information section
  • Change to date of revision
  • Change of special precautions for disposal

Updated on 17 April 2012 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The following text has been added to section 4.4 and 4.5 of the SmPC:

Section 4.4:

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

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.

Section 4.5: 
 

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.

Updated on 17 April 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 15 February 2012 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 15 February 2012 SmPC

Reasons for updating

  • Addition of legal category

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Legal Category

POM added

Updated on 4 January 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to drug interactions
  • Change to date of revision

Updated on 2 September 2010 PIL

Reasons for updating

  • Change due to user-testing of patient information
  • Change to name of manufacturer

Updated on 4 March 2010 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Sections 1, 2, 3, 6.1, 6.4, 6.6 - revised in line with SPC QRD Template

 Section 6.3 - Reduction of shelf life from 5 to 2 years. 

Sections 9 and 10 - Dates of renewal and revision

Updated on 2 February 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.4 - Lactose statement included

Section 4.8 - Side effects in MEDRA terminology

Section 5.1 - ATC Code included

Updated on 20 August 2008 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 7 February 2006 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 24 December 2004 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change from the BAN of the active substance to the rINN

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 29 May 2003 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)