4.1. Therapeutic indications

The treatment of chronic myeloid leukaemia:

• as pre-TKI treatment phase before confirmation of BCR-ABL fusion with an immediate need for therapy due to high leukocyte and thrombocyte counts

• as palliative care in patients in blastic phase with leucocytosis and thrombocytosis

The treatment of cancer of the cervix 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 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 (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 anaesthetics 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 regimens, 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

Paediatric population

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.

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

Oral.

See section 6.6 for precautions on handling the medicinal product.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Marked leukopenia (<2.5wbcx109/L), thrombocytopenia (<100x109/L), or severe anaemia.

4.4. Special warnings and precautions for use

Bone Marrow

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.

Anaemia

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. The macrocytosis may mask the incidental development of folic acid deficiency; regular determinations of serum folic acid are recommended. 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.

Cases of haemolytic anaemia in patients treated with Hydrea for myeloproliferative diseases have been reported (see section 4.8). Patients who develop persistent anaemia should have laboratory tests evaluated for haemolysis. In the setting of confirmed diagnosis of haemolytic anaemia, Hydrea should be discontinued.

Irradiation

Patients who have received irradiation therapy in the past may have an exacerbation of post irradiation erythema when Hydrea is given.

Renal

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

HIV

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).

Cancer

In patients receiving long-term therapy with hydroxycarbamide for myeloproliferative disorders, such as polycythaemia vera and thrombocythemia, secondary leukaemia has been reported. It is unknown whether this leukaemogenic effect is secondary to hydroxycarbamide or associated with the patient's underlying disease. Skin cancer has been reported in patients receiving long-term hydroxycarbamide. Patients should be advised to protect skin from sun exposure. In addition, patients should conduct self- inspection of the skin during the treatment and after discontinuation of the therapy with hydroxycarbamide and be screened for secondary malignancies during routine follow-up visits.

Vasculitis toxicities

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.

Uric acid

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.

Vaccinations

Concomitant use of Hydrea with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase some of the adverse reactions of the vaccine virus because normal defence mechanisms may be suppressed by hydroxycarbamide. Vaccination with a live vaccine in a patient taking Hydrea may result in severe infection. The patient's antibody response to vaccines may be decreased. The use of live vaccines should be avoided during treatment and for at least six months after treatment has finished and individual specialist advice sought (see section 4.5).

Respiratory disorders:

Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis have been reported in patients treated for myeloproliferative neoplasm and may be associated with fatal outcome. Patient developing pyrexia, cough, dyspnoea, or other respiratory symptoms should be closely monitored, investigated and treated. Promptly discontinue of hydroxyurea and treatment with corticosteroids appears to be associated with resolution of the pulmonary events (see section 4.8).

Interference with Continuous Glucose Monitoring Systems

Hydroxycarbamide may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems which may lead to hypoglycaemia if sensor glucose results are relied upon to dose insulin.

If CGM systems are to be used concurrently with hydroxycarbamide treatment, consult with the CGM prescriber about the need to consider alternative glucose monitoring methods.

Lactose

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per capsule, that is to say essentially 'sodium-free'.

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 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. This combination should be avoided. 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.

Vaccinations

There is an increased risk of severe or fatal infections with the concomitant use of live vaccines. Live vaccines are not recommended in immunosuppressed patients (see section 4.4).

Interference with Continuous Glucose Monitoring Systems

Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems. This may lead to missed hypoglycaemic episodes and can also cause hypoglycaemia if sensor glucose results are relied upon to dose insulin.

If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about appropriate glucose monitoring methods.

4.6. Fertility, pregnancy and lactation

Pregnancy

Hydrea can cause fetal harm when administered to a pregnant woman. Hydrea should not normally be administered to patients who are pregnant, unless the potential benefits outweigh the possible hazards.

Breast-feeding

Hydroxycarbamide is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants from hydroxycarbamide, 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 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.

Fertility

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

Female patients of reproductive potential should be counselled to use effective contraception during therapy and for at least 6 months after therapy.

Azoo- or oligospermia, sometimes reversible, have been observed in men. Male patient should be informed about the possibility of sperm conservation before the start of therapy. Hydroxycarbamide may be genotoxic.

Men under therapy are advised to use effective contraceptive measures during and at least 1 year after therapy.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Bone-marrow suppression is the major toxic effect of hydroxycarbamide.

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.

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

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/mm3 (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/mm3) 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.

Hypersensitivity

Drug induced fever

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

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).

System Organ Class

Frequency

MedDRA Term

Infections and Infestations

Rare

Gangrene

Neoplasms Benign and Malignant (including cysts and polyps)

Common

Skin cancer

Blood and Lymphatic System Disorders

Very common

Bone marrow failure, CD4 lymphocytes decreased, leukopenia, thrombocytopenia, platelet count decreased, anaemia

Not known

Haemolytic anaemia

Metabolism and Nutrition Disorders

Very common

Anorexia

Rare

Tumour lysis syndrome

Psychiatric Disorders

Common

Hallucination, disorientation

Nervous System Disorders

Common

Convulsion, dizziness, peripheral neuropathy1, somnolence, headache

Respiratory, Thoracic, and Mediastinal Disorders

Common

Pulmonary fibrosis, pulmonary oedema, lung infiltration, dyspnoea

Not known

Interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis, cough

Gastrointestinal Disorders

Very common

Pancreatitis1, nausea, vomiting, diarrhoea, stomatitis, constipation, mucositis, stomach discomfort, dyspepsia, abdominal pain, melaena

Hepatobiliary Disorders

Common

Hepatotoxicity1, hepatic enzyme increased, cholestasis, hepatitis

Musculoskeletal and connective tissue disorders

Very rare

Systemic lupus erythematosus

Skin and Subcutaneous Tissue Disorders

Very common

Cutaneous vasculitis, dermatomyositis, alopecia, rash maculo-papular, rash papular, skin exfoliation, skin atrophy, skin ulcer, erythema, skin hyperpigmentation, nail disorder

Very rare

Cutaneous lupus erythematosus

Not known

Nail pigmentation

Renal and Urinary Disorders

Very common

Dysuria, blood creatinine increased, blood urea increased, blood uric acid increased

General Disorders and Administration Site Conditions

Very common

Pyrexia, asthenia, chills, malaise

Reproductive system and breast disorders

Very common

azoospermia, oligospermia

1 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.