4.1. Therapeutic indications

Treatment of patients with chronic myeloid leukaemia (CML) in the chronic or accelerated phase of the disease.

Treatment of patients with essential thrombocythaemia or polycythaemia vera with a high risk for thromboembolic complications.

4.2. Posology and method of administration

Posology

Therapy should only be conducted by a physician experienced in oncology or haematology. Doses are based on real or ideal bodyweight of the patient, whichever is the less.

In CML hydroxycarbamide is usually given at an initial dose of 40 mg/kg daily dependent on the white cell count. The dose is reduced by 50 % (20 mg/kg daily) when the white cell count has dropped below 20 x 109/l. The dose is then adjusted individually to keep the white cell count at 5 – 10 x 109/l. The hydroxycarbamide dose should be reduced if white cell counts fall below 5 x 109/l and increased if white cell counts > 10 x 109/l are observed.

If the white cell count falls below 2.5 x 109/l, or the platelet count below 100 x 109/l, therapy should be interrupted until the counts rise significantly towards normal.

An adequate trial period for determining the antineoplastic effect of Hydroxycarbamide medac is six weeks. Therapy should be interrupted indefinitely if there is significant progress of the disease. If there is significant clinical response therapy may be continued indefinitely.

In essential thrombocythaemia hydroxycarbamide is usually given at starting doses of 15 mg/kg/day with dose adjustment to maintain a platelet count below 600 x 109/l without lowering the white blood cell count below 4 x 109/l.

In polycythaemia vera hydroxycarbamide should be started at a dose of 15 – 20 mg/kg/day. The hydroxycarbamide dose should be adjusted individually to maintain the haematocrit below 45 % and platelet count below 400 x 109/l. In most patients this can be achieved with hydroxycarbamide given continuously at average daily doses of 500 to 1,000 mg.

If haematocrit and platelet count can be sufficiently controlled therapy may be continued indefinitely.

Paediatric population

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

Elderly

Elderly patients may be more sensitive to the effects of hydroxycarbamide, and may require a lower dose regimen.

Impaired renal and/or liver function

No data are available. Dose recommendation cannot be given to patients with impaired renal and/or liver function (see section 4.4).

Method of administration

The capsules should be swallowed whole and not be allowed to disintegrate in the mouth.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Therapy should be discontinued if hypersensitivity to Hydroxycarbamide medac occurs.

• Severe bone marrow depression, leukocytopenia (< 2.5 x 109 leukocytes/l), thrombocytopenia (< 100 x 109 platelets/l) or severe anaemia.

4.4. Special warnings and precautions for use

Haematological toxicities

Hydroxycarbamide can cause bone marrow depression with leucopenia as the first and most commonly occurring sign. Thrombocytopenia and anaemia occur less frequently and are rare without preceding leucopenia. Complete blood counts including determination of haemoglobin level, total leukocyte differentiation counts, and platelet counts should be performed regularly also after the individual optimal dose has been established. The control interval should be individualised but is normally once a week. If the white cell count falls below 2.5 x 109/l, or the platelet count below 100 x 109/l, therapy should be interrupted until the counts rise significantly towards normal. (See section 4.2).

In case of anaemia before or during ongoing treatment red blood cells may be replaced when needed. Megaloblastic erythropoiesis, 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. Cases of haemolytic anaemia in patients treated with hydroxycarbamide for myeloproliferative diseases have been reported. Patients who develop severe anaemia should have laboratory tests evaluated for haemolysis. If diagnosis of haemolytic anaemia is established, hydroxycarbamide should be discontinued.

Monitoring during therapy

During therapy with Hydroxycarbamide medac frequent monitoring of blood counts should be conducted as well as monitoring of hepatic and renal function. Experience is limited in patients with impaired renal and/or liver function. Therefore, special care should be taken in the treatment of these patients, especially at the beginning of therapy.

Secondary leukaemia

In patients receiving long-term treatment with hydroxycarbamide for myeloproliferative disorders, such as polycythaemia vera and thrombocythaemia, secondary leukaemia may develop. To what extent this relates to the underlying disease or to treatment with hydroxycarbamide is presently unknown.

Skin cancer

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.

Leg ulcers

Hydroxycarbamide can induce painful leg ulcers which are usually difficult to treat and require cessation of therapy. Discontinuation of hydroxycarbamide usually leads to slow resolution of the ulcers over some weeks.

Vasculitic 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. 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 treatment with alternative cytoreductive medicinal products should be initiated as indicated.

Interstitial lung disease

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).

Serum uric acid increase

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. Patients should be instructed to drink abundantly.

Interference with laboratory tests

A published study has shown increases of laboratory values of urea, uric acid (5 – 9 %) and lactic acid (6 – 11 %) measured by in vitro enzymatic assays, in the presence of hydroxycarbamide (0.1 – 1 mM), indicating an analytical interference. The clinical relevance of these results is unknown.

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.

Reverse transcriptase inhibitors

The combination of hydroxycarbamide and nucleoside reverse transcriptase inhibitors (NRTI) may enhance the risk of side effects of NRTI, see also section 4.5.

Fertility

Hydroxycarbamide may be genotoxic. Therefore, women of childbearing potential should use effective contraceptive measures while being treated with hydroxycarbamide and for 6 months following completion of treatment. Men under therapy are advised to use safe contraceptive measures during and for 3 months after therapy. They should be informed about the possibility of sperm conservation before the start of therapy.

Hydroxycarbamide medac should not be administered to patients who are pregnant or to mothers who are breast‑feeding, unless the benefits outweigh the possible hazards (see section 4.6).

Lactose

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

Vaccinations

Concomitant use of Hydroxycarbamide medac 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 Hydroxycarbamide medac 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 has been sought (see section 4.5).

4.5. Interaction with other medicinal products and other forms of interaction

Hydroxycarbamide should be given with caution to patients with previous or concomitant radiotherapy or cytotoxic therapy. In these cases the patients have an increased risk to develop bone marrow depression, gastric irritation and mucositis (more severe, higher frequency). Furthermore, an exacerbation of erythema caused by previous or simultaneous irradiation may occur.

In-vitro studies have demonstrated hydroxycarbamide's ability to enhance the cytotoxicity of both ara‑C and fluoropyrimidines.

Hydroxycarbamide may enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors like didanosine and stavudine. Hydroxycarbamide inhibits HIV DNA synthesis and HIV replication by decreasing the amount of intracellular deoxynucleotides. 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. Hydroxycarbamide may also enhance potential side effects of nucleoside reverse transcriptase inhibitors such as hepatotoxicity, pancreatitis and peripheral neuropathy (see section 4.8).

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).

4.6. Fertility, pregnancy and lactation

Contraception in males and females

Due to the genotoxic potential of hydroxycarbamide (see section 5.3), women of childbearing potential should use effective contraceptive measures while being treated with hydroxycarbamide and for 6 months following completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child while receiving hydroxycarbamide and for 3 months following completion of treatment.

Pregnancy

Hydroxycarbamide may be a potent mutagenic agent. Animal studies with hydroxycarbamide indicated an increased incidence of congenital defects (see section 5.3). Hydroxycarbamide medac should not be used during pregnancy unless the clinical condition of the woman requires treatment with hydroxycarbamide.

If pregnancy still occurs during treatment the possibility of genetic consultation should be offered. Hydroxycarbamide crosses the placenta.

Breast-feeding

Hydroxycarbamide medac is excreted in human 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 Hydroxycarbamide medac, taking into account the importance of the drug to the mother.

Fertility

Hydroxycarbamide may be genotoxic, therefore, genetic consultation is recommended if a patient intends to have children after therapy with hydroxycarbamide.

Men should be informed about the possibility of sperm conservation before the start of therapy. Fertility in males might be affected by treatment. Reversible oligo- and azoospermia are very commonly observed.

4.7. Effects on ability to drive and use machines

The ability to react may be impaired during treatment with Hydroxycarbamide medac. This should be borne in mind when heightened attention is required, e.g. for driving and using machines.

4.8. Undesirable effects

Bone marrow depression is the dose limiting toxicity. Gastrointestinal side effects are common but rarely require dose reduction or cessation of treatment.

The frequencies of adverse events are categorised using the following convention: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Infections and Infestations

Rare

Gangrene

Neoplasms Benign and Malignant (including cysts and polyps)

Common

Skin Cancer (squamous cell cancer, basal cell carcinoma)

Blood and lymphatic system disorders

Very common

Bone marrow depression, CD4 lymphocytes decreased, leukocytopenia, anaemia, thrombocytopenia

Common

Megaloblastosis

Not known

Haemolytic anaemia

Immune system disorders

Rare

Hypersensitivity reaction

Metabolism and nutrition disorders

Very common

Anorexia

Rare

Tumour lysis syndrome

Not known

Hyperkalaemia

Psychiatric disorders

Common

Hallucinations, disorientation

Nervous system disorders

Common

Peripheral neuropathy1, somnolence, neurological disturbances including headache, dizziness and convulsion

Respiratory, thoracic and mediastinal disorders

Common

Pulmonary fibrosis, pulmonary oedema, acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnoea

Not known

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

Gastrointestinal disorders

Very common

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

Not known

Gastrointestinal ulcers

Hepatobiliary disorders

Common

Hepatotoxicity1, hepatic enzyme increased, cholestasis, hepatitis

Uncommon

Blood bilirubin increased

Skin and subcutaneous tissue disorders

Very common

Skin ulcers (especially leg ulcers), cutaneous vasculitis, pruritus, violet papules, dermatomyositis-like skin changes, alopecia, maculopapular rash, skin exfoliation, skin atrophy, erythema (e.g. facial erythema, acral erythema), skin hyperpigmentation, nail disorder (e.g. nail pigmentation, nail atrophy)

Uncommon

Actinic keratosis

Very rare

Systemic and cutaneous lupus erythematosus

Not known

Dry skin

Renal and urinary disorders

Very common

Dysuria, transient renal tubular dysfunction accompanied by increased blood uric acid, increased blood urea and increased blood creatinine

Very rare

Renal impairment

Reproductive system and breast disorders

Very common

Azoospermia, oligospermia

General disorders and administration site conditions

Very common

Drug fever, asthenia, chills, malaise

1Fatal 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.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

In patients receiving long-term treatment with hydroxycarbamide for myeloproliferative disorders such as polycythaemia vera and thrombocythaemia, secondary leukaemia may develop. To what extent this relates to the underlying disease or to treatment with hydroxycarbamide is presently unknown.

Blood and lymphatic system disorders

During hydroxycarbamide therapy megaloblastosis may occur which does not respond to treatment with folic acid or B12.

Bone-marrow suppression subsides, however, when therapy is discontinued.

Hydroxycarbamide can reduce plasma iron clearance and iron utilisation by erythrocytes. However, it does not appear to alter the red blood cell survival time.

Immune system disorders

Hypersensitive reactions: 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 readministration fever re-occurred within 24 hours.

Metabolism and nutrition disorders

Cases of hyponatraemia have been observed during post-marketing surveillance.

Gastrointestinal disorders

Severe gastric distress (nausea, emesis, anorexia) resulting from combined hydroxycarbamide and irradiation therapy may usually be controlled by temporarily discontinuing hydroxycarbamide administration.

Skin and subcutaneous tissue disorders

Hydroxycarbamide may aggravate the inflammation of mucous membranes secondary to irradiation. It can cause a recall of erythema and hyperpigmentation in previously irradiated tissues.

Erythema, atrophy of skin and nails, skin exfoliation, violet papules, alopecia, dermatomyositis-like skin changes, actinic keratosis, cutaneous ulcers (especially leg ulcers), cutaneous vasculitis, pruritus, hyperpigmentation of skin and nails, and dry skin have been observed partly after years of long-term daily maintenance therapy with hydroxycarbamide.

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

4.9. Overdose

Acute mucocutaneous symptoms have been observed in patients receiving hydroxycarbamide doses several times the recommended dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hands and feet, severe generalised hyperpigmentation of the skin, and stomatitis have also been observed.

Immediate treatment consists of gastric lavage, followed by supportive care and monitoring of the haematopoietic system.