4.1. Therapeutic indications

Siklos is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in adults, adolescents and children older than 2 years suffering from symptomatic sickle cell syndrome (see section 5.1).

4.2. Posology and method of administration

Treatment with Siklos should be initiated by a physician experienced in the management of patients with sickle cell syndrome.

Posology

In adults, adolescents and children older than 2 years

The posology should be based on the patient's body weight (b.w.).

The starting dose of hydroxycarbamide is 15 mg/kg b.w. and the usual dose is between 15 and 30 mg/kg b.w./day.

As long as the patient responds to therapy either clinically or haematologically (e.g. increase in haemoglobin F (HbF), Mean Corpuscular Volume (MCV), decrease in neutrophil count), the dose of Siklos should be maintained.

In case of non-response (re-occurrence of crises or lack of reduction in crisis rate), the daily dose may be increased by steps of 2.5 to 5 mg/kg b.w./day using the most appropriate strength.

Under exceptional circumstances a maximum dose of 35 mg/kg b.w./day may be justified under close haematological monitoring (see section 4.4).

If the patient does not respond to the maximum dose of hydroxycarbamide (35 mg/kg b.w./day) given over three to six months, permanent discontinuation of Siklos should be considered.

If blood counts are within the toxic range, Siklos should be temporarily discontinued until blood counts recover. Haematological recovery usually occurs within two weeks. Treatment may then be reinstated at a reduced dose. The dose of Siklos may then be increased again under close haematological monitoring. A dose producing haematological toxicity should not be tried more than two times.

The toxic range may be characterised by the following results of blood tests:

Neutrophils

Platelets

Haemoglobin

Reticulocytes

< 1 500/mm3

< 80 000/mm3

< 4.5 g/dL

< 80 000/mm3 if the haemoglobin concentration < 9 g/dL

Long-term data on the continued use of hydroxycarbamide in patients with sickle cell syndrome are available in children and adolescents, with a follow-up of 12 years in children and adolescents and over 13 years in adults. It is currently unknown how long patients should be treated with Siklos. The duration of treatment is the responsibility of the prescribing physician and should be based on the clinical and haematological status of each patient.

Special populations

Children less than 2 years of age

The safety and efficacy of hydroxycarbamide in children from birth up to 2 years have not yet been established. Limited data suggest that 20 mg/kg/d reduced painful episodes and were safe in children less than 2 years of age but safety of long-term treatment remains to be established. Therefore no recommendation on a posology can be made.

Renal impairment

As renal excretion is a main pathway of elimination, a dose reduction of Siklos should be considered in patients with renal impairment. In patients with creatinine clearance ≤ 60 mL/min, the initial Siklos dose should be decreased by 50%. Close monitoring of blood parameters is advised in these patients. Siklos must not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

There are no data that support specific dose adjustments in patients with hepatic impairment. Close monitoring of blood parameters is advised in these patients. Due to safety considerations, Siklos is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).

Method of administration

Conforming to the individual prescribed dose, the tablet or the half or quarter of the tablet should be taken once daily, preferably in the morning before breakfast and, when necessary, with a glass of water or a very small amount of food.

For patients who are not able to swallow the tablets, these can be disintegrated immediately before use in a small quantity of water in a teaspoon. Adding a drop of syrup or mixing with food can mask a possible bitter taste.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Severe hepatic impairment (Child-Pugh classification C).

Severe renal impairment (creatinine clearance < 30 mL/min).

Toxic ranges of myelosuppression as described in section 4.2.

Breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

Bone marrow depression

Treatment with Siklos requires close clinical monitoring. The haematological status of the patient, as well as renal and hepatic functions should be determined prior to, and repeatedly during treatment. During treatment with Siklos, blood counts must be monitored once a month at treatment initiation (i.e. for the first two months) and if the daily dose of hydroxycarbamide is up to 35 mg/kg b.w. Patients who are stable on lower doses should be monitored every 2 months.

Treatment with Siklos should be discontinued if bone marrow function is markedly depressed. Neutropenia is generally the first and most common manifestation of haematological suppression. Thrombocytopenia and anaemia occur less frequently, and are rarely seen without preceding neutropenia. Recovery from myelosuppression is usually rapid when therapy is discontinued. Siklos therapy can then be re-initiated at a lower dose (see section 4.2).

Renal and hepatic impairment

Siklos should be used with caution in patients with mild to moderate renal impairment (see section 4.2).

Since there are limited data in patients with mild to moderate liver impairment, Siklos should be used with caution (see section 4.2).

Leg ulcers and cutaneous vasculitis toxicities

In patients with leg ulcers, Siklos should be used with caution. Leg ulcers are a common complication of sickle cell syndrome, but have also been reported in patients treated with hydroxycarbamide. 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 and/or its dose reduced if cutaneous vasculitic ulcerations develop. Rarely, ulcers are caused by leukocytoclastic vasculitis.

Macrocytosis

Hydroxycarbamide causes macrocytosis, which may mask the incidental development of folic acid and vitamin B12 deficiency. Prophylactic administration of folic acid is recommended.

Carcinogenicity

Hydroxycarbamide is unequivocally genotoxic in a wide range of test systems. Hydroxycarbamide is presumed to be a transspecies carcinogen. In patients receiving long-term hydroxycarbamide for myeloproliferative disorders, secondary leukaemia has been reported. It is unknown whether this leukaemogenic effect is secondary to hydroxycarbamide or is associated with the patient's underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxycarbamide.

Safe administration and monitoring

Patients and/or parents or the legal responsible person must be able to follow directions regarding the administration of this medicinal product, their monitoring and care.

Interference with Continuous Glucose Monitoring systems

If a patient using a CGM is to be prescribed hydroxycarbamide, consult with the CGM prescriber about appropriate glucose monitoring methods (see section 4.5).

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

Specific interaction studies have not been performed with hydroxycarbamide.

Potentially fatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxycarbamide in combination with first generation antiretroviral medicinal products, particularly 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.

Concurrent use of hydroxycarbamide and other myelosuppressive medicinal products or radiation therapy may increase bone marrow depression, gastro-intestinal disturbances or mucositis. An erythema caused by radiation therapy may be aggravated by hydroxycarbamide.

Concomitant use of hydroxycarbamide with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reaction of the vaccine virus, because normal defence mechanisms may be suppressed by hydroxycarbamide therapy. Vaccination with a live vaccine in a patient taking hydroxycarbamide may result in severe infections. Generally, the patient's antibody response to vaccines may be decreased. Treatment with Siklos and concomitant immunisation with live virus vaccines should only be performed if benefits clearly outweigh potential risks.

Interference with Continuous Glucose Monitoring systems

Hydroxycarbamide 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 hydroxycarbamide, consult with the CGM prescriber about appropriate glucose monitoring methods.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing age receiving hydroxycarbamide should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.

An effective method of contraception is strongly recommended in women of childbearing potential.

Male and female patients on hydroxycarbamide wishing to conceive should stop treatment 3 to 6 months before pregnancy if possible. The evaluation of the risk-benefit ratio should be made on an individual basis taking into consideration the respective risk of hydroxycarbamide therapy against the switch to a blood transfusion programme.

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3). Patients on hydroxycarbamide should be made aware of the risks to the foetus.

There is limited amount of data from the use of hydroxycarbamide in pregnant women. Siklos is not recommended during pregnancy.

The patient should be instructed to immediately contact a doctor in case of suspected pregnancy.

Breast feeding

Hydroxycarbamide is excreted in human milk. Because of the potential for serious adverse reactions in infants, breastfeeding must be discontinued while taking Siklos.

Fertility

Fertility in males might be affected by treatment. Very common reversible oligo- and azoospermia have been observed in man, although these disorders are also associated with the underlying disease. Impaired fertility was observed in male rats (see section 5.3).

4.7. Effects on ability to drive and use machines

Siklos has minor influence on the ability to drive and use machines. Patients should be advised not to drive or operate machines, if dizziness is experienced while taking Siklos.

4.8. Undesirable effects

Summary of the safety profile

The safety profile of hydroxycarbamide in sickle cell syndrome was established from clinical trials and confirmed with long-term cohort studies including up to 1 903 adults and children of more than 2 years of age.

The most frequently reported adverse reaction is myelosuppression with neutropenia as the most common manifestation. Bone marrow depression is the dose-limiting toxic effect of hydroxycarbamide. When the maximum tolerated dose is not reached, transient myelotoxicity usually occurs in less than 10% of patients, while under the maximum tolerated dose more than 50% can experience reversible bone marrow suppression. These adverse reactions are expected based on the pharmacology of hydroxycarbamide. Gradual dose titration may help diminish these effects (see section 4.2).

The clinical data obtained in patients with sickle cell syndrome have not shown evidence of adverse reactions of hydroxycarbamide on hepatic and renal function.

Tabulated list of adverse reactions

The adverse reactions are listed below by system organ class and absolute frequency. Frequencies are defined as 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

Neoplasms, benign, malignant and unspecified:

Not known:

Leukaemia and in elderly patients, skin cancers

Blood and lymphatic system disorders:

Very common:

Bone marrow depression1 including neutropenia (< 1.5 x 109/L), reticulocytopenia (< 80 x 109/L), macrocytosis2

Common:

Thrombocytopenia (< 80 x 109/L), anaemia (haemoglobin < 4.5 g/dL)3

Nervous system disorders:

Common:

Headache

Uncommon:

Dizziness

Vascular disorders:

Not known:

Bleeding

Gastrointestinal disorders:

Uncommon:

Nausea

Not known:

Gastrointestinal disturbances, vomiting, gastrointestinal ulcer, severe hypomagnesaemia

Hepatobiliary disorders:

Rare:

Elevated liver enzymes

Skin and subcutaneous tissue disorders:

Common

Skin reactions (for example oral, ungual and cutaneous pigmentation) and oral mucositis.

Uncommon:

Rash, melanonychia, alopecia

Rare:

Leg ulcers

Very rare:

Systemic and cutaneous lupus erythematous

Not known:

Cutaneous dryness

Reproductive system and breast disorders:

Very common:

Oligospermia, azoospermia4

Not known:

Amenorrhea

General disorders and adminis­tration site conditions:

Not known:

Fever

Investigations:

Not known:

Weight gain5

1 Haematological recovery usually occurs within two weeks of withdrawal of hydroxycarbamide.

2 The macrocytosis caused by hydroxycarbamide is not vitamin B12 or folic acid dependent.

3 Mainly due to infection with Parvovirus, splenic or hepatic sequestration, renal impairment.

4 Oligospermia and azoospermia are in general reversible but have to be taken into account when fatherhood is desired (see section 5.3). These disorders are also associated with the underlying disease.

5 Weight gain may be an effect of improved general conditions.

Paediatric population

Frequency, type and severity of adverse reactions in children is generally similar to adults. Postmarketing data from one observational study with Siklos® (Escort HU) on a large set of patients (n=1 906) with sickle cell disease showed that patients aged 2 to 10 years were at higher risk for neutropenia and at lower risk for dry skin, alopecia, headache and anaemia. Patients aged 10 to 18 years were at lower risk for dry skin, skin ulcer, alopecia, weight increase and anaemia compared to adults.

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

Acute mucocutaneous toxicity has been reported in patients receiving hydroxycarbamide at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalised hyperpigmentation of the skin and stomatitis have been observed.

In patients with sickle cell syndrome, severe bone marrow depression was reported in isolated cases of hydroxycarbamide overdose between 2 and 10 times the prescribed dose (up to 8.57 times of the maximum recommended dose of 35 mg/kg b.w./day). It is recommended that blood counts are monitored for several weeks after overdose since recovery may be delayed.

Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function.