Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Addmedica, 37 rue de Caumartin, 75009 Paris, France, Phone: +33 1 72 69 01 86, Fax: +33 1 73 72 94 13, E-mail: contact@addmedica.com
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).
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 every two weeks 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 a 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).
Siklos should be used with caution in patients with mild to moderate renal impairment (see section 4.2).
Since there is no available data in patients with mild to moderate liver impairment, Siklos should be used with caution (see section 4.2).
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.
Continuous follow-up of the growth of treated children and adolescents is recommended.
Hydroxycarbamide causes macrocytosis, which may mask the incidental development of folic acid and vitamin B12 deficiency. Prophylactic administration of folic acid is recommended.
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 leukemogenic 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.
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.
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 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.
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 outweighing the respective risk of hydroxycarbamide therapy against the switch to a blood transfusion programme.
In the human, according to a retrospective analysis of a cohort of 123 adult patients treated with hydroxycarbamide, twenty-three pregnancies have been reported from 15 women treated with hydroxycarbamide and partners of 3 men treated with hydroxycarbamide. Most (61%) had a normal outcome with regard to term and normal birth. In the other cases with known evolution, pregnancy had been interrupted either voluntarily or upon medical advice. Thus, the data on a limited number of exposed pregnancies indicate no adverse effects on pregnancy or on the health of the foetus/newborn. Studies in animals have shown reproductive toxicity (see section 5.3). Patients on hydroxycarbamide should be made aware of the theoretical risks to the foetus.
Based on the limited amount of available information, in case of an exposure to hydroxycarbamide of pregnant female patients or pregnant partners of male patients, treated by hydroxycarbamide, a careful follow-up with adequate clinical, biological and ultrasonographic examinations should be considered.
Hydroxycarbamide is excreted in human milk. Because of the potential for serious adverse reactions in infants, breast-feeding must be discontinued while taking Siklos.
Fertility in males might be affected by treatment. Very common reversible oligo- and azoo-spermia have been observed in man, although these disorders are also associated with the underlying disease. Impaired fertility has been observed in male rats (see section 5.3).
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.
Specifically, the safety of hydroxycarbamide had been examined retroactively from cohorts of 123 adults over 13 years and 352 children older than 2 years and adolescents up to 12 years.
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 to 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.
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:
Not known: Parvovirus B19 infection
Not known: Leukaemia and in elderly patients, skin cancers
Very common: Bone marrow depression1 including neutropenia (<2.0 × 109/L), reticulocytopenia (<80 × 109/L), macrocytosis2
Common: Thrombocytopenia (<80 × 109/L), anaemia (haemoglobin <4.5 g/dl)3
Common: Headache
Uncommon: Dizziness
Not known: Bleeding
Uncommon: Nausea
Not known: Gastrointestinal disturbances, vomiting, gastrointestinal ulcer, severe hypomagnesaemia
Rare: Elevated liver enzymes
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
Very common: Oligospermia, azoospermia4
Not known: Amenorrhea
Not known: Fever
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 an infection with Parvovirus or a splenic sequestration.
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.
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 national reporting system listed in Appendix V.
Not applicable.
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