Siklos
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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Siklos 100 mg film-coated tablets. 
Siklos 1000 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Siklos 100 mg film-coated tablets  
Each film-coated tablet contains 100 mg of hydroxycarbamide. 
 
Siklos 1000 mg film-coated tablets  
Each film-coated tablet contains 1,000 mg of hydroxycarbamide. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Siklos 100 mg film-coated tablets 
Off-white oblong-shaped, film-coated tablet with half-scoring on both sides. 
The tablet can be divided into two equal parts. Each half of tablet is embossed “H” on one side. 
 
Siklos 1000 mg film-coated tablets  
Off-white, capsule-shaped, film-coated tablet with triple scoring on both sides. 
The tablet can be divided into four equal parts. Each quarter of tablet is embossed “T” on one side. 
 
 
4. CLINICAL PARTICULARS 
 
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). 



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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 < 1,500/mm3 
Platelets  < 80,000/mm3 
Haemoglobin < 4.5 g/dl 
Reticulocytes < 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 
Because of the scarce long term data on the treatment with hydroxycarbamide in children less than 
2 years of age, dose regimens have not been established and thus, in this population, the treatment with 
hydroxycarbamide is not recommended. 
 
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). 



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



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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. 
 
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 theoretical risks to the foetus. 
 
In humans, according to a prospective study including 635 females of childbearing potential treated 
with hydroxycarbamide, 110 pregnancies were reported in 101 women exposed to hydroxycarbamide 
during pregnancy. Additionally,  12 partners of men treated with hydroxycarbamide became pregnant. 
Most (64%) resulted in live birth. Thus, based on the data from a limited number of exposed 
pregnancies, no adverse effects on the mother or on the foetus/newborn was evidenced. 
 
Because of limited information, in case of an exposure to hydroxycarbamide of pregnant female 
patients or pregnant partners of male patients, treated by hydroxycarbamide, careful follow-up with 
adequate clinical, biological and ultrasonographic examinations should be considered.  
 
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. 



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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 1903 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: 
  



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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. 
 
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 national reporting system 
listed in Appendix V 
 
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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of 
bone marrow function. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX05. 
 
Mechanism of action 
All mechanisms of action of hydroxycarbamide are not fully understood. One of the mechanisms is the 
increase in foetal haemoglobin (HbF) concentrations in sickle cell patients. HbF interferes with the 
polymerisation of HbS and thus impedes the sickling of red blood cell, and in turn decreases 
vasocclusion and haemolysis. In all clinical studies, there was a significant increase in HbF from 
baseline after hydroxycarbamide use.  
 
Recently, hydroxycarbamide has shown to be associated with the generation of nitric oxide suggesting 
that nitric oxide stimulates cyclic guanosine monophosphatase (cGMP) production, which then 
activates a protein kinase and increases the production of HbF. Other known pharmacological effects 
of hydroxycarbamide which may contribute to its beneficial effects in sickle cell syndrome include 
decrease in neutrophils, increase in water content of red blood cells, increased deformability of sickled 
cells, and altered adhesion of red blood cells to the endothelium. 
 
In addition hydroxycarbamide causes an immediate inhibition of DNA synthesis by acting as a 
ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or protein. 
 
Pharmacodynamic effects 
Beside the inconstant correlation between reduction of crisis rate and the increase in HbF, the 
cytoreductive effect of hydroxycarbamide, particularly the decrease in neutrophils, was the factor with 
the strongest correlation with the reduction in crisis rate. 
 
Clinical efficacy and safety 
In nearly all clinical studies conducted in sickle cell syndrome, hydroxycarbamide reduced the 
frequency of vaso-occlusive episodes by 66% to 80%, in children and in adults. The same decrease 
was observed for the number of hospital admissions and the number of days of hospitalisation in the 
treated groups. The yearly frequency of acute chest syndrome was also reduced by 25 to 33% under 
hydroxycarbamide in several studies. Acute chest syndrome is a frequent life-threatening complication 
of sickle cell syndrome and is characterised by chest pain or fever or dyspnoea with recent infiltrate on 
chest X-ray. 
A sustained clinical benefit was demonstrated in patients remaining on hydroxycarbamide treatment 
for more than 8 years.  
 
5.2 Pharmacokinetic properties 
 
Absorption  
After oral administration of 20 mg/kg of hydroxycarbamide, a rapid absorption is observed with peak 
plasma levels of about 30 mg/L occurring after 0.75 and 1.2 h in children and adult patients with sickle 
cell syndrome, respectively. The total exposure up to 24 h post-dose is 124 mg*h/L in children and 
adolescents and 135 mg*h/L in adult patients. The oral bioavailability of hydroxycarbamide is almost 
complete as assessed in indications other than sickle cell syndrome. 
 
Distribution  
Hydroxycarbamide distributes rapidly throughout the human body, enters the cerebrospinal fluid, 
appears in peritoneal fluid and ascites, and concentrates in leukocytes and erythrocytes. The estimated 
volume of distribution of hydroxycarbamide approximates total body water. The volume of 



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distribution at steady state adjusted for bioavailability is 0.57 L/kg in patients with sickle cell 
syndrome (amounting to approximately 72 and 90 L in children and adults, respectively). The extent 
of protein binding of hydroxycarbamide is unknown. 
 
Biotransformation  
The biotransformation pathways as well as the metabolites are not fully characterised. Urea is one 
metabolite of hydroxycarbamide. 
Hydroxycarbamide at 30, 100 and 300 µM is not metabolised in vitro by cytochrome P450s of human 
liver microsomes. At concentrations ranging from 10 to 300 µM, hydroxycarbamide does not 
stimulate the in vitro ATPase activity of recombinant human P glycoprotein (PGP), indicating that 
hydroxycarbamide is not a PGP substrate. Hence, no interaction is to be expected in case of 
concomitant administration with substances being substrates of cytochromes P450 or P-glycoprotein. 
 
Elimination  
In a repeated dose study in adult patients with sickle cell syndrome approximately 60% of the 
hydroxycarbamide dose was detected in urine at steady state. In adults, the total clearance adjusted for 
bioavailability was 9.89 L/h (0.16 L/h/kg) thereof 5.64 and 4.25 L/h by renal and non-renal clearance, 
respectively. The respective value for total clearance in children was 7.25 L/h (0.20 L/h/kg) with 2.91 
and 4.34 L/h by renal and non-renal pathways. 
In adults with sickle cell syndrome, mean cumulative urinary hydroxycarbamide excretion was 62% of 
the administered dose at 8 hours, and thus higher than in cancer patients (35–40%). In patients with 
sickle cell syndrome hydroxycarbamide was eliminated with a half-life of approximately six to seven 
hours, which is longer than reported in other indications. 
 
Geriatric, gender, race  
No information is available regarding pharmacokinetic differences due to age (except paediatric 
patients), gender or race. 
 
Paediatric population  
In paediatric and adult patients with sickle cell syndrome the systemic exposure to hydroxycarbamide 
at steady state was similar by means of the area under the curve. The maximum plasma levels and the 
apparent volume of distribution related to body weight were well comparable between age groups. The 
time to reach maximum plasma concentration and the percentage of the dose excreted in urine were 
increased in children compared to adults. In paediatric patients, the half-life was slightly longer and 
the total clearance related to body weight slightly higher than in adult patients (see section 4.2).  
 
Renal impairment  
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dose of 
Siklos in patients with renal impairment. In an open single-dose study in adult patients with sickle cell 
syndrome (Yan JH et al, 2005) the influence of renal function on pharmacokinetics of 
hydroxycarbamide was assessed. Patients with normal (creatinine clearance CrCl>80 ml/min), mild 
(CrCl 60–80 ml/min), moderate (CrCl 30 - 60 ml/min), or severe (<30 ml/min) renal impairment 
received hydroxycarbamide as a single dose of 15 mg/kg b.w. by using 200 mg, 300 mg, or 400 mg 
capsules. In patients, whose CrCl was below 60 ml/min or patients with end-stage renal disease the 
mean exposure to hydroxycarbamide was approximately 64% higher than in patients with normal 
renal function. As evaluated in a further study, in patients with a CrCl<60 ml/min the area under the 
curve was approximately 51% higher than in patients with a CrCl ≥60 ml/min, which suggests that a 
dose reduction of hydroxycarbamide by 50% may be appropriate in patients with a CrCl < 60 ml/min. 
Haemodialysis reduced the exposure to hydroxycarbamide by 33% (see sections 4.2 and 4.4). 
Close monitoring of blood parameters is advised in these patients. 
 
Hepatic impairment  
There are no data that support specific guidance for dose adjustment in patients with hepatic 
impairment, but, due to safety considerations, Siklos is contraindicated in patients with severe hepatic 
impairment (see section 4.3). Close monitoring of blood parameters is advised in patients with hepatic 
impairment.  
 



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5.3 Preclinical safety data 
 
In preclinical toxicity studies the most common effects noted included bone marrow depression, 
lymphoid atrophy and degenerative changes in the epithelium of the small and large intestines. 
Cardiovascular effects and haematological changes were observed in some species. Also, in rats 
testicular atrophy with decreased spermatogenesis occurred, while in dogs reversible spermatogenic 
arrest was noted. 
 
Hydroxycarbamide is unequivocally genotoxic in a wide range of test systems. 
Conventional long-term studies to evaluate the carcinogenic potential of hydroxycarbamide have not 
been performed. However, hydroxycarbamide is presumed to be a transspecies carcinogen. 
 
Hydroxycarbamide crosses the placenta barrier and has been demonstrated to be a potent teratogen and 
embryotoxic in a wide variety of animal models at or below the human therapeutic dose. 
Teratogenicity was characterised by partially ossified cranial bones, absence of eye sockets, 
hydrocephaly, bipartite sternebrae, missing lumbar vertebrae. Embryotoxicity was characterized by 
decreased foetal viability, reduced live litter sizes, and developmental delays. 
 
Hydroxycarbamide administered to male rats at 60 mg/kg b.w./day (about double the recommended 
usual maximum dose in humans) produced testicular atrophy, decreased spermatogenesis and 
significantly reduced their ability to impregnate females. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium stearyl fumarate  
Silicified microcrystalline cellulose 
Basic butylated methacrylate copolymer 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
In-use  
Unused broken tablets must be replaced in the bottle and must be used within three months. 
 
6.4 Special precautions for storage 
 
Store below 30°C. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with polypropylene child-resistant closure with a dessicant 
unit. 
 
Siklos 100 mg film-coated tablets 
Pack sizes of 60, 90 or 120 tablets. 
Not all pack sizes may be marketed. 
 
Siklos 1000 mg film-coated tablets 
Pack size of 30 tablets. 



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6.6 Special precautions for disposal and other handling 
 
Siklos is a medicinal product that must be handled with care. People who are not taking Siklos and in 
particular pregnant women should avoid being in contact with hydroxycarbamide.  
Anyone handling Siklos should wash their hands before and after contact with the tablets. 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
In case the prescribed dose requires breaking the tablet in halves or quarters, this should be done out of 
the reach of food. Powder eventually spilled from the broken tablet should be wiped up with a damp 
disposable towel, which must be discarded. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
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 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Siklos 100 mg film-coated tablets 
EU/1/07/397/002 
EU/1/07/397/003 
EU/1/07/397/004 
 
Siklos 1000 mg film-coated tablets 
EU/1/07/397/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29/06/2007 
Date of latest renewal: 24/04/2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency: http://www.ema.europa.eu. 

  

mailto:contact@addmedica.com
http://www.ema.europa.eu/


12 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Delpharm Lille 
Parc d’Activités Roubaix-Est 
22 rue de Toufflers 
CS 50070 
59452 Lys-lez-Lannoy 
France 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2).  
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING  
AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 

 
The marketing autorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
• Additional risk minimisation measures  
 
The Marketing Authorisation Holder (MAH) shall ensure thatall physicians who are expected to 
prescribe Siklos are provided with a physician information pack containing the following: 
 

• Treatment guide for physicians  
• Patient treatment guide 
• Dosing sheet (in countries where both strengths are available) 

 
The treatment guide for physicians should contain the following key elements: 



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• The Summary of Product Characteristics 
• Need for contraception 
• Risk to male and female fertility, potential risk to foetus and breast feedingManagement of 

adverse drug reactions 
• Risk of medication error due to the availability of two different strengths (where both 

strengths are available) 
 

The treatment guide for the patient  should contain the following key elements: 
• Package leaflet 
• Handling of broken tablets 
• Need for contraception 
• Risk to male and female fertility, potential risk to foetus and breast feeding 
• Risk of medication error due to the availability of two different strengths (where both 

strengths are available) 
 
If necessary, pharmacists should receive targeted communication on the risk of medication error due 
to the confusion between the two strengths where both are available.  
 
The MAH must implement this educational plan nationally, and as agreed with the competent 
authorities in the Member States 
 
  



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

  



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A. LABELLING 
 
  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Siklos 100 mg film-coated tablets 
hydroxycarbamide 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg of hydroxycarbamide. 
 
 

3. LIST OF EXCIPIENTS 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 tablets 
90 tablets 
120 tablets 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: Handle tablets with caution.  
 
 

8. EXPIRY DATE 
 
EXP: 
In-use shelf life of broken tablets: 3 months 
 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30 °C. 
 
 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Addmedica, 37 rue de Caumartin, 75009 Paris, France 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/397/002 60 tablets 
EU/1/07/397/003 90 tablets 
EU/1/07/397/004 120 tablets 
 
 

13. BATCH NUMBER 
 
Lot: 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
siklos 100 mg 
 
 

17. UNIQUE IDENTIFIER- 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 

18. UNIQUE IDENTIFIER- HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



19 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE  

 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Siklos 100 mg tablets 
hydroxycarbamide 
Oral use 
 
 

2. METHOD OF ADMINISTRATION 
 
 

3. EXPIRY DATE 
 
EXP: 
 
 

4. BATCH NUMBER 
 
Lot: 
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
60 tablets 
90 tablets 
120 tablets 
 
 

6. OTHER 
 
Cytotoxic 
 
Addmedica 
 
  



20 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Siklos 1000 mg film-coated tablets 
hydroxycarbamide 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1,000 mg of hydroxycarbamide. 
 
 

3. LIST OF EXCIPIENTS 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: Handle tablets with caution.  
 
 

8. EXPIRY DATE 
 
EXP: 
In-use shelf life of broken tablets: 3 months 
 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30 °C 
 
 
 
 
 



21 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Addmedica, 37 rue de Caumartin, 75009 Paris, France 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/397/001 
 
 

13. BATCH NUMBER 
 
Lot: 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
siklos 1000 mg 
 
 

17. UNIQUE IDENTIFIER- 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 

18. UNIQUE IDENTIFIER- HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
  



22 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
BOTTLE  

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Siklos 1000 mg tablets 
hydroxycarbamide 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1,000 mg of hydroxycarbamide. 
 
 

3. LIST OF EXCIPIENTS 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: Handle tablets with caution.  
 
 

8. EXPIRY DATE 
 
EXP: 
 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30 °C. 
 
 
 
 
 
 



23 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Addmedica 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/397/001 
 
 

13. BATCH NUMBER 
 
Lot: 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 

  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



25 

Package leaflet: information for the user 
 

Siklos 100 mg film-coated tablets 
Siklos 1000 mg film-coated tablets 

hydroxycarbamide 
 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, or pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, or pharmacist or nurse. This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Siklos is and what it is used for 
2. What you need to know before you take Siklos 
3. How to take Siklos 
4. Possible side effects 
5 How to store Siklos 
6. Contents of the pack and other information 
 
 
1. What Siklos is and what it is used for 
 
Siklos is used to prevent painful crises, including sudden chest pain, caused by sickle cell disease, in 
adults, adolescents and children older than 2 years.  
 
Sickle cell disease is an inherited blood disorder that affects the disc shaped red cells of the blood.  
Some cells become abnormal, rigid and take a crescent or sickle shape which leads to anemia. 
The sickle cells also get stuck in blood vessels, blocking blood flow. This can cause acute pain crises 
and organ damage. 
 
For severe painful crises, most patients require hospitalisation. Siklos will decrease the number of 
painful crises as well as the need for hospitalisation linked with the disease.  
 
The active substance of Siklos, hydroxycarbamide, is a substance which inhibits growth and 
proliferation of some cells, such as blood cells. These effects lead to a reduction of circulating red, 
white and coagulation blood cells (myelosuppressive effect). In sickle cell disease, hydroxycarbamide 
helps also to prevent red blood cells from taking abnormal shape. 
 
2. What you need to know before you take Siklos 
 
Do not take Siklos 
- if you are allergic to hydroxycarbamide or any of the other ingredients of this medicine (listed in 

section 6), 
- if you suffer from severe liver disease, 
- if you suffer from severe kidney disease, 
- if you are myelosuppressed (if you have decreased production of red, white, or coagulating 

blood cells) as described in section 3 “How to take Siklos, Treatment follow-up”, 
- if you are breast-feeding (see section “Pregnancy, breast-feeding and fertility”). 
 
 



26 

Warnings and precautions 
 
Talk to your doctor or pharmacist or nurse before taking Siklos 
 
- if you have a liver disease, 
- if you have a kidney disease, 
- if you have leg ulcers, 
- if you are taking other myelosuppressive medicines (decrease production of red, white, or 

coagulating blood cells) or receiving radiation therapy, 
- if you have a known lack of vitamin B12 or folate. 
 
If you experience (or have experienced) any of the above, please tell your doctor. If you have any 
question, please ask your doctor or pharmacist or nurse. 
 
Patients and/or parents or the legal responsible person must be able to follow directions regarding the 
administration of this medicine, their monitoring and care. 
 
Other medicines and Siklos 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
Information sharing is especially required for 
- some antiretroviral medicines (those that inhibit or destroy a retrovirus such as HIV), e.g. 

didanosine, stavudine and indinavir(a drop in your white cell count may occur) , 
- myelosuppressive medicines (those that decrease production of red, white, or coagulating blood 

cells) and radiation therapy, 
- some vaccines. 
 
Pregnancy, breast-feeding and fertility 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
 
Siklos is not recommended during pregnancy. Please contact your doctor if you think you may be 
pregnant. The use of effective contraception is strongly recommended. 
 
If you become pregnant or plan to become pregnant while taking Siklos, your doctor will discuss with 
you the potential benefits and risks of continuing using Siklos.  
 
For male patients taking Siklos, if your partner becomes pregnant or plans to become pregnant, your 
doctor will discuss with you the potential benefits and risks of continuing using Siklos. 
 
The active substance of Siklos passes into human breast-milk. You must not breast-feed while taking 
Siklos. 
 
Hydroxycarbamide may decrease sperm production in male patients while they are being treated. 
 
Driving and using machines 
 
Some people may experience dizziness when using Siklos. Do not drive or use any tools or machines if 
you experience dizziness whilst taking Siklos. 
 
3. How to take Siklos 
 
Always take Siklos exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure. 
 



27 

Dose 
 
Your doctor will tell you how much of Siklos to take each day and will describe the dose in 
whole, half or quarter tablets. 
 
The prescribed dose of Siklos must be taken once daily, preferably in the morning before breakfast.  
It can be taken with a glass of water or a very small amount of food. 
If you cannot swallow the tablets, you can disintegrate them in water immediately before use: 
• Place the required dose (preferably broken if Siklos 1000 mg tablet is used) in a teaspoon and add 

some water. 
• As soon as the tablet is disintegrated, swallow the content of the teaspoon. You can add a drop of 

syrup or mix the content with food to mask a possible bitter taste. 
• Then drink a large glass of water or any other drink. 
 
Handling 
 
Siklos is a cytotoxic medicine that must be handled with care. 
Any person, in particular pregnant women, who are not taking Siklos should avoid direct contact with 
the parts when breaking a tablet. Wash your hands before and after contact with the tablets. 
In case the prescribed dose requires breaking the tablet in halves or quarters, this should be done out of 
the reach of food. Powder spilled from the broken tablet should be wiped up with a damp disposable 
towel which must be thrown out. For the storage of unused broken tablets, see section 5 “How to store 
Siklos”. 
 
Treatment follow-up 
 
Your doctor will tell you how long to take Siklos. 
 
When taking Siklos you will have regular blood tests and check your liver and kidney. 
Depending on the dose you take, these tests may be performed monthly or every two months.  
 
Depending on these results your doctor will adjust your dose of Siklos. 
 
If you take more Siklos than you should 
 
If you take more Siklos than you should or if a child has taken any, contact your doctor or the nearest 
hospital immediately as you may need urgent medical treatment. The most common symptoms of 
overdose with Siklos are: 
- Redness of the skin, 
- Soreness (touch is painful) and swelling of the palms of hands and soles of feet followed by the 

hands and feet becoming scaly, 
- Skin becoming strongly pigmented (locally changes of colour), 
- Soreness or swelling in the mouth. 
 
If you forget to take Siklos 
 
Do not take a double dose to make up for a forgotten tablet. Continue as normal when it is time to take 
the next dose as prescribed by your doctor. 
 
If you stop taking Siklos 
 
Do not stop your treatment unless advised by your doctor. 
If you have any further question on the use of this medicine, ask your doctor or pharmacist. 
 
 



28 

4. Possible side effects 
 
Like all medicines, Siklos can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately if you notice any of the following serious side effects: 
-    A severe infection, 
-   Tiredness and/or looking pale, 
- Unexplained bruising (accumulation of blood under the skin) or bleeding, 
- Unusual headache, 
- Difficulties in breathing. 
 
Tell your doctor as soon as possible if you notice any of the following side effects: 
- Fever or chills, 
- Feeling sick, or a general feeling of being unwell, 
- Rash (itching red eruption of the skin), 
- Ulcers or wounds on your legs, 
- Sore (open skin infection) on your skin, 
- Disorientation (confusion) and dizziness. 
 
DETAILS OF SIDE EFFECTS 
 
Very common side effects (may affect more than 1 in 10 people): 
Low blood cell counts (myelosuppression), enlargement of red blood cells,  
Absence or low amount of sperm in the semen (azoospermia or oligospermia). Siklos may hence 
decrease the ability of men to father children. 
 
Common side effects (may affect up to 1 in 10 people): 
Reduced number of red blood cells (anaemia), low platelet count, headache, skin reactions, 
inflammation or ulceration of the mouth (oral mucositis).  
 
Uncommon side effects (may affect up to 1 in 100 people): 
Dizziness, nausea, itching red eruption of the skin (rash), black nails (melanonychia), and hair loss. 
 
Rare side effects (may affect up to 1 in 1,000 people): 
Wounds on the legs (leg ulcers), and modification of liver function.  
 
Very rare side effects (may affect up to 1 in 10,000 people) or unknown frequency (frequency 
cannot be estimated from the available data): 
Inflammation of the skin causing red scaly patches and possibly occurring together with pain in the 
joints. 
 
Isolated cases of malignant disease of blood cells (leukaemia), skin cancer in elderly patients, bleeding, 
gastrointestinal disturbances, vomiting, skin dryness, fever, absence of menstrual cycles 
(amenorrhoea), and weight gain. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Siklos 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Siklos after the expiry date which is stated on the carton and the bottle after EXP.  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


29 

 
Store below 30°C. 
 
Unused broken tablets must be replaced in the bottle and must be used within three months. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Siklos contains 
 
- The active substance is hydroxycarbamide.  

Each Siklos 100 mg film-coated tablet contains 100 mg hydroxycarbamide. 
Each Siklos 1000 mg film-coated tablet contains 1,000 mg hydroxycarbamide. 
 

- The other ingredients are sodium stearyl fumarate, silicified microcrystalline cellulose and basic 
butylated methacrylate copolymer. 

 
What Siklos looks like and contents of the pack 
 
Siklos 100 mg film-coated tablets are off-white, oblong-shaped tablets with a break line on both sides. 
The tablet can be divided into two equal parts. 
Each half of tablet is embossed “H” on one side. 
Siklos 100 mg is supplied in plastic bottles containing 60, 90 or 120 tablets. 
 
Siklos 1000 mg film-coated tablets are off-white, capsule-shaped tablets marked with three score lines 
on both sides. The tablet can be divided into four equal parts. 
Each quarter of tablet is embossed “T” on one side. 
Siklos 1000 mg is supplied in plastic bottles containing 30 tablets. 
 
All pack sizes may not be marketed. 
 
 
Marketing Authorisation Holder 
Addmedica 
37 rue de Caumartin  
75009 Paris 
France 
 
Manufacturer 
Delpharm Lille 
Parc d’Activités Roubaix-Est 
22 rue de Toufflers 
CS 50070 
59452 Lys-lez-Lannoy 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Addmedica 
Tel : +32-(0)2-808 2973 
  

Lietuva 
Addmedica 
37 rue de Caumartin  
75009 Paris - Prancūzija 
Tel : +33 (0)1 72 69 01 86 



30 

 
България 
Addmedica 
37 rue de Caumartin  
75009 Paris - Франция 
Tel : +33 (0)1 72 69 01 86 
 

Luxembourg/Luxemburg 
Addmedica 
37 rue de Caumartin  
75009 Paris/Parijs 
France/Frankreich/Frankrijk 
Tel : +33 (0)1 72 69 01 86 
 

Česká republika 
Addmedica 
37 rue de Caumartin  
75009 Paris - Francie 
Tel : +33 (0)1 72 69 01 86  
 

Magyarország 
Addmedica 
37 rue de Caumartin  
75009 Párizs - Franciaország 
Tel : +33 (0)1 72 69 01 86 

Danmark 
Addmedica 
37 rue de Caumartin  
75009 Paris - Frankrig 
Tel : +33 (0)1 72 69 01 86  
 

Malta 
Addmedica 
37 rue de Caumartin  
75009 Pariġi - Franza 
Tel : +33 (0)1 72 69 01 86 

Deutschland 
Addmedica 
Tel : +49-(0)30-8878 9408 
 

Nederland 
Addmedica 
Tel : +31-(0)20-208 2161 
 

Eesti 
Addmedica 
37 rue de Caumartin  
75009 Pariis - Prantsusmaa 
Tel : +33 (0)1 72 69 01 86 
 

Norge 
Addmedica 
37 rue de Caumartin  
75009 Paris - Frankrike 
Tel : +33 (0)1 72 69 01 86 

Ελλάδα 
DEMO ABEE 
Τηλ : +30 210 81 61 802 

Österreich 
Addmedica 
37 rue de Caumartin  
75009 Paris - Frankreich 
Tel : +33 (0)1 72 69 01 86 
 

España 
Laboratorios Farmacéuticos ROVI, S.A. 
Tel : +34 91 375 62 30 
 
 

Polska 
Addmedica 
37 rue de Caumartin  
75009 Paryż - Francja 
Tel : +33 (0)1 72 69 01 86 
 

France 
Addmedica 
37 rue de Caumartin  
75009 Paris 
Tel : +33 (0)1 72 69 01 86 
 

Portugal 
Laboratórios Farmacêuticos ROVI, S.A. 
Tel : +351 213 105 610 

Hrvatska 
Addmedica 
37 rue de Caumartin  
75009 Paris 
Tel : +33 (0)1 72 69 01 86 
 
 
 
 

România 
Addmedica 
37 rue de Caumartin  
75009 Paris - Franţa 
Tel : +33 (0)1 72 69 01 86 
 
 
 
 



31 

Ireland 
Addmedica 
Tel : +353-(0)1-903 8043 
 

Slovenija 
Addmedica 
37 rue de Caumartin  
75009 Pariz - Francija 
Tel : +33 (0)1 72 69 01 86  
 

Ísland 
Addmedica 
37 rue de Caumartin  
75009 Paris - Frakkland 
Tel : +33 (0)1 72 69 01 86 

Slovenská republika 
Addmedica 
37 rue de Caumartin  
75009 Paris - Francúzsko 
Tel : +33 (0)1 72 69 01 86 
 

Italia 
Addmedica 
37 rue de Caumartin  
75009 Parigi - Francia 
Tel : +33 (0)1 72 69 01 86 

Suomi/Finland 
Addmedica 
37 rue de Caumartin  
75009 Pariisi -Ranska 
Tel : +33 (0)1 72 69 01 86 
 

Κύπρος 
The Star Medicines Importers Co Ltd 
Τηλ : +357 25 37 1056 

Sverige 
Addmedica 
37 rue de Caumartin  
75009 Paris - Frankrike 
Tel : +33 (0)1 72 69 01 86 
 

Latvija 
Addmedica 
37 rue de Caumartin  
75009 Paris - Francija 
Tel : +33 (0)1 72 69 01 86 
 

United Kingdom 
Addmedica 
Tel : +44-(0)203-695 9305 
 

  
 
This leaflet was last approved in  
 
Detailed information on this medicine is available on the European Medicines Agency website 
http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments. 
 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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{'Title': '2. what you need to know before you take siklos', 'Section_Content': 'do not take siklos - if you are allergic to hydroxycarbamide or any of the other ingredients of this medicine (listed in section 6), - if you suffer from severe liver disease, - if you suffer from severe kidney disease, - if you are myelosuppressed (if you have decreased production of red, white, or coagulating blood cells) as described in section 3 "how to take siklos, treatment follow-up", - if you are breast-feeding (see section "pregnancy, breast-feeding and fertility"). warnings and precautions talk to your doctor or pharmacist or nurse before taking siklos - if you have a liver disease, - if you have a kidney disease, - if you have leg ulcers, - if you are taking other myelosuppressive medicines (decrease production of red, white, or coagulating blood cells) or receiving radiation therapy, - if you have a known lack of vitamin b12 or folate. if you experience (or have experienced) any of the above, please tell your doctor. if you have any question, please ask your doctor or pharmacist or nurse. patients and/or parents or the legal responsible person must be able to follow directions regarding the administration of this medicine, their monitoring and care. other medicines and siklos tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. information sharing is especially required for - some antiretroviral medicines (those that inhibit or destroy a retrovirus such as hiv), e.g. didanosine, stavudine and indinavir(a drop in your white cell count may occur) , - myelosuppressive medicines (those that decrease production of red, white, or coagulating blood cells) and radiation therapy, - some vaccines. pregnancy, breast-feeding and fertility if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. siklos is not recommended during pregnancy. please contact your doctor if you think you may be pregnant. the use of effective contraception is strongly recommended. if you become pregnant or plan to become pregnant while taking siklos, your doctor will discuss with you the potential benefits and risks of continuing using siklos. for male patients taking siklos, if your partner becomes pregnant or plans to become pregnant, your doctor will discuss with you the potential benefits and risks of continuing using siklos. the active substance of siklos passes into human breast-milk. you must not breast-feed while taking siklos. hydroxycarbamide may decrease sperm production in male patients while they are being treated. driving and using machines some people may experience dizziness when using siklos. do not drive or use any tools or machines if you experience dizziness whilst taking siklos.', 'Entity_Recognition': [{'Text': 'siklos', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 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{'Title': '3. how to take siklos', 'Section_Content': 'always take siklos exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. dose your doctor will tell you how much of siklos to take each day and will describe the dose in whole, half or quarter tablets. the prescribed dose of siklos must be taken once daily, preferably in the morning before breakfast. it can be taken with a glass of water or a very small amount of food. if you cannot swallow the tablets, you can disintegrate them in water immediately before use: place the required dose (preferably broken if siklos 1000 mg tablet is used) in a teaspoon and add some water. as soon as the tablet is disintegrated, swallow the content of the teaspoon. you can add a drop of syrup or mix the content with food to mask a possible bitter taste. then drink a large glass of water or any other drink. handling siklos is a cytotoxic medicine that must be handled with care. any person, in particular pregnant women, who are not taking siklos should avoid direct contact with the parts when breaking a tablet. wash your hands before and after contact with the tablets. in case the prescribed dose requires breaking the tablet in halves or quarters, this should be done out of the reach of food. powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown out. for the storage of unused broken tablets, see section 5 "how to store siklos". treatment follow-up your doctor will tell you how long to take siklos. when taking siklos you will have regular blood tests and check your liver and kidney. depending on the dose you take, these tests may be performed monthly or every two months. depending on these results your doctor will adjust your dose of siklos. if you take more siklos than you should if you take more siklos than you should or if a child has taken any, contact your doctor or the nearest hospital immediately as you may need urgent medical treatment. the most common symptoms of overdose with siklos are: - redness of the skin, - soreness (touch is painful) and swelling of the palms of hands and soles of feet followed by the hands and feet becoming scaly, - skin becoming strongly pigmented (locally changes of colour), - soreness or swelling in the mouth. if you forget to take siklos do not take a double dose to make up for a forgotten tablet. continue as normal when it is time to take the next dose as prescribed by your doctor. if you stop taking siklos do not stop your treatment unless advised by your doctor. if you have any further question on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'siklos', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the prescribed dose of siklos', 'Type': 'TREATMENT', 'BeginOffset': 243, 'EndOffset': 272}, {'Id': 5, 'BeginOffset': 553, 'EndOffset': 559, 'Score': 0.7753192186355591, 'Text': 'siklos', 'Category': 'MEDICATION', 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, siklos can cause side effects, although not everybody gets them. tell your doctor immediately if you notice any of the following serious side effects: - a severe infection, - tiredness and/or looking pale, - unexplained bruising (accumulation of blood under the skin) or bleeding, - unusual headache, - difficulties in breathing. tell your doctor as soon as possible if you notice any of the following side effects: - fever or chills, - feeling sick, or a general feeling of being unwell, - rash (itching red eruption of the skin), - ulcers or wounds on your legs, - sore (open skin infection) on your skin, - disorientation (confusion) and dizziness. details of side effects very common side effects (may affect more than 1 in 10 people): low blood cell counts (myelosuppression), enlargement of red blood cells, absence or low amount of sperm in the semen (azoospermia or oligospermia). siklos may hence decrease the ability of men to father children. common side effects (may affect up to 1 in 10 people): reduced number of red blood cells (anaemia), low platelet count, headache, skin reactions, inflammation or ulceration of the mouth (oral mucositis). uncommon side effects (may affect up to 1 in 100 people): dizziness, nausea, itching red eruption of the skin (rash), black nails (melanonychia), and hair loss. rare side effects (may affect up to 1 in 1,000 people): wounds on the legs (leg ulcers), and modification of liver function. very rare side effects (may affect up to 1 in 10,000 people) or unknown frequency (frequency cannot be estimated from the available data): inflammation of the skin causing red scaly patches and possibly occurring together with pain in the joints. isolated cases of malignant disease of blood cells (leukaemia), skin cancer in elderly patients, bleeding, gastrointestinal disturbances, vomiting, skin dryness, fever, absence of menstrual cycles (amenorrhoea), and weight gain. reporting of side effects if you get any side effects, talk to your doctor or, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'siklos', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'siklos', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 26}, {'Id': 18, 'BeginOffset': 37, 'EndOffset': 49, 'Score': 0.960091769695282, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.799491286277771}]}, {'Id': 19, 'BeginOffset': 157, 'EndOffset': 169, 'Score': 0.9456402063369751, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 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{'Title': '5 how to store siklos', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use siklos after the expiry date which is stated on the carton and the bottle after exp. store below 30. unused broken tablets must be replaced in the bottle and must be used within three months. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'siklos', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 167, 'EndOffset': 170}, {'Text': 'unused broken tablets', 'Type': 'TREATMENT', 'BeginOffset': 171, 'EndOffset': 192}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 396, 'EndOffset': 410}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what siklos contains - the active substance is hydroxycarbamide. each siklos 100 mg film-coated tablet contains 100 mg hydroxycarbamide. each siklos 1000 mg film-coated tablet contains 1,000 mg hydroxycarbamide. - the other ingredients are sodium stearyl fumarate, silicified microcrystalline cellulose and basic butylated methacrylate copolymer. what siklos looks like and contents of the pack siklos 100 mg film-coated tablets are off-white, oblong-shaped tablets with a break line on both sides. the tablet can be divided into two equal parts. each half of tablet is embossed "h" on one side. siklos 100 mg is supplied in plastic bottles containing 60, 90 or 120 tablets. siklos 1000 mg film-coated tablets are off-white, capsule-shaped tablets marked with three score lines on both sides. the tablet can be divided into four equal parts. each quarter of tablet is embossed "t" on one side. siklos 1000 mg is supplied 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