- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Siklos 100 mg
Siklos 1000 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Siklos 100 mg
Siklos 1000 mg
For the full list of excipients, see section 6.1.
Siklos 100 mg
Siklos 1000 mg
Siklos is indicated for the prevention of recurrent painful
4.2Posology and method of administration
Treatment with Siklos should be initiated by a physician experienced in the management of Sickle Cell Syndrome.
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 of haemoglobin F (HbF), Mean Corpuscular Volume (MCV), neutrophil count) the dose of Siklos should be maintained.
In case of
Under exceptional circumstances a maximum dose of 35 mg/kg b.w./day might be justified under close haematological monitoring (see section 4.4).
In the event a patient does still not respond when treated with the maximum dose of hydroxycarbamide (35 mg/kg b.w./day) 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. Haematologic recovery usually occurs within two weeks. Treatment may then be reinstituted 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:
< 4.5 g/dl
< 80,000/mm3 if the haemoglobin concentration < 9 g/dl
Children less than 2 years of age
Because of the rarity of long term data on 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.
As renal excretion is a main pathway of elimination, dose reduction of Siklos should be considered in patients with renal impairment. In patients with a 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).
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
Siklos 100 mg
Conforming to the individual dose, the tablet should be taken once daily, preferably in the morning before breakfast with a glass of water or a very small amount of food.
Siklos 1000 mg
Conforming to the individual dose, the tablet or the halves or quarters of the tablet should be taken once daily, preferably in the morning before breakfast and, where 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.
Hypersensitivity to the active substance or to any of the excipients.
Severe hepatic impairment
Severe renal impairment (creatinine clearance < 30 ml/min).
Toxic ranges of myelosuppression as described in section 4.2.
4.4Special warnings and precautions for use
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
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.
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
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.
4.5Interaction 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
Concurrent use of hydroxycarbamide and other myelosuppressive medicinal products or radiation therapy may increase bone marrow depression,
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.
4.6Fertility, 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
In the human, according to a retrospective analysis of a cohort of 123 adult patients treated with hydroxycarbamide,
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
Hydroxycarbamide is excreted in human milk. Because of the potential for serious adverse reactions in infants,
Fertility in males might be affected by treatment. Very common reversible oligo- and
4.7Effects 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.
Summary of the safety profile
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
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:
Infections and infestations:
Parvovirus B19 infection
Neoplasms, benign, malignant and unspecified
Leukaemia and in elderly patients, skin cancers
Blood and lymphatic system disorders:
Bone marrow depression1 including neutropenia (< 2.0 x 109/L),
reticulocytopenia (< 80 x 109/L), macrocytosis2
Thrombocytopenia (< 80 x 109/L), anaemia (haemoglobin
< 4.5 g/dl)3
Nervous system disorders:
Gastrointestinal disturbances, vomiting, gastrointestinal ulcer,
Elevated liver enzymes
Skin and subcutaneous tissue disorders:
Skin reactions (for example oral, ungual and cutaneous
pigmentation) and oral mucositis.
Rash, melanonychia, alopecia
Reproductive system and breast disorders:
Oligospermia , azoospermia4
General disorders and administration site conditions:
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.
4Oligospermia 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
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, neutropenia was reported in isolated cases of hydroxycarbamide overdose (1.43 times and 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.
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX05.
Mechanism of action
The specific mechanism of action of hydroxycarbamide is not fully understood. One of the mechanisms by which hydroxycarbamide acts is the elevation of foetal haemoglobin (HbF) concentrations in sickle cell patients. HbF interferes with the polymerisation of HbS and thus impedes the sickling of red blood cell. 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 of neutrophils, increase of the water content of erythrocytes, increase of the 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.
Beside the inconstant correlation between reduction of crisis rate and the increase in HbF, the cytoreductive effect of hydroxycarbamide, particularly the drop of neutrophils, was the factor with the strongest correlation to a reduced crisis rate.
Clinical efficacy and safety
In nearly all clinical studies conducted in Sickle Cell Syndrome, hydroxycarbamide reduced the frequency of
A sustained clinical benefit was demonstrated in patients remaining on hydroxycarbamide treatment for up to 8 years.
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
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 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.
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
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
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
Geriatric, gender, race
No information is available regarding pharmacokinetic differences due to age (except paediatric patients), gender or race.
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
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
Close monitoring of blood parameters is advised in these patients.
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.
5.3Preclinical 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.
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.
6.1List of excipients
Sodium stearyl fumarate
Silicified microcrystalline cellulose
Basic butylated methacrylate copolymer
Siklos 1000 mg
Unused broken tablets must be replaced in the bottle and must be used within three months.
6.4Special precautions for storage
Store below 30°C.
6.5Nature and contents of container
High density polyethylene (HDPE) bottle with polypropylene
Siklos 100 mg
Pack sizes of 60, 90 or 120 tablets.
Not all pack sizes may be marketed.
Siklos 1000 mg
Pack size of 30 tablets.
6.6Special 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.
Siklos 1000 mg
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
101 rue Saint Lazare
75009 Paris France
Phone: +33 1 72 69 01 86
Fax: +33 1 73 72 94 13
8.MARKETING AUTHORISATION NUMBER(S)
Siklos 100 mg
Siklos 1000 mg
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 29/06/2007
Date of latest renewal: 28/06/2012
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.