ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Siklos 100 mg film-coated tablets.
2.
Each film-coated tablet contains 100 mg of hydroxycarbamide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
Off-white round, film-coated tablet.
4.
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).
Treatment with Siklos should be initiated by a physician experienced in the management of 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 of
haemoglobin F (HbF), Mean Corpuscular Volume (MCV), neutrophil count) the dose of Siklos should
be maintained.
In case of non-response (re-occurrence of crises or no decrease 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 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:
Neutrophils
Platelets
< 80,000/mm
3
Haemoglobin
< 4.5 g/dl
2
< 2,000/mm
3
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 treating physician and should be based on the clinical
and haematological status of the individual patient.
< 80,000/mm
3
if the haemoglobin concentration < 9 g/dl
Children less than 2 years of age
Because of the rarity of 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.
Children and adolescents (2-18 years old)
In children and adolescents with Sickle Cell Syndrome, systemic exposure to hydroxycarbamide is
similar to adult patients. Hence, no dose-adjustments are necessary in younger patients.
Renal impairment
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 should 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 dose, 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 (Child-Pugh classification C) or 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.
3
Reticulocytes
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.
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 is recommended.
Hydroxycarbamide causes macrocytosis, which may mask the incidental development of folic acid and
vitamin B
12
deficiency. Prophylactic administration of folic acid is recommended.
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.
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.
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/mm
3
.
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
Women of childbearing potential
: 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.
Pregnancy
: Studies in animals have shown reproductive toxicity with adverse effects on fertility (see
section 5.3). Patients on hydroxycarbamide should be made aware of the theoretical risks to the foetus.
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.
Based on the limited amount of available information, in case of an exposure to hydroxycarbamide
during pregnancy, a careful follow-up with adequate clinical, biological and ultrasonographic
examinations should be considered.
Breastfeeding
: Hydroxycarbamide is excreted in human milk. Because of the potential for serious
adverse reactions in infants, breastfeeding must be discontinued while taking Siklos.
Fertility
: Reversible azo- and oligo-spermia have been rarely observed in man, although these
disorders are also associated with the underlying disease (see section 5.3).
No studies on the effect on the ability to drive and use machines have been performed. However,
patients should be informed that dizziness has been reported from literature, but not commonly.
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 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:
5
Infections and infestations:
Not known: Parvovirus B19 infection
Neoplasms, benign, malignant and unspecified
Not known: Leukaemia and in elderly patients, skin cancers
Blood and lymphatic system disorders:
Very common:
Bone marrow depression
1
including neutropenia (< 2.0 x 10
9
/l),
reticulocytopenia (< 80 x 10
9
/l), macrocytosis
2
Common:
Thrombocytopenia (< 80 x 10
9
/l), anaemia (haemoglobin < 4.5 g/dl)
3
Nervous system disorders:
Uncommon:
Headache
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
Not known: Cutaneous dryness
Reproductive system and breast disorders:
Very rare: Azoospermia, oligospermia
4
Not known: Amenorrhea
General disorders and administration site conditions:
Not known:
Fever
Investigations:
Not known:
Weight gain
5
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.
The clinical data obtained in patients with Sickle Cell Syndrome have not shown evidence of adverse
reactions of hydroxycarbamide on hepatic and renal function.
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
6
Common:
Dizziness
1
Haematological recovery usually occurs within two weeks of withdrawal of hydroxycarbamide.
2
The macrocytosis caused by hydroxycarbamide is not vitamin B
12
or folic acid dependent.
3
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX05.
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 up to 8 years.
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.
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 distribution at steady state adjusted for bioavailability is 0.57 l/kg in patients
7
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.
Metabolism:
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.
8
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. 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.
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.
6.1 List of excipients
Sodium stearyl fumarate
Silicified microcrystalline cellulose
Basic butylated methacrylate copolymer
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store below 30°C.
6.5
Nature and contents of container
High density polyethylene (HDPE) bottle with polypropylene (PP) child-resistant cap with a dessicant
unit.
Pack size: 60, 90 or 120 film-coated tablets.
Not all pack sizes may be marketed.
9
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 ones hands before and after contact with the tablets.
Any unused product or waste material should be disposed of in the accordance with local
requirements.
7.
Addmedica
101 rue Saint Lazare
75009 Paris
France
Phone: +33 1 72 69 01 86
Fax: +33 1 73 72 94 13
E-mail : contact@addmedica.com
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency: http://www.ema.europa.eu.
10
1.
Siklos 1000 mg film-coated tablets.
2.
Each film-coated tablet contains 1,000 mg of hydroxycarbamide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
Off-white, capsule-shaped, film-coated tablet with triple scoring on both sides.
The tablet can be divided into four equal parts.
4.
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).
Treatment with Siklos should be initiated by a physician experienced in the management of 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 of
haemoglobin F (HbF), Mean Corpuscular Volume (MCV), neutrophil count) the dose of Siklos should
be maintained.
In case of non-response (re-occurrence of crises or no decrease 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 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:
11
Neutrophils
< 2,000/mm
3
Haemoglobin
< 4.5 g/dl
Reticulocytes
< 80,000/mm
3
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 treating physician and should be based on the clinical
and haematological status of the individual patient.
Children less than 2 years of age
Because of the rarity of 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.
Children and adolescents (2-18 years old)
In children and adolescents with Sickle Cell Syndrome, systemic exposure to hydroxycarbamide is
similar to adult patients. Hence, no dose-adjustments are necessary in younger patients.
Renal impairment
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 should 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 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 (Child-Pugh classification C) or 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.
12
< 80,000/mm
3
Platelets
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.
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 is recommended.
Hydroxycarbamide causes macrocytosis, which may mask the incidental development of folic acid and
vitamin B
12
deficiency. Prophylactic administration of folic acid is recommended.
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.
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.
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/mm
3
.
13
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 potential
: 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.
Pregnancy
: Studies in animals have shown reproductive toxicity with adverse effects on fertility (see
section 5.3). Patients on hydroxycarbamide should be made aware of the theoretical risks to the foetus.
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.
Based on the limited amount of available information, in case of an exposure to hydroxycarbamide
during pregnancy, a careful follow-up with adequate clinical, biological and ultrasonographic
examinations should be considered.
Breastfeeding
: Hydroxycarbamide is excreted in human milk. Because of the potential for serious
adverse reactions in infants, breastfeeding must be discontinued while taking Siklos.
Fertility
: Reversible azo- and oligo-spermia have been rarely observed in man, although these
disorders are also associated with the underlying disease (see section 5.3).
No studies on the effect on the ability to drive and use machines have been performed. However,
patients should be informed that dizziness has been reported from literature, but not commonly.
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).
14
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:
Not known: Parvovirus B19 infection
Neoplasms, benign, malignant and unspecified
Not known: Leukaemia and in elderly patients, skin cancers
Blood and lymphatic system disorders:
Very common:
Bone marrow depression
1
including neutropenia (< 2.0 x 10
9
/l),
reticulocytopenia (< 80 x 10
9
/l), macrocytosis
2
Common:
Thrombocytopenia (< 80 x 10
9
/l), anaemia (haemoglobin < 4.5 g/dl)
3
Nervous system disorders:
Common:
Headache
Uncommon:
Dizziness
Vascular disorders:
Not known:
Bleeding
Gastrointestinal disorders:
Uncommon:
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
Not known: Cutaneous dryness
Reproductive system and breast disorders:
Very rare: Azoospermia, oligospermia
4
Not known: Amenorrhea
General disorders and administration site conditions:
Not known:
Fever
Investigations:
Not known:
Weight gain
5
The macrocytosis caused by hydroxycarbamide is not vitamin B
12
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.
The clinical data obtained in patients with Sickle Cell Syndrome have not shown evidence of adverse
reactions of hydroxycarbamide on hepatic and renal function.
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
15
Not known:
Nausea
1
Haematological recovery usually occurs within two weeks of withdrawal of hydroxycarbamide.
2
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX05.
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 up to 8 years.
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.
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.
16
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 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.
Metabolism:
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
17
severe hepatic impairment (see section 4.2). Close monitoring of blood parameters is advised in
patients with hepatic impairment.
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. 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.
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.
6.1 List of excipients
Sodium stearyl fumarate
Silicified microcrystalline cellulose
Basic butylated methacrylate copolymer
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months.
6.4 Special precautions for storage
Store below 30°C.
For storage of unused broken tablets see section 6.6;
18
6.5
Nature and contents of container
High density polyethylene (HDPE) bottle with polypropylene (PP) child-resistant cap with a dessicant
unit.
Pack size: 30 film-coated tablets.
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.
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. Unused broken tablets must be replaced in the box.
Anyone handling Siklos should wash ones hands before and after contact with the tablets.
Any unused product or waste material should be disposed of in the accordance with local
requirements.
7.
Addmedica
101 rue Saint Lazare
75009 Paris
France
Phone: +33 1 72 69 01 86
Fax: +33 1 73 72 94 13
E-mail: contact@addmedica.com
8.
EU/1/07/397/001
9.
29/06/2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency: http://www.ema.europa.eu.
19
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
20
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Elaiapharm
2881 Route des Crêtes
Z.I. Les Bouillides - Sophia Antipolis
F-06560 Valbonne
France
B. CONDITIONS OF THE MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
·
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder (MAH) shall ensure that, prior to launch, all physicians who
are expected to prescribe Siklos are provided with a physician information pack containing the
following:
·
Treatment guide for physicians
·
Patient information pack
The treatment guide for physicians should contain the following key elements:
·
The Summary of Product Characteristics
·
Need for periodic blood counts and dose adjustment
·
Need for contraception
·
Risk to male and female fertility, potential risk to foetus and breast feeding
·
Growth follow-up of treated children
·
Handling of broken tablets
·
Management of adverse drug reactions
·
Risk of medication error due to the availability of two different strengths
The patient information pack should contain the following key elements:
·
Package leaflet
·
Handling of broken tablets
·
Need for periodic blood counts
·
Information on crisis or infections
·
Need for contraception
·
Risk to male and female fertility, potential risk to foetus and breast feeding
·
Key signs and symptoms of serious adverse reactions
·
When to seek urgent attention from the health care provider
·
Information on growth follow-up of treated children for their parents
·
Risk of medication error due to the availability of two different strengths
21
·
The MAH must implement this educational plan nationally, prior to marketing, and as agreed
with the competent authorities in the Member States
·
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan as agreed in version 9 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products of human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
-
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
-
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
-
At the request of the European Medicines Agency
22
ANNEX III
LABELLING AND PACKAGE LEAFLET
23
A. LABELLING
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Handle tablets with care.
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store below 30 °C.
25
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Addmedica, 101 rue Saint Lazare – 75009 Paris - France
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
SIKLOS 100 mg
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Handle tablets with care.
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store below 30 °C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
27
APPROPRIATE
Addmedica, 101 rue Saint Lazare – 75009 Paris - France
EU/1/07/397/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
SIKLOS 1000 mg
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
BOTTLE
1.
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
Addmedica
29
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Handle tablets with care.
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store below 30 °C.
30
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Addmedica, 101 rue Saint Lazare – 75009 Paris - France
EU/1/07/397/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
31
B. PACKAGE LEAFLET
32
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
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
1.
What Siklos is and what it is used for
3.
How to take Siklos
4.
Possible side effects
5
How to store Siklos
6.
Further 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 Syndrome,
in children older than 2 years and adults.
Sickle cell disease is an inherited blood disorder that affects the rounded 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 the most severe crises, most patients require hospitalisations.Siklos will decrease the number of
painful crises as well as the need for hospitalisation linked with the disease.
The active substance of Siklos, i.e. 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 Syndrome,
hydroxycarbamide helps to prevent red blood cells from taking abnormal shape.
2.
BEFORE YOU TAKE SIKLOS
Do not take Siklos
-
if you are allergic (hypersensitive) to hydroxycarbamide or any of the other ingredients of
Siklos, (see section “FURTHER INFORMATION”),
-
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 the section “HOW TO TAKE SIKLOS” (treatment follow-up),
-
if you are breast-feeding (see section “Pregnancy and breast-feeding”).
33
2.
Before you take Siklos
Take special care with Siklos
-
if you have a liver disease,
-
if you have a kidney disease,
-
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.
Taking other medicines
Please inform your doctor or pharmacist if you are taking:
-
antiretroviral medicines (those that inhibit or destroy a retrovirus such as HIV), e.g. didanosine,
stavudine and indinavir (a median decline in some of your white blood cells called CD4 cells of
approximately 100/mm
3
may occur) ,
-
myelosuppressive medicines (decrease production of red, white, or coagulating blood cells) and
radiation therapy,
-
some vaccines (if you have doubts, please ask your pharmacist or your doctor).
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
even medecines obtained without a prescription.
Taking Siklos with food and drink
Please take Siklos in the morning before breakfast and, where necessary, with a glass of water or a
very small amount of food to ensure optimal absorption.
Pregnancy and breast-feeding
Siklos is not recommended during pregnancy.
If you are a woman you have to use
adequate birth control measures
during treatment with
hydroxycarbamide. 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 Siklos.
For the 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 Siklos.
The active substance of Siklos passes into human breast-milk. You must not breast-feed while taking
Siklos.
Driving and using machines
Dizziness is an uncommon side effect of Siklos. Do not drive or use any tools or machines if you
experience dizziness whilst taking Siklos.
3.
HOW TO TAKE SIKLOS
Handling
Siklos is a medicine that must be handled with care.
Any person, in particular pregnant women, who are not taking Siklos should avoid to come in direct
contact with the parts when breaking a tablet. Wash your hands before and after contact with the
tablets.
34
-
if you have leg ulcers,
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 HOW TO STORE
SIKLOS.
Dosages
Always take Siklos exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Your doctor will tell you how much of Siklos to take each day and define the dose in whole, half
or quarter tablets.
The prescribed dose of Siklos must be taken once daily, preferably in the morning before breakfast. If
necessary, 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.
Treatment follow-up
The duration of treatment is the responsibility of your treating doctor and should be based on your
physical condition and blood count. The treating doctor will monitor your blood count and adjust your
dose accordingly.
When taking Siklos you will have regular blood tests and tests on your liver and kidney
functions. Depending on the dose you take, these tests may be performed every two weeks or
every two months.
According to these results your doctor will adjust your dose of Siklos.
The growth of treated children should be regularly monitored by the treating doctor.
If you take more Siklos than you should
If you take more Siklos that you should or if a child has taken any, immediately contact your doctor or
the nearest hospital as you may need urgent medical treatment. The most common symptoms of
overdose with Siklos are:
-
Soreness (touch is painful)
-
Swelling of the palms of hands and soles of feet followed by the hands and feet becoming scaly
-
Skin becoming strongly pigmented (coloured)
-
Soreness or swelling in the mouth.
If you forget to take Siklos
Do not take a double dose to make up for 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.
35
-
Redness of the skin
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Siklos can cause side effects, although not everybody gets them.
ACTIONS TO TAKE IN CASE OF SIDE EFFECTS
Tell your doctor immediately if you experience any of the following:
-
A severe infection
-
Tiredness and/or looking pale
-
Unexplained bruising (accumulation of blood under the tissues) or bleeding
-
Headache
-
Difficulties in breathing.
All these are serious side effects of Siklos. You may need medical attention.
Tell your doctor as soon as possible if you notice any of the following side effects of Siklos:
-
Rash (itching red eruption of the skin)
-
Sore (open skin infection) on your skin.
-
Fever or chills
-
Feeling sick, weak, lacking energy or a general feeling of being unwell
-
Disorientation (confusion) and dizziness
DETAILS OF SIDE EFFECTS
Very common side effects (occurring in more than 1 in 10 people):
Low blood cell counts (myelosuppression), enlargement of red blood cells, decreased resistance to
infections.
Common side effects (occurring in less than 1 in 10 people, but more than 1 in 100):
Reduced number of red blood cells (anemia), low platelet count, headache, skin reactions,
inflammation or ulceration of the mouth (oral mucositis).
Uncommon side effects (occurring in less than 1 in 100 people, but more than 1 in 1,000):
Dizziness, nausea, itching red eruption of the skin (rash), black nails (melanonychia), hair loss.
Rare side effects (occurring in less than 1 in 1,000 people, but more than 1 in 10,000):
Wounds on the legs (leg ulcers), modification of liver function,
Very rare side effects or unknown frequency (frequency cannot be estimated from the available
data):
Absence or low amount of sperm in the semen (azoospermia or oligospermia). Siklos may hence
decrease the ability of men to father children.
Isolated cases of malignant disease of blood cells (leukaemia), skin cancer in elderly patients, viral
infection with
Parvovirus B19
, bleeding, gastrointestinal disturbances, vomiting, skin dryness, fever,
absence of menstrual cycles (amenorrhoea), and weight gain.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
5.
HOW TO STORE SIKLOS
Keep out of the reach and sight of children.
36
-
Ulcers or wounds on your legs
Do not use Siklos after the expiry date which is stated on the carton and the bottle after EXP. The
expiry date refers to the last day of that month.
Store below 30
°
C.
Unused Siklos 1000 mg broken tablets must be replaced in the box.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER 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
methacrylate copolymer.
What Siklos looks like and contents of the pack
Siklos 100 mg film-coated tablets are off-white, round tablets.
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.
Siklos 1000 mg is supplied in plastic bottle of 30 tablets.
All pack sizes may not be marketed.
Marketing Authorisation Holder
Addmedica
101 rue Saint Lazare
75009 Paris
France
Manufacturer
Elaiapharm
2881 Route des Crêtes
Z.I. Les Bouillides - Sophia Antipolis
06560 Valbonne
France
For any information about thismedicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Nordic Pharma
Laanstraat 16
B-2610 Wilrijk
Tel : +32 (0)3 820 52 24
Luxembourg/Luxemburg
Nordic Pharma
Laanstraat 16
B-2610 Wilrijk
België/Belgique/Belgien
Tel : +32 (0)3 820 52 24
37
България
Addmedica
101 rue Saint Lazare
75009 Paris - Франция
Tel : +33 (0)1 72 69 01 86
Magyarország
Addmedica
101 rue Saint Lazare
75009 Párizs - Franciaország
Tel : +33 (0)1 72 69 01 86
Česká republika
101 rue Saint Lazare
75009 Paris - Francie
Telefon: +33 (0)1 72 69 01 86
Malta
Addmedica
101 rue Saint Lazare
75009 Pariġi - Franza
Tel : +33 (0)1 72 69 01 86
Danmark
Addmedica
101 rue Saint Lazare
75009 Paris - Frankrig
Telefon: +33 (0)1 72 69 01 86
Nederland
Nordic Pharma B.V.
Tel.: +31 (0)35-5480580
Email: info@nordicpharma.nl
Deutschland
Nordic Pharma GmbH
Fraunhoferstrasse 4
85737 Ismaning
Tel.: +49 (0)89 88 96 90 680
Norge
Addmedica
101 rue Saint Lazare
75009 Paris - Frankrike
Tel : +33 (0)1 72 69 01 86
Eesti
Addmedica
101 rue Saint Lazare
75009 Pariis - Prantsusmaa
Tel : +33 (0)1 72 69 01 86
Österreich
Addmedica
101 rue Saint Lazare
75009 Paris - Frankreich
Tel : +33 (0)1 72 69 01 86
Ελλάδα
DEMO ABEE
Τηλ.: +30 210 81 61 802
Polska
Addmedica
101 rue Saint Lazare
75009 Paryż - Francja
Tel : +33 (0)1 72 69 01 86
España
Laboratorios Farmacéuticos ROVI, S.A.
Tel: +34 91 375 62 30
Portugal
Laboratórios Farmacêuticos ROVI, S.A.
Tel: +351 213 105 610
France
Addmedica
101 rue Saint Lazare
75009 Paris
Tel : +33 (0)1 72 69 01 86
România
Addmedica
101 rue Saint Lazare
75009 Paris - Franţa
Tel : +33 (0)1 72 69 01 86
Ireland
Nordic Pharma Ltd.
Reading, Berkshire RG7 4SA - UK
Tel : +44 (0)118 929 82 33
Slovenija
Addmedica
101 rue Saint Lazare
75009 Pariz - Francija
Tel : +33 (0)1 72 69 01 86
Ísland
Slovenská republika
38
Addmedica
101 rue Saint Lazare
75009 Paris - Frakkland
Tel : +33 (0)1 72 69 01 86
Addmedica
101 rue Saint Lazare
75009 Paris - Francúzsko
Tel : +33 (0)1 72 69 01 86
Italia
Addmedica
101 rue Saint Lazare
75009 Parigi - Francia
Tel : +33 (0)1 72 69 01 86
Suomi/Finland
Addmedica
101 rue Saint Lazare
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
101 rue Saint Lazare
75009 Paris - Frankrike
Tel : +33 (0)1 72 69 01 86
Latvija
Addmedica
101 rue Saint Lazare
75009 Paris - Francija
Tel : +33 (0)1 72 69 01 86
United Kingdom
Nordic Pharma Ltd.
Reading, Berkshire RG7 4SA - UK
Tel : +44 (0)118 929 82 33
Lietuva
Addmedica
101 rue Saint Lazare
75009 Paris - Prancūzija
Tel : +33 (0)1 72 69 01 86
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.
39
Source: European Medicines Agency
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