SIKLOS 100 MG TABLETS - summary of medicine characteristics

Siklos 100 mg film-coated tablet.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Siklos 100 mg film-coated tablet

Each film-coated tablet contains 100 mg of hydroxycarbamide.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Siklos 100 mg film-coated tablet

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.

4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

Posology

In adults, adolescents and children older than 2 years

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

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

between 15 and 30 mg/kg b.w./day.

As long as the patient responds to therapy either clinically or haematologica­lly (e.g.

increase in haemoglobin F (HbF), Mean Corpuscular Volume (MCV), decrease in neutrophil count), the dose of Siklos should be maintained.

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

Under exceptional circumstances a maximum dose of 35 mg/kg b.w./day may be

justified under close haematological monitoring (see section 4.4).

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

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

The toxic range may be characterised by the following results of blood tests: Neutrophils < 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 followup of 12 years in children and adolescents and over 13 years in adults. It is currently unknown how long patients should be treated with Siklos. The duration of treatment is the responsibility of the prescribing physician and should be based on the clinical and haematological status of each patient.

Special , populations

Children less than 2 years of age

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

Renal impairment

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

Hepatic impairment

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

Method of administration

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

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

4.3 Contraindications

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

Severe hepatic impairment (Child-Pugh classification C).

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

Toxic ranges of myelosuppression as described in section 4.2.

Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Bone marrow depression

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

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

Renal and hepatic impairment

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

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

Leg ulcers and cutaneous vasculitis toxicities

In patients with leg ulcers, Siklos should be used with caution. Leg ulcers are a common complication of sickle cell syndrome, but have also been reported in patients treated with hydroxycarbamide. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued and/or its dose reduced if cutaneous vasculitic ulcerations develop. Rarely, ulcers are caused by leukocytoclastic vasculitis.

Macrocytosis

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

Carcinogenicity

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

Safe administration and monitoring

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

4.5 Interaction with other medicinal products and other forms of interaction

Specific interaction studies have not been performed with hydroxycarbamide.

Potentially fatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxycarbamide in combination with first generation antiretroviral medicinal products, particularly didanosine plus stavudine. Patients treated with hydroxycarbamide in combination with didanosine, stavudine, and indinavir showed a median decline in CD4 cells of approximately 100/mm3.

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

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Con­traception in males and females

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

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

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

Pregnancy

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

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

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

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

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

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

Tabulated list of adverse reactions

The adverse reactions are listed below by system organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1 000 to <1/100), rare (>1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

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        Oligos­permia, azoospermia4

common:

___________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.

Pediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the 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.

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. Increased HbF also increases red blood cell survival and total haemoglobin level and thus reduces anaemia in these patients.

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.

In severe chronic anaemia, data from a selected cohort of the uncontrolled ESCORT HU were collected in a subset of 27 pediatric patients treated with Siklos for 12 months who had haemoglobin levels less than 7 g/dL at baseline. Of these, only 6 (22%) patients had levels less than 7 g/dL at Month 12. While there have been a majority of patients (56%) who had a change from baseline equal to or exceeding 1 g/dL, due to the large proportion of missing data, potential for regression to the mean and that an effect of transfusions could not be excluded, no robust efficacy conclusions can be made from this uncontrolled study.

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 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 |1M is not metabolised in vitro by cytochrome P450s of human liver microsomes. At concentrations ranging from 10 to 300 liVI, 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 hydroxy carbamide 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.

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.

6.1 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 tablet

Pack sizes of 60 tablets.

6.6 Special precautions for disposal

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 : question@addme­dica.com

8 MARKETING AUTHORISATION NUMBER(S)

Siklos 100 mg film-coated tablet 36580/0002