ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
LITAK 2 mg/ml solution for injection
2.
Each ml of solution contains 2 mg of cladribine (2-CdA). Each vial contains 10 mg of cladribine in
5 ml of solution.
For a full list of excipients, see section 6.1.
3.
Solution for injection.
Clear, colourless solution.
4.
LITAK is indicated for the treatment of hairy cell leukaemia.
Therapy with LITAK should be initiated by a qualified physician with experience in cancer
chemotherapy.
Posology
The recommended posology for hairy cell leukaemia is a single course of LITAK given by
subcutaneous bolus injection at a daily dose of 0.14 mg/kg body weight for 5 consecutive days.
Deviations from the posology indicated above are not advised.
Elderly
Experience with patients older than 65 years is limited. Elderly patients should be treated by individual
assessment and careful monitoring of the blood counts and of the renal and hepatic function. The risk
requires assessment on a case-by-case basis (see section 4.4).
Renal and hepatic impairment
There are no data on the use of LITAK in patients with renal or hepatic impairment. LITAK is
contraindicated in patients with moderate to severe renal impairment (creatinine clearance
≤ 50 ml/min) or with moderate to severe hepatic impairment (Child-Pugh score > 6) (see sections 4.3,
4.4 and 5.2).
Paediatric use
LITAK is contraindicated in patients less than 18 years of age (see section 4.3).
Method of administration
LITAK is supplied as a ready-to-use solution for injection. The recommended dose is directly
withdrawn by a syringe and injected as a subcutaneous bolus injection without dilution. LITAK should
be inspected visually for particulate matter and discoloration prior to administration. LITAK should
warm up to room temperature prior to administration.
2
Self-administration by the patient
LITAK can be self-administered by the patient. Patients should be instructed and trained
appropriately. Detailed instructions are contained in the Package Leaflet.
Hypersensitivity to the active substance or any of the excipients.
Patients less than 18 years of age.
Moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) or moderate to severe hepatic
impairment (Child-Pugh score > 6) (see also section 4.4).
Concomitant use of other myelosuppressive medicinal products.
Cladribine is an antineoplastic and immunosuppressive substance that can induce considerable toxic
adverse reactions, such as myelo- and immunosuppression, long-lasting lymphocytopenia, and
opportunistic infections. Patients undergoing treatment with cladribine should be closely monitored for
signs of haematologic and non-haematologic toxicities.
Particular caution is advised and risks/benefits should be carefully evaluated if administration of
cladribine is considered in patients with increased infection risk, manifested bone marrow failure or
infiltration, myelosuppressive pre-treatments, as well as in patients with suspected or manifested renal
and hepatic insufficiency. Patients with active infection should be treated for the underlying condition
prior to receiving therapy with cladribine. Although anti-infective prophylaxis is not generally
recommended, it may be beneficial for patients immunocompromised prior to therapy with cladribine or
for patients with a pre-existing agranulocytosis.
If severe toxicity occurs, the physician should consider delaying or discontinuing the therapy with the
medicinal product until serious complications resolve. In case of infections, antibiotic treatment should
be initiated as required.
It is recommended that patients receiving cladribine should receive irradiated cellular blood
components/products to prevent transfusion-related graft-versus-host disease (Ta-GVHD).
Secondary malignancies
Like other nucleoside analogues, treatment with cladribine is associated with myelosuppression and
profound and prolonged immunosuppression. Treatment with these agents is associated with the
occurrence of second malignancies. Secondary malignancies are expected to occur in patients with
hairy cell leukaemia. Their frequency varies widely, ranging from 2% to 21%. The peak risk is at 2
years after diagnosis with a median between 40 and 66 months. The cumulative frequencies of second
malignancy are 5%, 10-12% and 13-14% following 5, 10 and 15 years respectively after diagnosis of
hairy cell leukaemia. Following cladribine, the incidence of second malignancies ranges from 0% to
9.5% after a median observation period of 2.8 to 8.5 years. The frequency of second malignancy
following treatment with LITAK was 3.4% in all 232 hairy cell leukaemia patients treated, during a
10-year period. The highest incidence of second malignancy with LITAK was 6.5% after a median
follow-up of 8.4 years. Therefore, patients treated with cladribine should be regularly monitored.
Haematologic toxicity
During the first month following treatment, myelosuppression is most notable and red blood cell or
platelet transfusions may be required. Patients with symptoms of bone marrow depression should be
treated with caution, since further suppression of bone marrow function should be anticipated.
Therapeutic risks and benefits should be carefully evaluated in patients with active or suspected
3
infections. The risk of severe myelotoxicity and long-lasting immunosuppression is increased in
patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.
Dose reduction and regular monitoring of the patient is required in such cases. Pancytopenia is
normally reversible and the intensity of bone marrow aplasia is dose-dependent. An increased
incidence of opportunistic infections is expected during, and for 6 months following, therapy with
cladribine. Careful and regular monitoring of peripheral blood counts is essential during, and for 2 to 4
months following, treatment with cladribine to detect potential adverse reactions and consequent
complications (anaemia, neutropenia, thrombocytopenia, infections, haemolysis or bleedings), and to
survey haematologic recovery. Fever of unknown origin frequently occurs in patients treated for hairy
cell leukaemia and is manifested predominantly during the first 4 weeks of therapy. The origin of
febrile events should be investigated by appropriate laboratory and radiologic tests. Less than a third
of febrile events are associated with a documented infection. In case of fever related to infections or
agranulocytosis, an antibiotic treatment is indicated.
Renal and hepatic impairment
There are no data on the use of LITAK in patients with renal or hepatic impairment. Clinical experience
is very limited and safety of LITAK in these patients is not well established (see sections 4.3 and 5.2).
Careful treatment is required in patients with known or suspected renal or hepatic impairment. For all
patients treated with LITAK, periodic assessment of renal and hepatic function is advised as clinically
indicated.
Elderly
Elderly patients should be treated by individual assessment and careful monitoring of the blood counts
and of the renal and hepatic function. The risk requires assessment on a case-by-case basis (see section
4.2).
Prevention of tumour lysis syndrome
In patients with a high tumour burden, prophylactic allopurinol therapy to control serum levels of uric
acid, together with adequate or increased hydration, should be commenced 24 hours before the start of
chemotherapy. A daily oral dose of 100 mg of allopurinol is recommended for a period of 2 weeks. In
case of an accumulation of the serum uric acid above the normal range, the dose of allopurinol may be
increased to 300 mg/day.
Fertility
Men being treated with cladribine should be advised not to father a child up to 6 months after
treatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibility
of infertility due to therapy with cladribine (see sections 4.6 and 5.3).
Due to a potential increase of haematological toxicity and bone marrow suppression, cladribine must
not be used concomitantly with other myelosuppressive medicinal products. An influence of cladribine
on the activity of other antineoplastic agents has not been observed
in vitro
(e.g. doxorubicin, vincristine,
cytarabine, cyclophosphamide) and
in vivo
. However, an
in vitro
study revealed cross-resistance
between cladribine and nitrogen mustard (chlormethine); for cytarabine, one author has described an
in vivo
cross-reaction without loss of activity.
Due to the similar intracellular metabolism, cross-resistance with other nucleoside analogues, such as
fludarabine or 2’-deoxycoformycin may occur. Therefore, simultaneous administration of nucleoside
analogues with cladribine is not advisable.
Corticosteroids have been shown to enhance the risk for severe infections when used in combination
with cladribine and should not be given concomitantly with cladribine.
Since interactions with medicinal products undergoing intracellular phosphorylation, such as antiviral
agents, or with inhibitors of adenosine uptake may be expected, their concomitant use with cladribine
is not recommended.
4
Pregnancy
Cladribine causes serious birth defects when administered during pregnancy. Animal studies and
in vitro
studies with human cell lines demonstrated the teratogenicity and mutagenicity of cladribine. Cladribine
is contraindicated in pregnancy.
Women of childbearing potential must use effective contraception during treatment with cladribine and
for 6 months after the last cladribine dose. In case of pregnancy during therapy with cladribine, the
woman should be informed about the potential hazard to the foetus.
Lactation
It is unknown whether cladribine is excreted in human milk. Because of the potential for serious
adverse reactions in nursing infants, lactation is contraindicated during treatment with cladribine and
for 6 months after the last cladribine dose.
Fertility
The effects of cladribine on fertility have not been studied in animals. However, a toxicity study
conducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidly
generating cells, including testicular cells. The effect on human fertility is unknown. Antineoplastic
agents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expected
to have adverse effects on human gametogenesis (see section 5.3).
Men being treated with cladribine should be advised not to father a child up to 6 months after
treatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibility
of infertility due to therapy with cladribine (see section 4.4).
LITAK has a major influence on the ability to drive and use machines. In case certain adverse reactions
with a potential impact on performance occur (e.g. dizziness, very common, or drowsiness, which may
occur due to anaemia, which is very common), patients should be advised not to drive or use machines.
Very common adverse reactions observed during the three most relevant clinical trials with cladribine
in 279 patients treated for various indications and in 62 patients with hairy cell leukaemia (HCL) were
myelosuppression, especially severe neutropenia (41% (113/279), HCL 98% (61/62)), severe
thrombocytopenia (21% (58/279), HCL 50% (31/62)) and severe anaemia (14% (21/150), HCL 55%
(34/62)), as well as severe immunosuppression/lymphopenia (63% (176/279), HCL 95% (59/62)),
infections (39% (110/279), HCL 58% (36/62)) and fever (up to 64%).
Culture-negative fever following treatment with cladribine occurs in 10-40% of patients with hairy
cell leukaemia and is rarely observed in patients with other neoplastic disorders. Skin rashes (2-31%)
are mainly described in patients with other concomitantly administered medicinal products known to
cause rash (antibiotics and/or allopurinol). Gastrointestinal adverse reactions like nausea (5-28%),
vomiting (1-13%), and diarrhoea (3-12%) as well as fatigue (2-48%), headache (1-23%), and
decreased appetite (1-22%) have been reported during treatment with cladribine. Cladribine is unlikely
to cause alopecia; mild and transient alopecia for a few days was observed in 4/523 patients during the
treatment, but could not clearly be associated with cladribine.
Adverse reactions that have been reported are listed in the table below by frequency category and
system organ class. The frequencies are defined as follows: 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). For severity, please see text below the table.
5
Infections and infestations
Very common: infections * (e.g. pneumonia *, septicaemia *)
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps)
Common: second malignancies *
Rare: tumour lysis syndrome *
Blood and lymphatic system
disorders
Very common: pancytopenia/myelosuppression *, neutropenia,
thrombocytopenia, anemia, lymphopenia
Uncommon: haemolytic anaemia *
Rare: hypereosinophilia
Very rare: amyloidosis
Immune system disorders
Very common: immunosuppression *
Rare: graft-versus-host disease *
Metabolism and nutrition
disorders
Very common: decreased appetite
Uncommon: cachexia
Nervous system disorders
Very common: headache, dizziness
Common: insomnia, anxiety
Uncommon: somnolence, paraesthesia, lethargy, polyneuropathy,
confusion, ataxia
Rare: apoplexy, neurological disturbances in speech and
swallowing
Very rare:
depression, epileptic seizure
Eye disorders
Uncommon: conjunctivitis
Very rare: blepharitis
Cardiac disorders
Common: tachycardia, heart murmur, hypotension, epistaxis,
myocardial ischemia *
Rare: Cardiac failure, atrial fibrillation, cardiac decompensation
Vascular disorders
Very common: purpura
Common: petechiae, haemorrhages *
Uncommon: phlebitis
Respiratory, thoracic and
mediastinal disorders
Very common: abnormal breath sounds, abnormal chest sounds,
cough
Common: shortness of breath, pulmonary interstitial infiltrates
mostly due to infectious aetiology, mucositis
Uncommon: pharyngitis
Very rare: lung embolism
Gastrointestinal disorders
Very common: nausea, vomiting, constipation, diarrhoea
Common: gastrointestinal pain, flatulence
Rare: ileus
Hepato-biliary disorders
Common: reversible, mostly mild increases in bilirubin and
transaminases
Rare: hepatic failure
Very rare: cholecystitis
Skin and subcutaneous tissue
disorders
Very common: rash, localised exanthema, diaphoresis
Common: pruritus, skin pain, erythema, urticaria
Rare: Stevens-Johnson syndrome/Lyell syndrome
Musculoskeletal and connective
tissue disorders
Common: myalgia, arthralgia, arthritis, bone pain
Renal and urinary disorders
Rare: renal failure
General disorders and
administration site conditions
Very common: injection site reactions, fever, fatigue, chills,
asthenia
Common: oedema, malaise, pain
* see descriptive section below.
Non-haematological adverse reactions
6
Non-haematological adverse reactions are generally mild to moderate in severity. Treatment of nausea
with antiemetics is usually not necessary. Adverse reactions related to skin and subcutaneous tissue
are mostly mild or moderate and transient, usually resolving within a cycle interval of 30 days.
Blood counts
Since patients with an active hairy cell leukaemia mostly present with low blood counts, especially
low neutrophil counts, more than 90% of the cases have transient severe neutropenias (< 1.0 x 10
9
/l).
The use of haematopoietic growth factors neither improves the recovery of neutrophil counts nor
decreases the incidence of fever. Severe thrombocytopenias (< 50 x 10
9
/l) are observed in about 20%
to 30% of all patients. Lymphocytopenia lasting for several months and immunosuppression with an
increased risk of infections are expected. The recovery of cytotoxic T-lymphocytes and natural killer
cells occurs within 3 to 12 months. A complete recovery of T-helper cells and B-lymphocytes is
delayed for up to 2 years. Cladribine induces a severe and prolonged reduction of CD4+ and CD8+
T-lymphocytes. At present there exists no experience on possible long-term consequences of this
immunosuppression.
Infections
Severe long-term lymphocytopenias have been reported rarely which, however, could not be
associated with late infectious complications. Very common severe complications, in some cases with
fatal outcome, are opportunistic infections (e.g.
Pneumocystis carinii
,
Toxoplasma gondii
, listeria,
candida, herpes viruses, cytomegalovirus and atypical mycobacteria). Forty percent of the patients
who were treated with LITAK at a dose of 0.7 mg/kg body weight per cycle suffered from infections.
These were on average more severe than the infections manifested in 27% of all patients receiving a
reduced dose of 0.5 mg/kg body weight per cycle. Forty-three percent of patients with hairy cell
leukaemia experienced infectious complications at standard dose regimen. One third of these
infections have to be considered as severe (e.g. septicaemia, pneumonia). At least 10 cases with acute
autoimmune haemolytic anaemia have been reported. All patients were successfully treated with
corticosteroids.
Rare serious adverse reactions
Serious adverse reactions like ileus, severe hepatic failure, renal failure, cardiac failure, atrial
fibrillation, cardiac decompensation, apoplexy, neurological disturbances in speech and swallowing,
tumour lysis syndrome with acute renal failure, transfusion-related graft-versus-host disease,
Stevens-Johnson syndrome/Lyell syndrome (toxic epidermal necrolysis), haemolytic anaemia,
hypereosinophilia (with erythematous skin rash, pruritus, and facial oedema) are rare.
Fatal outcome
The majority of deaths related to the medicinal product are due to infectious complications. Further
rare cases with fatal outcome, reported in association with LITAK chemotherapy, were second
malignancy, cerebro- and cardiovascular infarctions, graft-versus-host disease caused by multiple
transfusions of non-irradiated blood, as well as tumour lysis syndrome with hyperuricaemia, metabolic
acidosis, and acute renal failure.
Frequently observed symptoms of overdose are nausea, vomiting, diarrhoea, severe bone marrow
depression (including anaemia, thrombocytopenia, leukopenia, and agranulocytosis), acute renal
insufficiency, as well as irreversible neurologic toxicity (paraparesis/quadriparesis), Guillain-Barré
syndrome, and Brown-Séquard syndrome. Acute, irreversible neuro- and nephrotoxicity have been
described in individual patients treated at a dose which was ≥ 4 times higher than the recommended
regimen for hairy cell leukaemia.
No specific antidote exists. Immediate discontinuation of therapy, careful observation, and initiation of
appropriate supportive measures (blood transfusions, dialysis, haemofiltration, anti-infectious therapy,
etc.) are the indicated treatment of overdose of cladribine. Patients who have received an overdose of
cladribine should be monitored haematologically for at least four weeks.
7
5.
5.1
Pharmacodynamicproperties
Pharmacotherapeutic group: Purine analogues, ATC code: L01BB04
Cladribine is a purine nucleoside analogue acting as an antimetabolite. The single substitution of
hydrogen for chlorine at position 2 distinguishes cladribine from its natural counterpart
2'-deoxyadenosine and renders the molecule resistant to deamination by adenosine deaminase.
Mechanism of action
Cladribine is a prodrug which is taken up rapidly in cells after parenteral administration, and is
phosphorylated intracellularly to the active nucleotide 2-chlorodeoxyadenosine-5'-triphosphate
(CdATP) by deoxycytidine kinase (dCK). An accumulation of active CdATP is observed
predominantly in cells with a high dCK activity and a low deoxynucleotidase activity, particularly in
lymphocytes and in other haematopoietic cells. The cytotoxicity of cladribine is dose-dependent.
Non-haematologic tissues seem to be unaffected, explaining the low incidence of non-haematopoietic
toxicity of cladribine
Unlike other nucleoside analogues, cladribine is toxic in rapidly proliferating cells as well as in resting
cells. No cytotoxic effect of cladribine could be observed in cell lines of solid tumours. The
mechanism of action of cladribine is attributed to the incorporation of CdATP into DNA strands: the
synthesis of new DNA in dividing cells is blocked and the DNA repair mechanism is inhibited,
resulting in an accumulation of DNA strand breaks and a decrease of NAD (nicotinamide adenine
dinucleotide) and ATP concentration, even in resting cells. Furthermore, CdATP inhibits
ribonucleotide reductase, the enzyme responsible for the conversion of ribonucleotides into
deoxyribonucleotides. Cell death occurs from energy depletion and apoptosis.
Clinical efficacy
In the clinical trial using LITAK subcutaneously, 63 patients with hairy cell leukaemia (33 newly
diagnosed patients and 30 patients with relapsed or progressive disease) were treated. The overall
response rate was 97% with long-lasting remission, with 73% of patients staying in complete remission
after four years follow-up time.
5.2 Pharmacokinetic properties
Absorption
Cladribine shows complete bioavailability after parenteral administration; the mean area under the
plasma concentration
versus
time curve (AUC) is comparable after continuous or intermittent 2-hour
intravenous infusion and after subcutaneous injection.
Distribution
After subcutaneous bolus injection of a 0.14 mg/kg cladribine dose, a C
max
of 91 ng/ml is reached on
average after 20 minutes only. In another study using a dose of 0.10 mg/kg body weight/day, the
maximum plasma concentration C
max
after continuous intravenous infusion was 5.1 ng/ml (t
max
: 12
hours) compared to 51 ng/ml after subcutaneous bolus injection (t
max
: 25 minutes).
Intracellular concentration of cladribine exceeds its plasma concentration by 128 to 375 times.
The mean volume of distribution of cladribine is 9.2 l/kg. Plasma protein binding of cladribine is 25%
on average, with a wide interindividual variation (5-50%).
Metabolism
The prodrug cladribine is metabolised intracellularly, predominantly by deoxycytidine kinase, to
2-chlorodeoxyadenosine-5'-monophosphate, that is further phosphorylated to the diphosphate by
8
nucleoside monophosphate kinase and to the active metabolite
2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by nucleoside diphosphate kinase.
Elimination
Pharmacokinetic studies in humans showed that the plasma concentration curve of cladribine fits a 2-
or 3-compartment model with α- and β-half-lives of on average 35 minutes and 6.7 hours,
respectively. The biexponential decline of the serum concentration of cladribine after subcutaneous
bolus injection is comparable to elimination parameters after 2-hour intravenous infusion with an
initial and terminal half-life of approximately 2 hours and 11 hours, respectively. The intracellular
retention time of cladribine nucleotides
in vivo
is clearly prolonged as compared to the retention time
in the plasma: Half-lives t
1/2
of initially 15 hours and subsequently more than 30 hours were measured
in leukaemic cells.
Cladribine is eliminated mainly by the kidneys. The renal excretion of unmetabolised cladribine
occurs within 24 hours and accounts for 15% and 18% of the dose after 2-hour intravenous and
subcutaneous administration, respectively. The fate of the remainder is unknown. The mean plasma
clearance amounts to 794 ml/min after intravenous infusion and to 814 ml/min after subcutaneous
bolus injection at a dose of 0.10 mg/kg body weight/day.
Special populations
Renal and hepatic impairment
There are no studies available using cladribine in patients with renal or hepatic impairment (see also
section 4.2 and section 4.4). Clinical experience is very limited and safety of LITAK in these patients is
not well established. LITAK is contraindicated in patients with moderate to severe renal impairment or
with moderate to severe hepatic impairment (see section 4.3).
Paediatric use
The use of LITAK in children has not been investigated (see section 4.2).
Elderly
Experience with patients older than 65 years is limited. Elderly patients should be treated by individual
assessment and careful monitoring of the blood counts and of the renal and hepatic function.
5.3 Preclinical safety data
Cladribine is moderately acutely toxic to mice, with an LD
50
of 150 mg/kg by intraperitoneal
administration.
In 7- to 14-day continuous intravenous infusion studies in cynomolgus monkeys, the target organs
were the immune system (≥ 0.3 mg/kg/day), bone marrow, skin, mucous membranes, nervous system
and testes (≥ 0.6 mg/kg/day) and kidneys (≥ 1 mg/kg/day). Unless fatal, indications were that most or
all of these effects would be slowly reversible upon cessation of exposure.
Cladribine is teratogenic in mice (at doses of 1.5-3.0 mg/kg/day, given on gestation days 6-15). Effects
on sternal ossification were seen at 1.5 and 3.0 mg/kg/day. Increased resorptions, reduced live litter
sizes, reduced foetal weights and increased foetal malformations of the head, trunk and appendages
were seen at 3.0 mg/kg/day. In rabbits, cladribine is teratogenic at doses of 3.0 mg/kg/day (given on
gestation days 7-19). At this dose, severe limb anomalies were seen as well as a significant decrease in
the mean foetal weight. Reduced ossification was observed at 1.0 mg/kg/day.
Carcinogenesis/mutagenesis
Long-term studies in animals to evaluate the carcinogenic potential of cladribine have not been
conducted. On the basis of available data, no evaluation can be made of the carcinogenic risk of
cladribine to humans.
Cladribine is a cytotoxic medicinal product, which is mutagenic to cultured mammalian cells.
Cladribine is incorporated into DNA strands and inhibits DNA synthesis and repair. Exposure to
9
cladribine induces DNA fragmentation and cell death in various normal and leukaemic cells and cell
lines at concentrations of 5 nM to 20 µM.
Fertility
The effects of cladribine on fertility have not been studied in animals. However, a toxicity study
conducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidly
generating cells, including testicular cells. The effect on human fertility is unknown. Antineoplastic
agents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expected
to have adverse effects on human gametogenesis (see sections 4.4 and 4.6).
6.
6.1 List of excipients
Sodium chloride
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
Water for injections
6.2 Incompatibilities
LITAK must not be mixed with other medicinal products.
6.3 Shelf life
4 years.
From a microbiological point of view, unless the opening precludes the risk of microbiological
contamination, the product should be used immediately. If not used immediately, in-use storage times
and conditions are the responsibility of the user.
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
6.5 Nature and contents of container
10 ml type I glass vial with rubber stopper (bromobutyl) and flip-off aluminium cap.
Packs contain 1 or 5 vials, each with 5 ml of solution. Not all pack-sizes may be marketed.
6.6 Special precautions for disposal and other handling
Procedures for proper handling and disposal of antineoplastic medicinal products should be used.
Cytotoxic medicinal products should be handled with caution. Avoid contact by pregnant women.
The use of disposable gloves and protective garments is recommended when handling and
administering LITAK. If LITAK contacts the skin or mucous membranes, rinse the area immediately
with copious amounts of water.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration
prior to administration.
The vials are for single use only. Any unused product or waste material should be disposed of in
accordance with local requirements.
10
7.
Lipomed GmbH
Hegenheimer Strasse 2
D-79576 Weil/Rhein
Germany
8.
EU/1/04/275/001
EU/1/04/275/002
9.
Date of first authorisation: 14/04/2004
Date of last renewal: 19/04/2009
11
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
12
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Lipomed GmbH
Hegenheimer Strasse 2
D-79576 Weil/Rhein
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
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
Not applicable.
•
OTHER CONDITIONS
The holder of this marketing authorisation must inform the European Commission about the marketing
plans for the medicinal product authorised by this decision.
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (1-VIAL PACK)
1.
LITAK 2 mg/ml solution for injection
cladribine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml solution contains 2 mg cladribine.
10 mg/5 ml
3.
LIST OF EXCIPIENTS
Contains sodium chloride, sodium hydroxide, hydrochloric acid and water for injections
4.
1 vial containing 5 ml solution for injection
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use
Read the package leaflet before 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
Cytotoxic. Special handling precautions (see package leaflet)
For single use only
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
Do not freeze
16
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Lipomed GmbH
Hegenheimer Strasse 2
D-79576 Weil/Rhein
Germany
EU/1/04/275/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (5-VIAL PACK)
1.
LITAK 2 mg/ml solution for injection
cladribine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml solution contains 2 mg cladribine.
10 mg/5 ml
3.
LIST OF EXCIPIENTS
Contains sodium chloride, sodium hydroxide, hydrochloric acid and water for injections
4.
5 vials each containing 5 ml solution for injection
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use
Read the package leaflet before 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
Cytotoxic. Special handling precautions (see package leaflet)
For single use only
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
18
Do not freeze
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Lipomed GmbH
Hegenheimer Strasse 2
D-79576 Weil/Rhein
Germany
EU/1/04/275/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
LITAK 2 mg/ml solution for injection
cladribine
Subcutaneous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 mg/5 ml
6.
OTHER
Cytotoxic
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
LITAK 2 mg/ml solution for injection
cladribine
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
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 LITAK is and what is it used for
2.
Before you use LITAK
3.
How to use LITAK
4.
Possible side effects
5.
How to store LITAK
6.
Further information
1.
WHAT LITAK IS AND WHAT IT IS USED FOR
LITAK contains the active substance cladribine. Cladribine is a cytostatic agent. It affects the growth
of malignant (cancerous) white blood cells which play a role in hairy cell leukaemia. LITAK is used to
treat this disease.
2.
BEFORE YOU USE LITAK
Do not use LITAK
-
if you are allergic (hypersensitive) to cladribine or any of the other ingredients of LITAK
-
if you are pregnant or breast-feeding
-
if you have moderate to severe kidney or liver impairment
-
if you are using other medicines which affect the production of blood cells in the bone marrow
(myelosuppression).
Take special care with LITAK
Tell your doctor if you have or have had:
-
infections
if you suffer from an infection, this will be treated before you start using LITAK.
if you notice any signs of infections (such as flu-like symptoms or fever) during or after
treatment with LITAK, inform your doctor immediately.
-
fever
Before and during treatment with LITAK, you will have regular blood tests to check whether it is safe
for you to continue with your treatment. Your doctor may decide that you should receive blood
transfusions to improve your level of blood cells. In addition, the proper function of your liver and
your kidneys will be checked.
If you want to father a child, please tell your doctor before treatment with LITAK is started. You
should not father a child during treatment and up to 6 months after treatment with LITAK. Your
doctor may advise you about the possibility to store deep-frozen sperm (cryoconservation).
Using other medicines
22
-
Keep this leaflet. You may need to read it again.
-
if you are less than 18 years of age
-
liver or kidney problems
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. In particular, tell your doctor if you are using any
medicines containing:
-
corticosteroids, commonly used to treat inflammation
You must not use LITAK with other medicines that affect the production of blood cells in the bone
marrow (myelosuppression).
Pregnancy and breast-feeding
Your must not use LITAK if you are pregnant. You must take adequate contraceptive precautions
during therapy and for at least six months after your last LITAK dose. If pregnancy occurs during your
treatment, you must immediately inform your doctor.
You must not breast-feed while you are treated with LITAK and for at least six months after your last
LITAK dose.
Driving and using machines
LITAK has a major effect on the ability to drive and use machines. If you feel drowsy, which may
occur due to a low number of red blood cells caused by LITAK treatment, or dizzy, you should not
drive or use machines.
3.
HOW TO USE LITAK
Always use LITAK as your doctor has told you. You should check with your doctor or pharmacist if
you are not sure.
Your doctor will calculate your dose according to your body weight and explain the treatment
schedule in detail. The recommended daily dose is 0.14 mg per kg body weight for five consecutive
days (single treatment course).
LITAK has to be injected under your skin (subcutaneous injection), at about the same time each day.
If you are injecting LITAK yourself, first you must receive adequate training by your doctor or nurse.
You will find detailed instructions for injection at the end of this leaflet.
You may also receive an additional medicine containing the active substance allopurinol in order to
reduce excess of uric acid.
If you use more LITAK than you should
In case you inject an incorrect dose, tell your doctor immediately.
If you forget to use LITAK
Do not inject a double dose to make up for a forgotten dose. In case you miss an injection of a dose,
tell your doctor immediately.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, LITAK can have side effects, although not everybody gets them.
Tell your doctor immediately if you have any of the following during or after treatment with LITAK:
-
any signs of infections (such as flu-like symptoms)
-
fever
23
-
antiviral agents, used to treat viral infections
Repeated occurrence of malignant (cancerous) disease cannot be excluded. This means that the risk
that you develop a malignant disease in the future is slightly higher than for healthy people. This
slightly increased risk can be due to hairy cell leukaemia or to therapies used to treat the disease
including LITAK.
Side effects may occur with certain frequencies, which are defined as follows:
-
very common: affects more than 1 user in 10
-
common: affects 1 to 10 users in 100
-
uncommon: affects 1 to 10 users in 1,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data.
Very common side effects
Infections.
Fever.
Low numbers of certain white blood cells (neutrophils and lymphocytes) and platelets in blood
tests.
Low number of red blood cells, which may result in anaemia, with symptoms such as tiredness
and drowsiness.
Reduced function of your body’s immune system.
Headache, dizziness.
Abnormal breath sounds, abnormal chest sounds, cough.
Feeling sick, vomiting, constipation and diarrhoea.
Skin eruption (rash), swelling, redness as well as soreness around the site of injection, sweating.
Skin reactions are mostly mild to moderate and usually resolve within a few days.
Tiredness, chills, decreased appetite.
Weakness.
Common side effects
Repeated occurrence of malignant (cancerous) disease.
Low number of platelets, which can cause unusual bleeding (for example nose or skin bleeds).
Sleeplessness, anxiety.
Increased heart rate, abnormal heart sound, low blood pressure, decreased blood supply to the
heart muscle.
Shortness of breath, swelling in lung tissue due to infection, inflammation of mouth and tongue.
Abdominal pain and presence of excessive amount of gas in the stomach or bowels, mostly mild
increases in liver laboratory values (bilirubin, transaminases) which will return to normal values
once treatment is over.
Swelling in tissues (oedema), not feeling well, pain (muscle pain, joint pain, and bone pain).
Uncommon side effects
Anaemia caused by destruction of red blood cells.
Sleepiness, numbness and tingling of the skin, feebleness, inactivity, disorder of peripheral
nerves, confusion, impaired ability to coordinate movements.
Eye inflammation.
Sore throat.
Inflammation of a vein.
Severe weight loss.
Rare side effects
Reduced liver function.
Reduced kidney function.
Complications caused by cancer treatment due to break-down of cancer cells.
Rejection response to blood transfusions.
24
-
rare: affects 1 to 10 users in 10,000
Itching, itching skin eruption (urticaria), redness of the skin and skin pain.
Increased number of certain white blood cells (eosinophils).
Disturbances in speech and swallowing.
Heart failure.
Abnormal heart rhythm.
Inability of the heart to maintain adequate blood circulation.
Obstruction of the bowels.
Serious allergic skin reaction (Stevens-Johnson syndrome or Lyell syndrome).
Very rare side effects
Depression, epileptic attack.
Swelling of the eyelid.
Inflammation of the gallbladder.
Reduced function of organs due to high amounts of a specific substance produced by the body
(a glycoprotein).
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 LITAK
Keep out of the reach and sight of children.
Store in a refrigerator (2°C-8°C). Do not freeze.
Do not use LITAK after the expiry date which is stated on the vial label and the outer carton after
EXP. The expiry date refers to the last day of that month.
From a microbiological point of view, unless the opening precludes the risk of microbiological
contamination, the product should be used immediately. If not used immediately, in-use storage times
and conditions are the responsibility of the user.
Do not use LITAK if you notice that the vial is damaged or that the solution is not clear or contains
any particles.
Any unused product or waste material should be disposed of in accordance with local requirements.
6.
FURTHER INFORMATION
What LITAK contains
-
The active substance is cladribine. Each ml solution contains 2 mg cladribine. Each vial contains
10 mg cladribine in 5 ml solution.
-
The other ingredients are sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid
(for pH adjustment) and water for injections.
What LITAK looks like and contents of the pack
LITAK is available in glass vials containing 5 ml of clear, colourless solution for injection.
Pack size of 1 or 5 vials. Not all pack-sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Lipomed GmbH
Hegenheimer Strasse 2
D-79576 Weil/Rhein
Germany
25
Stroke.
Blood clot in the lung.
For any information about this medicine, please contact the Marketing Authorisation Holder.
This leaflet was last approved in
INSTRUCTIONS FOR INJECTION
This section contains information on how to give an injection of LITAK. It is important that you do
not try to give yourself the injection unless you have been instructed by your doctor or nurse. Your
doctor will tell you how much LITAK you need and how often and when you have to inject yourself.
LITAK should be injected into the tissue just under the skin (subcutaneous injection). If you have any
question with regard to giving the injection, please ask your doctor or nurse for help.
LITAK is a cytotoxic and should therefore be handled with caution. When LITAK is not
self-administered by the patient, the use of disposable gloves and protective garments is recommended
when handling and administering LITAK. If LITAK contacts the skin or eyes, rinse the involved
surface immediately with copious amounts of water. Pregnant women must avoid contact with
LITAK.
What do I need for the injection?
To give yourself a subcutaneous injection, you will need:
- one vial of LITAK (or two vials if you need to inject more than 5 ml).
Do not use vials which are damaged, or if the solution is not clear or if it contains any particles.
-
one sterile syringe (e.g. 10 ml LUER syringe),
-
one sterile injection needle (e.g. 0.5 x 19 mm, 25 G x ¾’’),
-
alcohol wipes,
-
a puncture-proof container for safe disposal of the used syringe.
What should I do before I give myself a subcutaneous injection of LITAK?
1.
Before injection, allow LITAK to warm up to room temperature.
2.
Wash your hands thoroughly.
3.
Find a comfortable, well-lit place and put everything you need where you can reach it.
How do I prepare the injection?
Before you inject LITAK, you must do the following:
1.
Remove the red protective cap from the LITAK vial. Do not remove the rubber stopper of the
vial. Clean the rubber top of the vial with an alcohol wipe. Remove the syringe from the
wrapping without touching the tip of the syringe. Remove the injection needle from the
wrapping and place it firmly on the tip of the syringe. Remove the needle guard without
touching the needle.
2.
Push the needle through the rubber stopper of the vial and turn the vial and the syringe upside
down. Be sure that the tip of the needle is in the solution.
26
3.
Draw the correct volume of LITAK into the syringe by pulling back the plunger (your doctor
will inform you how many ml of LITAK you need to inject).
4.
Pull the needle out of the vial.
5.
Make sure there is no air left in the syringe: point the needle upwards and push the air out.
6.
Check you have the right volume.
7.
Inject straight away.
Where should I give my injection?
The most suitable places to inject yourself are
shown here: the top of your thighs and the
abdomen, except for the area around the navel.
If someone else is injecting you, they can also
use the outer surface of the upper arms or the
buttocks.
How do I give my injection?
1.
Disinfect your skin by using an alcohol wipe,
wait for the area to dry and pinch the skin
between your thumb and forefinger, without
squeezing it.
2.
Put the needle fully into the skin at an angle
of about 45°, as shown in the picture.
3.
Pull slightly on the plunger to check that no blood vessel has been punctured. If you see blood
in the syringe, remove the needle and re-insert it in another place.
4.
Inject the liquid slowly and evenly for approximately one minute, always keeping the skin
pinched.
5.
After injecting the liquid, remove the needle.
6.
Put the used syringe in the puncture-proof container. Use a new syringe and injection needle for
each injection. The vials are for single use only. Return any portion of the contents remaining
after use to your doctor or pharmacist for proper disposal.
Disposing of used syringes
Put used syringes into a puncture-proof container and keep it out of the reach and sight of children.
27
Dispose the puncture-proof container as instructed by your doctor, nurse or pharmacist.
Do not put used syringes into the normal household garbage bin.
28
Source: European Medicines Agency
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