LITAK 2mg / ml solution for injection medication leaflet

LITAK 2 mg/ml solution for injection

Each ml of solution contains 2 mg of cladribine (2-CdA). Each vial contains 10 mg of cladribine in5 ml of solution.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution.

LITAK is indicated for the treatment of hairy cell leukaemia.

Therapy with LITAK should be initiated by a qualified physician with experience in cancerchemotherapy.

The recommended posology for hairy cell leukaemia is a single course of LITAK given bysubcutaneous 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.

Experience with patients older than 65 years is limited. Elderly patients should be treated by individualassessment and careful monitoring of the blood counts and of the renal and hepatic function. The riskrequires assessment on a case-by-case basis (see section 4.4).

There are no data on the use of LITAK in patients with renal or hepatic impairment. LITAK iscontraindicated 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 pct. 4.3,4.4 and 5.2).

LITAK is contraindicated in patients less than 18 years of age (see section 4.3).

LITAK is supplied as a ready-to-use solution for injection. The recommended dose is directlywithdrawn by a syringe and injected as a subcutaneous bolus injection without dilution. LITAK shouldbe inspected visually for particulate matter and discoloration prior to administration. LITAK shouldwarm up to room temperature prior to administration.

Self-administration by the patient

LITAK can be self-administered by the patient. Patients should be instructed and trainedappropriately. Detailed instructions are contained in the Package Leaflet.

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

Pregnancy and lactation.

Patients less than 18 years of age.

Moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) or moderate to severe hepaticimpairment (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 toxicadverse reactions, such as myelo- and immunosuppression, long-lasting lymphocytopenia, andopportunistic infections. Patients undergoing treatment with cladribine should be closely monitored forsigns of haematologic and non-haematologic toxicities.

Particular caution is advised and risks/benefits should be carefully evaluated if administration ofcladribine is considered in patients with increased infection risk, manifested bone marrow failure orinfiltration, myelosuppressive pre-treatments, as well as in patients with suspected or manifested renaland hepatic insufficiency. Patients with active infection should be treated for the underlying conditionprior to receiving therapy with cladribine. Although anti-infective prophylaxis is not generallyrecommended, it may be beneficial for patients immunocompromised prior to therapy with cladribine orfor patients with a pre-existing agranulocytosis.

If severe toxicity occurs, the physician should consider delaying or discontinuing the therapy with themedicinal product until serious complications resolve. In case of infections, antibiotic treatment shouldbe initiated as required.

It is recommended that patients receiving cladribine should receive irradiated cellular bloodcomponents/products to prevent transfusion-related graft-versus-host disease (Ta-GVHD).

Cases of PML, including fatal cases, have been reported with cladribine. PML was reported 6 monthsto several years after treatment with cladribine. An association with prolonged lymphopenia has beenreported in several of these cases. Physicians should consider PML in the differential diagnosis inpatients with new or worsening neurological, cognitive or behavioural signs or symptoms.

Suggested evaluation for PML includes neurology consultation, magnetic resonance imaging of thebrain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) ora brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow-up and evaluation may be warranted if no alternative diagnosis can be established. Patients withsuspected PML should not receive further treatment with cladribine.

Secondary malignancies

Like other nucleoside analogues, treatment with cladribine is associated with myelosuppression andprofound and prolonged immunosuppression. Treatment with these agents is associated with theoccurrence of second malignancies. Secondary malignancies are expected to occur in patients withhairy cell leukaemia. Their frequency varies widely, ranging from 2% to 21%. The peak risk is at 2years after diagnosis with a median between 40 and 66 months. The cumulative frequencies of secondmalignancy are 5%, 10-12% and 13-14% following 5, 10 and 15 years respectively after diagnosis ofhairy cell leukaemia. Following cladribine, the incidence of second malignancies ranges from 0% to9.5% after a median observation period of 2.8 to 8.5 years. The frequency of second malignancyfollowing treatment with LITAK was 3.4% in all 232 hairy cell leukaemia patients treated, during a10-year period. The highest incidence of second malignancy with LITAK was 6.5% after a medianfollow-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 orplatelet transfusions may be required. Patients with symptoms of bone marrow depression should betreated 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 suspectedinfections. The risk of severe myelotoxicity and long-lasting immunosuppression is increased inpatients 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 isnormally reversible and the intensity of bone marrow aplasia is dose-dependent. An increasedincidence of opportunistic infections is expected during, and for 6 months following, therapy withcladribine. Careful and regular monitoring of peripheral blood counts is essential during, and for 2 to 4months following, treatment with cladribine to detect potential adverse reactions and consequentcomplications (anaemia, neutropenia, thrombocytopenia, infections, haemolysis or bleedings), and tosurvey haematologic recovery. Fever of unknown origin frequently occurs in patients treated for hairycell leukaemia and is manifested predominantly during the first 4 weeks of therapy. The origin offebrile events should be investigated by appropriate laboratory and radiologic tests. Less than a thirdof febrile events are associated with a documented infection. In case of fever related to infections oragranulocytosis, an antibiotic treatment is indicated.

There are no data on the use of LITAK in patients with renal or hepatic impairment. Clinical experienceis 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 allpatients treated with LITAK, periodic assessment of renal and hepatic function is advised as clinicallyindicated.

Elderly patients should be treated by individual assessment and careful monitoring of the blood countsand of the renal and hepatic function. The risk requires assessment on a case-by-case basis (see section4.2).

Prevention of tumour lysis syndrome

In patients with a high tumour burden, prophylactic allopurinol therapy to control serum levels of uricacid, together with adequate or increased hydration, should be commenced 24 hours before the start ofchemotherapy. A daily oral dose of 100 mg of allopurinol is recommended for a period of 2 weeks. Incase of an accumulation of the serum uric acid above the normal range, the dose of allopurinol may beincreased to 300 mg/day.

Men being treated with cladribine should be advised not to father a child up to 6 months aftertreatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibilityof 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 mustnot be used concomitantly with other myelosuppressive medicinal products. An influence of cladribineon 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-resistancebetween cladribine and nitrogen mustard (chlormethine); for cytarabine, one author has described anin vivo cross-reaction without loss of activity.

Due to the similar intracellular metabolism, cross-resistance with other nucleoside analogues, such asfludarabine or 2’-deoxycoformycin may occur. Therefore, simultaneous administration of nucleosideanalogues with cladribine is not advisable.

Corticosteroids have been shown to enhance the risk for severe infections when used in combinationwith cladribine and should not be given concomitantly with cladribine.

Since interactions with medicinal products undergoing intracellular phosphorylation, such as antiviralagents, or with inhibitors of adenosine uptake may be expected, their concomitant use with cladribineis not recommended.

Cladribine causes serious birth defects when administered during pregnancy. Animal studies and in vitrostudies with human cell lines demonstrated the teratogenicity and mutagenicity of cladribine. Cladribineis contraindicated in pregnancy.

Women of childbearing potential must use effective contraception during treatment with cladribine andfor 6 months after the last cladribine dose. In case of pregnancy during therapy with cladribine, thewoman should be informed about the potential hazard to the foetus.

Limited data from case reports have shown that cladribine is excreted in human milk. The quantity isnot yet well established. 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 cladribinedose.

The effects of cladribine on fertility have not been studied in animals. However, a toxicity studyconducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidlygenerating cells, including testicular cells. The effect on human fertility is unknown. Antineoplasticagents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expectedto 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 aftertreatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibilityof 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 reactionswith a potential impact on performance occur (e.g. dizziness, very common, or drowsiness, which mayoccur 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 cladribinein 279 patients treated for various indications and in 62 patients with hairy cell leukaemia (HCL) weremyelosuppression, especially severe neutropenia (41% (113/279), HCL 98% (61/62)), severethrombocytopenia (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 hairycell 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 tocause 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%), anddecreased appetite (1-22%) have been reported during treatment with cladribine. Cladribine is unlikelyto cause alopecia; mild and transient alopecia for a few days was observed in 4/523 patients during thetreatment, but could not clearly be associated with cladribine.

Adverse reactions that have been reported are listed in the table below by frequency category andsystem organ class. The frequencies are defined as follows: Very common (≥1/10), common (≥1/100to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), notknown (cannot be estimated from the available data). For severity, please see text below the table.

Infections and infestations Very common: infections * (e.g. pneumonia *, septicaemia *)

Neoplasms benign, malignant Common: second malignancies *and unspecified (incl cysts and Rare: tumour lysis syndrome *polyps)

Blood and lymphatic system Very common: pancytopenia/myelosuppression *, neutropenia,disorders 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 Very common: decreased appetitedisorders 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 andswallowing

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 Very common: abnormal breath sounds, abnormal chest sounds,mediastinal disorders cough

Common: shortness of breath, pulmonary interstitial infiltratesmostly 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 andtransaminases

Rare: hepatic failure

Very rare: cholecystitis

Skin and subcutaneous tissue Very common: rash, localised exanthema, diaphoresisdisorders Common: pruritus, skin pain, erythema, urticaria

Rare: Stevens-Johnson syndrome/Lyell syndrome

Musculoskeletal and connective Common: myalgia, arthralgia, arthritis, bone paintissue disorders

Renal and urinary disorders Rare: renal failure

General disorders and Very common: injection site reactions, fever, fatigue, chills,administration site conditions asthenia

Common: oedema, malaise, pain

* see descriptive section below.

Non-haematological adverse reactions

Non-haematological adverse reactions are generally mild to moderate in severity. Treatment of nauseawith antiemetics is usually not necessary. Adverse reactions related to skin and subcutaneous tissueare 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, especiallylow neutrophil counts, more than 90% of the cases have transient severe neutropenias (< 1.0 x 109/l).

The use of haematopoietic growth factors neither improves the recovery of neutrophil counts nordecreases the incidence of fever. Severe thrombocytopenias (< 50 x 109/l) are observed in about 20%to 30% of all patients. Lymphocytopenia lasting for several months and immunosuppression with anincreased risk of infections are expected. The recovery of cytotoxic T-lymphocytes and natural killercells occurs within 3 to 12 months. A complete recovery of T-helper cells and B-lymphocytes isdelayed 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 thisimmunosuppression.

Severe long-term lymphocytopenias have been reported rarely which, however, could not beassociated with late infectious complications. Very common severe complications, in some cases withfatal outcome, are opportunistic infections (e.g. Pneumocystis carinii, Toxoplasma gondii, listeria,candida, herpes viruses, cytomegalovirus and atypical mycobacteria). Forty percent of the patientswho 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 areduced dose of 0.5 mg/kg body weight per cycle. Forty-three percent of patients with hairy cellleukaemia experienced infectious complications at standard dose regimen. One third of theseinfections have to be considered as severe (e.g. septicaemia, pneumonia). At least 10 cases with acuteautoimmune haemolytic anaemia have been reported. All patients were successfully treated withcorticosteroids.

Rare serious adverse reactions

Serious adverse reactions like ileus, severe hepatic failure, renal failure, cardiac failure, atrialfibrillation, 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. Furtherrare cases with fatal outcome, reported in association with LITAK chemotherapy, were secondmalignancy, cerebro- and cardiovascular infarctions, graft-versus-host disease caused by multipletransfusions of non-irradiated blood, as well as tumour lysis syndrome with hyperuricaemia, metabolicacidosis, and acute renal failure.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Frequently observed symptoms of overdose are nausea, vomiting, diarrhoea, severe bone marrowdepression (including anaemia, thrombocytopenia, leukopenia, and agranulocytosis), acute renalinsufficiency, as well as irreversible neurologic toxicity (paraparesis/quadriparesis), Guillain-Barrésyndrome, and Brown-Séquard syndrome. Acute, irreversible neuro- and nephrotoxicity have beendescribed in individual patients treated at a dose which was ≥ 4 times higher than the recommendedregimen for hairy cell leukaemia.

No specific antidote exists. Immediate discontinuation of therapy, careful observation, and initiation ofappropriate supportive measures (blood transfusions, dialysis, haemofiltration, anti-infectious therapy,etc.) are the indicated treatment of overdose of cladribine. Patients who have received an overdose ofcladribine should be monitored haematologically for at least four weeks.

Pharmacotherapeutic group: Purine analogues, ATC code: L01BB04

Cladribine is a purine nucleoside analogue acting as an antimetabolite. The single substitution ofhydrogen for chlorine at position 2 distinguishes cladribine from its natural counterpart2'-deoxyadenosine and renders the molecule resistant to deamination by adenosine deaminase.

Cladribine is a prodrug which is taken up rapidly in cells after parenteral administration, and isphosphorylated intracellularly to the active nucleotide 2-chlorodeoxyadenosine-5'-triphosphate(CdATP) by deoxycytidine kinase (dCK). An accumulation of active CdATP is observedpredominantly in cells with a high dCK activity and a low deoxynucleotidase activity, particularly inlymphocytes 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-haematopoietictoxicity of cladribine

Unlike other nucleoside analogues, cladribine is toxic in rapidly proliferating cells as well as in restingcells. No cytotoxic effect of cladribine could be observed in cell lines of solid tumours. Themechanism of action of cladribine is attributed to the incorporation of CdATP into DNA strands: thesynthesis 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 adeninedinucleotide) and ATP concentration, even in resting cells. Furthermore, CdATP inhibitsribonucleotide reductase, the enzyme responsible for the conversion of ribonucleotides intodeoxyribonucleotides. Cell death occurs from energy depletion and apoptosis.

In the clinical trial using LITAK subcutaneously, 63 patients with hairy cell leukaemia (33 newlydiagnosed patients and 30 patients with relapsed or progressive disease) were treated. The overallresponse rate was 97% with long-lasting remission, with 73% of patients staying in complete remissionafter four years follow-up time.

Cladribine shows complete bioavailability after parenteral administration; the mean area under theplasma concentration versus time curve (AUC) is comparable after continuous or intermittent 2-hourintravenous infusion and after subcutaneous injection.

After subcutaneous bolus injection of a 0.14 mg/kg cladribine dose, a Cmax of 91 ng/ml is reached onaverage after 20 minutes only. In another study using a dose of 0.10 mg/kg body weight/day, themaximum plasma concentration Cmax after continuous intravenous infusion was 5.1 ng/ml (tmax: 12hours) compared to 51 ng/ml after subcutaneous bolus injection (tmax: 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%).

The prodrug cladribine is metabolised intracellularly, predominantly by deoxycytidine kinase, to2-chlorodeoxyadenosine-5'-monophosphate, that is further phosphorylated to the diphosphate bynucleoside monophosphate kinase and to the active metabolite2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by nucleoside diphosphate kinase.

Pharmacokinetic studies in humans showed that the plasma concentration curve of cladribine fits a2- 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 subcutaneousbolus injection is comparable to elimination parameters after 2-hour intravenous infusion with aninitial and terminal half-life of approximately 2 hours and 11 hours, respectively. The intracellularretention time of cladribine nucleotides in vivo is clearly prolonged as compared to the retention timein the plasma: Half-lives t1/2 of initially 15 hours and subsequently more than 30 hours were measuredin leukaemic cells.

Cladribine is eliminated mainly by the kidneys. The renal excretion of unmetabolised cladribineoccurs within 24 hours and accounts for 15% and 18% of the dose after 2-hour intravenous andsubcutaneous administration, respectively. The fate of the remainder is unknown. The mean plasmaclearance amounts to 794 ml/min after intravenous infusion and to 814 ml/min after subcutaneousbolus injection at a dose of 0.10 mg/kg body weight/day.

There are no studies available using cladribine in patients with renal or hepatic impairment (see alsosection 4.2 and section 4.4). Clinical experience is very limited and safety of LITAK in these patients isnot well established. LITAK is contraindicated in patients with moderate to severe renal impairment orwith 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).

Experience with patients older than 65 years is limited. Elderly patients should be treated by individualassessment and careful monitoring of the blood counts and of the renal and hepatic function.

Cladribine is moderately acutely toxic to mice, with an LD50 of 150 mg/kg by intraperitonealadministration.

In 7- to 14-day continuous intravenous infusion studies in cynomolgus monkeys, the target organswere the immune system (≥ 0.3 mg/kg/day), bone marrow, skin, mucous membranes, nervous systemand testes (≥ 0.6 mg/kg/day) and kidneys (≥ 1 mg/kg/day). Unless fatal, indications were that most orall 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). Effectson sternal ossification were seen at 1.5 and 3.0 mg/kg/day. Increased resorptions, reduced live littersizes, reduced foetal weights and increased foetal malformations of the head, trunk and appendageswere seen at 3.0 mg/kg/day. In rabbits, cladribine is teratogenic at doses of 3.0 mg/kg/day (given ongestation days 7-19). At this dose, severe limb anomalies were seen as well as a significant decrease inthe mean foetal weight. Reduced ossification was observed at 1.0 mg/kg/day.

Long-term studies in animals to evaluate the carcinogenic potential of cladribine have not beenconducted. On the basis of available data, no evaluation can be made of the carcinogenic risk ofcladribine 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 tocladribine induces DNA fragmentation and cell death in various normal and leukaemic cells and celllines at concentrations of 5 nM to 20 µM.

The effects of cladribine on fertility have not been studied in animals. However, a toxicity studyconducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidlygenerating cells, including testicular cells. The effect on human fertility is unknown. Antineoplasticagents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expectedto have adverse effects on human gametogenesis (see sections 4.4 and 4.6).

Sodium chloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

LITAK must not be mixed with other medicinal products.

4 years.

From a microbiological point of view, unless the opening precludes the risk of microbiologicalcontamination, the product should be used immediately. If not used immediately, in-use storage timesand conditions are the responsibility of the user.

Store in a refrigerator (2°C-8°C).

Do not freeze.

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.

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 andadministering LITAK. If LITAK contacts the skin or mucous membranes, rinse the area immediatelywith copious amounts of water.

Parenteral medicinal products should be inspected visually for particulate matter and discolorationprior to administration.

The vials are for single use only. Any unused product or waste material should be disposed of inaccordance with local requirements.

Lipomed GmbH

Hegenheimer Strasse 2

D-79576 Weil/Rhein

Germany

EU/1/04/275/001

EU/1/04/275/002

Date of first authorisation: 14/04/2004

Date of last renewal: 27/03/2009

Detailed information on this medicinal product is available on the website of the European Medicines

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