Leustat Injection.

LEUSTAT (cladribine) Injection is a synthetic antineoplastic agent for continuous intravenous infusion. It is a clear, colourless, sterile, preservative-free, isotonic solution. LEUSTAT Injection is available in single-use vials containing 10 mg (1 mg/ml) of cladribine, a chlorinated purine nucleoside analogue. Each millilitre of LEUSTAT Injection contains 1 mg of the active ingredient, cladribine, and 9 mg (0.15 mEq) of sodium chloride as an inactive ingredient. The solution has pH range of 5.5 to 8.0. Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH.

A sterile, buffered solution in vials containing 10 mg (1 mg/ml) of cladribine for dilution and subsequent continuous intravenous infusion.

LEUSTAT Injection is indicated for the primary or secondary treatment of patients with Hairy Cell Leukaemia (HCL).

LEUSTAT is also indicated for the treatment of patients with B-cell chronic lymphocytic leukaemia (CLL) who have not responded to, or whose disease has progressed during or after, treatment with at least one standard alkylating-agent-containing regimen.

Usual dose:

Adults and elderly:

HCL: The recommended treatment for Hairy Cell Leukaemia is a single course of LEUSTAT given by continuous intravenous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day (3.6 mg/m²/day). Deviations from this dosage regimen are not advised. Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs.

CLL: In patients with CLL, the recommended treatment consists of a continuous intravenous infusion of LEUSTAT for 2 hours on days 1 to 5 of a 28 day cycle at a dose of 0.12 mg/kg/day (4.8 mg/m²/day). The patient's response to therapy should be determined every two cycles of treatment. It is recommended that LEUSTAT Injection be administered in responding patients for 2 cycles after maximum response has occurred, up to a maximum of 6 cycles. Therapy should be discontinued after 2 cycles in non-responding patients. Response for this treatment decision is defined as a lymphocyte reduction of 50% or more, ie if lymphocyte count decreases by 50% or more, administer 2 more cycles and re-evaluate response for decision whether to continue with 2 more cycles up to a maximum of 6 cycles.

Children:

Safety and efficacy in children have not been established.

Specific risk factors predisposing to increased toxicity from LEUSTAT have not been defined. In view of the known toxicities of agents of this class, it would be prudent to proceed carefully in patients with known or suspected renal insufficiency or severe bone marrow impairment of any aetiology. Patients should be monitored closely for haematological and renal and hepatic toxicity.

Preparation and administration of intravenous solutions:

LEUSTAT Injection must be diluted with the designated diluent prior to administration. Since the product does not contain any anti-microbial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of a solution of LEUSTAT. For full details concerning preparation of an infusion solution, see 6.6 Instructions for Use/Handling.

LEUSTAT Injection is contra-indicated in those patients who are hypersensitive to this drug or any of its components. LEUSTAT is contra-indicated in pregnant women and nursing mothers.

LEUSTAT Injection is a potent antineoplastic agent with potentially significant toxic side effects. It should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

CLL: The weight of evidence suggests that a patient whose disease has progressed while treated with fludaribine is unlikely to respond to treatment with LEUSTAT Injection and therefore use in such a patient is not recommended.

Patients should be monitored closely for infections. Patients with active infection should be treated for the underlying condition prior to receiving therapy with LEUSTAT Injection. Patients who are or who become Coombs' positive should be monitored carefully for occurrence of haemolysis.

Patients with high tumour burden or who are considered at risk for the development of hyperuricaemia as a result of tumour breakdown should receive appropriate prophylactic treatment.

4.4.1 Bone Marrow Suppression:

HCL: During the first two weeks after treatment initiation, mean platelet count, absolute neutrophil count (ANC), and haemoglobin concentration declined and then subsequently increased with normalisation of mean counts by day 15, week 5 and week 8, respectively. The myelosuppressive effects of LEUSTAT were most notable during the first month following treatment. Forty three percent (43%) of patients received transfusions with RBCs and 13% received transfusions with platelets during month 1. Careful haematological monitoring, especially during the first 4 to 8 weeks after treatment with LEUSTAT is recommended. (See 4.8, Undesirable Effects).

CLL: During the first 2 cycles of therapy with LEUSTAT Injection, haemoglobin concentration, platelet count and absolute neutrophil count declined to a nadir usually observed in Cycle 2. There appeared to be no cumulative toxicity upon administration of further cycles of therapy. Careful haematological monitoring is recommended throughout administration of LEUSTAT Injection.

4.4.2 Neurotoxicity:

4.4.3 Fever/Infection:

CLL: Pyrexia was reported in 22-24% of CLL patients during Cycle 1 of therapy with LEUSTAT Injection, and in less than 3% of patients during subsequent cycles. Forty of 123 patients (32.5%) reported at least one infection during Cycle 1. Infections that occurred in 5% or more were: respiratory infection/inflammation (8.9%), pneumonia (7.3%), bacterial infection (5.7%), and viral skin infections (5.7%). Approximately 70% of patients had at least one infection during the overall study period of 6 years, including treatment and follow-up.

Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empirical antibiotics should be initiated as clinically indicated. Given the known myelosuppressive effects of LEUSTAT, practitioners should carefully evaluate the risks and benefits of administering this drug to patients with active infections. Since fever may be accompanied by increased fluid loss, patients should be kept well hydrated (See 4.8, Undesirable effects).

4.4.4

4.4.5 Effect on Renal and Hepatic Function:

4.4.6

4.4.7 Laboratory Tests:

4.4.8 Carcinogenesis/Mutagenesis:

4.4.9 Impairment of Fertility:

4.4.10 Extravasation:

Caution should be exercised if LEUSTAT Injection is administered following or in conjunction with other drugs known to cause myelosuppression. Following administration of LEUSTAT Injection, caution should be exercised before administering other immunosuppressive or myelosuppressive therapy. (See 4.4.1 and 4.8.1.2 Bone Marrow Suppression).

LEUSTAT Injection is teratogenic in mice and rabbits and consequently has the potential to cause foetal harm when administered to a pregnant woman. There are no human data, but LEUSTAT Injection is contra-indicated in pregnancy.

A significant increase in foetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m²) and increased resorptions, reduced litter size and increased foetal malformations were observed when mice received 3.0 mg/kg/day (9 mg/m²). Foetal death and malformations were observed in rabbits that received 3.0 mg/kg/day (33.0 mg/m²). No foetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m²) or in rabbits at 1.0 mg/kg/day (11.0 mg/m²).

Although there is no evidence of teratogenicity in humans due to LEUSTAT, other drugs which inhibit DNA synthesis (eg methotrexate and aminopterin) have been reported to be teratogenic in humans. LEUSTAT has been shown to be embryotoxic in mice when given at doses equivalent to the recommended dose.

It is not known whether this drug is excreted in human milk. Because it may be excreted in human milk and because there is potential for serious adverse reactions in nursing infants, LEUSTAT should not be given to a nursing mother.

Given the patients underlying medical condition and the safety profile of LEUSTAT Injection, caution should be exercised when a patient is performing activities requiring substantial physical well-being (See 4.8, Undesirable Effects).

4.8.1 Clinical Trial Experience

4.8.1.1 Overview:

During the first 14 days, events reported by greater than 5% but less than 20% of patients included:

Injection site reactions (ie redness, swelling, pain), thrombosis and phlebitis appear usually to be related to the infusion procedure and/or indwelling catheter, rather than to the medication or the vehicle.

From day 15 to the last day of follow-up, the following effects were reported in greater than 5% of patients: fatigue (14%), rash (10%), headache (7%), oedema (7%), arthralgia (7%), malaise (6%), diaphoresis (6%).

CLL: The following safety data are based on 124 patients with CLL enrolled in an open-label safety study. Haematological parameters declined during Cycle 1 and Cycle 2, reaching nadir values in Cycle 2; the percentage of patients having a haemoglobin level below 8.5 g/dL in Cycle 2 was 46.1%. The percentage of patients with platelet counts below 20 x 10(9)/L was 22.5% during Cycle 2. Absolute neutrophil count was below 500 x 10(6)/L in 61.8% of patients in Cycle 2. Adverse experiences reported frequently during the first 14 days after initiating treatment included: skin reaction at the injection site (22.8%), pyrexia (17.9%), fatigue (16.3%), oedema (13.8%), headache (13.0%), cough (11.4%), purpura (10.6%), diaphoresis (8.9%), diarrhoea (7.3%), nausea (6.5%), coagulation defect (6.5%), abnormal breath sounds (5.7%), pneumonia (5.7%), and abnormal chest sounds (5.7%). Adverse experiences that occurred in 5% or more of patients during the remainder of follow-up for Cycle 1 were: pyrexia (6.7%), and preterminal events (6.7%). Drug-related adverse experiences reported during cycles of therapy subsequent to Cycle 1 were limited to the following: skin reaction at medication site (22.8%), phlebitis (5.0%), bacterial skin infection (2.0%), cellulitis (1.0%), nausea (1.0%), skin pain (1.0%), and bacterial infection (1.0%). Skin reactions at the injection site were felt to be more likely related to the indwelling IV catheter and not study drug related. LEUSTAT Injection was not associated with renal or hepatic toxicities.

4.8.1.2 Bone Marrow Suppression:

Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/µl. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/µl. Fifteen (15) months after treatment, mean CD4 counts remained below 500/µl. CD8 counts behaved similarly, though increasing counts were observed after 9 months. There were no serious opportunistic infections reported during this time. The clinical significance of the prolonged CD4 lymphopenia is unclear.

Prolonged bone marrow hypocellularity (< 35%) was observed. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or LEUSTAT Injection toxicity.

CLL: Patients with CLL treated with LEUSTAT Injection were more severely myelosuppressed prior to therapy than HCL patients; increased myelo-suppression was observed during Cycle 1 and Cycle 2 of therapy, reaching a nadir during Cycle 2. The percentage of patients having a haemoglobin level below 8.5 g/dL was 16.9% at baseline, 37.9% in Cycle 1, and 46.1% in Cycle 2. The percentage of patients with platelet counts below 20 x 10(9)/L was 4.0% at baseline, 20.2% during Cycle 1, and 22.5% during Cycle 2. Absolute neutrophil count was below 500 x 10(6)/L in 19.0% of patients at baseline, 56.5% in Cycle 1, 61.8% in Cycle 2, 59.3% in Cycle 3 and 55.9% in Cycle 4. There appeared to be no cumulative toxicity upon administration of multiple cycles of therapy. Marked blood chemistry abnormalities noted during the study were pre-existing, or were isolated abnormalities which resolved, or were associated with death due to the underlying disease.

4.8.1.3 Fever/Infection:

HCL: As with other agents having known immunosuppressive effects, opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by cladribine. Fever was a frequently observed side effect during the first month of study.

During the first month, 12% of patients experienced severe fever (ie greater than or equal to 40°C). Documented infections were noted in fewer than one-third of all febrile episodes. Of the 124 patients treated, 11 were noted to have a documented infection in the month prior to treatment. In the month following treatment, 31% of patients had a documented infection: 13.7% of patients had bacterial infection, 6.5% had viral and 6.5% had fungal infections. Seventy percent (70%) of these patients were treated empirically with antibiotics.

During the first month, serious infections (eg septicaemia, pneumonia), were reported in 7% of all patients; the remainder were mild or moderate. During the second month, the overall rate of documented infection was 8%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding LEUSTAT therapy.

CLL: During Cycle 1, 23.6% of patients experienced pyrexia, and 32.5% experienced at least one documented infection. Infections that occurred in 5% or more of the patients during Cycle 1 were: respiratory infection/inflammation (8.9%), pneumonia (7.3%), bacterial infection (5.6%), and viral skin infections (5.7%). In Cycles 2 through 9, 71.3% of the patients had at least one infection. Infections that occurred in 10% or more of patients were: pneumonia (28.7%), bacterial infection (21.8%), viral skin infection (20.8%), upper respiratory infection (12.9%), other intestinal infection/inflammation (12.9%), oral candidiasis (11.9%), urinary tract infection (11.9%), and other skin infections (11.9%). Overall, 72.4% of the patients had at least one infection during therapy with LEUSTAT Injection. Of these, 32.6% had been administered concomitant immunosuppressive therapy (prednisone).

4.8.1.4 Effects of High Doses:

Nephrotoxicity: Six patients (19%) developed manifestations of acute renal dysfunction/insufficiency (eg acidosis, anuria, elevated serum creatinine, etc) within 7 to 13 days after starting treatment with LEUSTAT, 5 of the affected patients required dialysis. Renal insufficiency was reversible in 2 of these patients. Evidence of tubular damage was noted at autopsy in 2 (of 4) patients whose renal function had not recovered at the time of death. Several of these patients had also been treated with other medications having known nephrotoxic potential.

Neurotoxicity: Eleven patients (35%) experienced delayed onset neurological toxicity. In the majority, this was characterised by progressive irreversible motor weakness, of the upper and/or lower extremities (paraparesis/quadraparesis), noted 35 to 84 days after starting high dose therapy.

Non-invasive neurological testing was consistent with demyelinating disease.

4.8.2 Post-marketing Experience:

Haematological: bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anaemia; haemolytic anaemia, which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment; hypereosinophilia. Rare cases of myelodysplastic syndrome have been reported.

Hepatic: reversible, generally mild, increases in bilirubin and transaminases.

Nervous System: confusion, neuropathy, ataxia, insomnia and somnolence.

Respiratory System: pulmonary interstitial infiltrates, in most cases an infectious aetiology was identified.

Skin/Subcutaneous: urticaria.

Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by LEUSTAT Injection.

High doses of LEUSTAT have been associated with serious neurological toxicity (including irreversible paraparesis/quadraparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anaemia and thrombocytopenia (See 4.4, Special Warnings and Special Precautions for Use). There is no known specific antidote to overdosage. It is not known whether the drug can be removed from the circulation by dialysis or haemofiltration. Treatment of overdosage consists of discontinuation of LEUSTAT Injection, careful observation and appropriate supportive measures.

LEUSTAT Injection (cladribine) is a synthetic antineoplastic agent.

Cellular Resistance and Sensitivity: The selective toxicity cladribine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase, deoxynucleotidase and adenosine deaminase. It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by cladribine as toxic deoxynucleotides accumulate intracellularly.

Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. LEUSTAT Injection can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.

When LEUSTAT Injection was given by continuous intravenous infusion over 7 days the mean steady-state serum concentration was estimated to be 5.7 ng/ml with an estimated systemic clearance of 663.5 ml/h/kg. Accumulation of LEUSTAT over the seven day treatment period was not noted.

Plasma concentrations are reported to decline multi-exponentially after intravenous infusions with terminal half-lives ranging from approximately 3-22 hours. In general, the apparent volume of distribution of cladribine is very large (mean approximately 9l/kg), indicating an extensive distribution of cladribine in body tissues. The mean half-life of cladribine in leukaemic cells has been reported to be 23 hours.

There is little information available on the metabolism or route of excretion of cladribine in man. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumours during a 5-day continuous intravenous infusion of 3.5-8.1 mg/m²/day of LEUSTAT. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.

Cladribine penetrates into cerebrospinal fluid. One report indicates that concentrations are approximately 25% of those in plasma.

Cladribine is bound approximately 20% to plasma proteins.

Carcinogenesis/Mutagenesis: No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine. Cladribine induced chromosomal effects when tested in both an in vivo bone marrow micronucleus assay in mice and an in vitro assay using CHO-WBL cells. Cladribine is mutagenic in mammalian cells in culture. Cladribine was not mutagenic to bacteria and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures.

Other preclinical safety data has been included in specific sections of SPC. However, a full tabulation is attached in Appendix 1.

9.0 mg (0.15 mEq) of sodium chloride as an inactive ingredient. Phosphoric acid and/or dibasic sodium phosphate to adjust the pH to a range of 5.5 to 8.0.

Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.

Solutions containing LEUSTAT Injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed.

If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed with a compatible diluent before and after infusion of LEUSTAT (See 4.2 or 6.6).

The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine.

The shelf life for LEUSTAT Injection is 3 years.

When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) protected from light, unopened vials of LEUSTAT Injection are stable until the expiration date indicated on the package. Freezing does not adversely affect the solution.

If freezing occurs, thaw naturally to room temperature. DO NOT heat or microwave. Once thawed, the vial of LEUSTAT Injection is stable until expiry if refrigerated. DO NOT REFREEZE.

Once diluted, solutions containing LEUSTAT Injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to start of administration.

Store refrigerated at 2° to 8°C (36° to 46°F). Protect from light during storage.

LEUSTAT Injection is supplied as a sterile, preservative-free, isotonic solution containing 10 mg (1 mg/ml) of cladribine (as 10 ml) in a single-use, flint glass 20 ml vial.

Preparation and administration of intravenous solutions: LEUSTAT Injection must be diluted with the designated diluent prior to administration. Since the drug product does not contain any anti-microbial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of a solution of LEUSTAT.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A precipitate may occur during the exposure of LEUSTAT to low temperatures; it may be resolubilised by allowing the solution to warm naturally to room temperature and by shaking vigorously. DO NOT HEAT OR MICROWAVE.

Care must be taken to assure the sterility of prepared solutions. Once diluted, solutions of LEUSTAT Injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to start of administration. Vials of LEUSTAT Injection are for single-use only. Any unused portion should be discarded in an appropriate manner.

The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering LEUSTAT Injection. The use of disposable gloves and protective garments is recommended. If LEUSTAT Injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water.

Preparation of a Single Daily Dose:

HCL: Add the calculated dose for a 24 hour period (0.09 mg/kg or 0.09 ml/kg or 3.6 mg/m²) of LEUSTAT Injection to an infusion bag containing 100 ml to 500 ml of 0.9% sodium chloride injection (PhEur). Infuse intravenously continuously over 24 hours. Repeat daily for a total of 7 consecutive days.

CLL: Add the calculated dose for a 2 hour period (0.12 mg/kg or 4.8 mg/m²) of LEUSTAT Injection to an infusion bag containing 100 ml to 500 ml of 0.9% sodium chloride injection (PhEur). Infuse intravenously continuously over 2 hours. Repeat daily for a total of 5 consecutive days.

The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Admixtures of LEUSTAT Injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in most commonly available PVC infusion containers.

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Bucks

HP12 4EG

PL 0242/0232

3 February 1995

July 2008