CEPLENE 0.5mg / 0.5ml solution for injection medication leaflet

Ceplene 0.5 mg/0.5 mL solution for injection

One vial of 0.5 mL of solution contains 0.5 mg of histamine dihydrochloride.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless aqueous solution.

Ceplene maintenance therapy is indicated for adult patients with acute myeloid leukaemia (AML) infirst remission concomitantly treated with interleukin-2 (IL-2). The efficacy of Ceplene has not beenfully demonstrated in patients older than age 60.

Ceplene maintenance therapy should be administered following completion of consolidation therapyin patients concomitantly treated with IL-2 under the supervision of a physician experienced in themanagement of acute myeloid leukaemia.

For dosing instructions for Ceplene in combination with IL-2, see posology below.

Interleukin-2 (IL-2)

IL-2 is administered twice daily as a subcutaneous injection 1 to 3 minutes prior to theadministration of Ceplene; each dose of IL-2 is 16,400 IU/kg (1 µg/kg).

Interleukin-2 (IL-2) is commercially available as a recombinant IL-2; aldesleukin. The dispensing andstorage directions in the section 6.6 are specific to aldesleukin.

Ceplene0.5 mL solution is sufficient for a single dose (see section 6.6).

Ceplene is administered 1 to 3 minutes after each injection of IL-2. Each 0.5 mL Ceplene dose isinjected slowly, over 5-15 minutes.

Treatment cycles

Ceplene and IL-2 are administered for 10 treatment cycles: each cycle consists of a treatment period of21 days (3 weeks) followed by a three-week or six-week treatment-free period.

For cycles 1-3, each cycle consists of 3 weeks of treatment, followed by a 3-week treatment freeperiod. For cycles 4-10, each cycle consists of 3 weeks of treatment, followed by a 6-week treatmentfree period.

The recommended dosing regimen is presented in Tables 1 and 2.

Table 1: For treatment cycles 1-3 with Ceplene and IL-2

Week number (w)* Treatment*

Cycle 1 Cycle 2 Cycle 3w.1 to w.3 w.7 to w.9 w.13 to w.15 IL-2 16 400 IU/kg followed by 0.5 mL Ceplene.

(Days 1-21) (Days 1-21) (Days 1-21) Twice daily.

w.4 to w.6 w.10 to w.12 w.16 to w.18 Treatment-free (3 weeks)

*see dose modification for provisions for the modification to dose and dosage schedule

Table 2: For treatment cycles 4-10 with Ceplene and IL-2, same as for Table 1 above, with theexception of number of cycles and duration of rest periods

Week number (w)* Treatment*

Cycles4 5 6 7 8 9 10w.19 w.28 w.37 w.46 w.55- w.64 w.73 IL-2 16 400 IU/kg followed by 0.5 mLto to to to to to to Ceplene. Twice dailyw.21 w.30 w.39 w.48 w.57 w.66 w.75w.22 w.31 w.40 w.49 w.58 w.67 w.76 Treatment-free (6 weeks)to to to to to to tow.27 w.36 w.45 w.54 w.63 w.72 w.81

*see dose modification for provisions for the modification to dose and dosage schedule

Patients should be monitored for the expected symptomatic adverse reactions and laboratory changesassociated with this treatment. Doses of Ceplene and IL-2 should be modified as necessary based onindividual patient tolerance to treatment. It is recommended that dose modifications be addressedearly in treatment. The dose reductions can be temporary or permanent.

Should Ceplene related toxicities occur (such as hypotension, headache), the injection time can beincreased from 5 minutes to a maximum duration of 15 minutes.

For patients experiencing grade 1 toxicity events

No altered dose recommendations with the exception of grade 1 neurologic toxicity and grade 1generalised toxic dermatitis. For the dose recommendations for these grade 1 toxicity events refer tothe relevant sections below:

For patients experiencing grade 1-4 neurologic toxicity

- for grade 1 to 3 toxicity, treatment should be discontinued until grade 0 toxicity event hasbeen achieved. Treatment should then be resumed at a 20% dose reduction for both Cepleneand IL-2.

- for grade 4 toxicity, discontinuation of treatment should be considered.

For patients experiencing grade 1-4 generalised toxic dermatitis

- for grade 1 toxicity, the treatment should be delayed for 48 hours or until all symptoms havebeen resolved. Treatment should then be resumed using the full dose of Ceplene, butreducing the IL-2 dose by 20%.

- for grade 2 toxicity, the IL-2 dose should be reduced 50% and only increased to full dose ifthe symptoms do not reappear. Ceplene and IL-2 doses should be separated by 60 minutes,which should be maintained throughout treatment.

- for grade 3 and 4 toxicity, treatment should be discontinued and not resumed until eventshave been resolved. Treatment should only be resumed after consideration of risk - benefitto the patient.

For patients experiencing grade 2 (including cardiac function, renal, hepatic) toxicity

- treatment should be discontinued until the event has returned to grade 1

- the time of injection of the dose of Ceplene should be extended to a maximum of 15 minutes.

- for cardiac, hepatic or renal toxicities the dose should be reduced by 20% for both Cepleneand IL-2.

For patients experiencing grade 3 and 4 (including hypotension, arrhythmia) toxicities

- treatment should be discontinued until the event is resolved. A maximum delay of onetreatment cycle can be considered for the resolution of grade 3 and 4 events.

For persistent hypotension, headache, arrhythmia, cardiac, hepatic and renal toxicities

- the time of injection of the dose of Ceplene should be extended to a maximum of15 minutes.

- the dose amount of both Ceplene and IL-2 should be reduced by 20%.

Fever

- IL-2 can be discontinued for 24 hours and then restarted at a 20% dose reduction level.

Abnormal WBC counts

- the dose of IL-2 can be reduced by 20% for the remaining duration of the treatment courseand if abnormal WBC counts re-occur during the following cycle a permanent IL-2 reductionis recommended.

Localised toxic dermatitis

- treatment should be discontinued until symptoms resolved. Treatment can be resumed byadministering Ceplene at the full dose and IL-2 at 50%.

The efficacy of Ceplene has not been fully demonstrated in patients older than age 60.

Patients with renal impairment may be more sensitive to the blood pressure lowering effects of

Ceplene. Although the degree of renal impairment has no demonstrable effect on the pharmacokineticdisposition of Ceplene, caution is warranted when Ceplene is administered to patients with severerenal impairment. However, no Ceplene dose reduction is normally required in renally impairedpatients.

Ceplene should be used with caution in patients with moderate to severe hepatic impairment (seesection 5.2). Plasma Ceplene levels are higher in patients with moderate and severe liver impairment,and these patient groups tend to experience more tachycardia and lower blood pressure after Ceplenedosing than do patients with normal or mildly affected liver function. Plasma drug levels were notpredictive of adverse effects, however, and effects did not correlate closely with drug exposure. Dosereduction of Ceplene is normally not required in hepatically impaired patients, but caution should beused in these patients.

The safety and efficacy of Ceplene in children below 18 years of age have not yet been established.

No data are available.

Ceplene is for subcutaneous use only.

One to 3 minutes after the subcutaneous administration of IL-2 has been completed, Ceplene should beadministered by slow subcutaneous injection at a rate not to exceed 0.1 mL (0.1 mg histaminedihydrochloride) per minute. The usual time for administering a 0.5 mL Ceplene dose is 5 minutes.

To reduce potential adverse reactions, the administration time may be lengthened to a maximum of15 minutes, see below. Ceplene can be administered via an ambulatory infusion syringe pump or bycontrolled manual subcutaneous injection by syringe with a timer.

The first dose of Ceplene and IL-2 on day 1 of the initiation of the first cycle of treatment should beadministered in the clinic under direct supervision by a physician. Patient monitoring on day 1 shouldinclude vital signs, including pulse, blood pressure and respiratory rate. If the patient experiences asignificant change in vital signs, the physician should evaluate the status of the patient and continue tomonitor vital signs; these patients should be monitored during subsequent treatments.

Subsequent injections of Ceplene may be self-administered at home by a patient who demonstrates agood understanding of necessary precautions and who has demonstrated adequate injection skills.

Injections should be preferably administered in a supervised setting in the presence of an adult familymember, friend, or other care provider who is capable of responding appropriately should signs orsymptoms of hypotension occur.

The preferred injection areas are the thighs and the abdomen. Ceplene should not be injected into thesame anatomic region as IL-2.

The twice daily dosing of IL-2 and Ceplene should be separated by a minimum of 6 hours. Patientsshould remain at rest for 20 minutes after injection of Ceplene.

For instructions on reconstitution and dilution of Interleukin-2 (aldesleukin) before administration, seecommercially available IL-2 SmPC.

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

- Patients with significantly compromised cardiac function, e.g., NYHA Class III/IV.

- Patients receiving systemic steroid therapy, clonidine and H2 blocking agents.

- Patients who have received an allogenic stem cell transplant.

- During pregnancy.

- During breast feeding.

Ceplene should be administered 1 to 3 minutes after IL-2 administration, and not concomitantly.

Rapid subcutaneous injection or injection into a vascular space may result in severe hypotension,tachycardia, or syncope.

Treatment with Ceplene in conjunction with IL-2 should be used with caution in patients with poorlycompensated cardiac function. Patients with cardiac disease should be evaluated for ventricularejection fraction and wall function by echocardiography or nuclear medicine stress test and thentreated with caution.

Patients should be monitored during treatment for possible clinical complications due to hypotensionor hypovolaemia. Ceplene should be administered in the clinic under supervision of the physician onday 1 of the initial treatment cycle. Patient monitoring on day 1 should include vital signs, includingpulse, blood pressure and respiratory rate.

Patient monitoring during subsequent treatment days or cycles should be performed as long as thepatient continues to experience significant changes in vital signs during administration of Ceplene. Ifsignificant hypotension or related symptoms are observed in subsequent treatment cycles, dosereduction should be initiated and if required, administered in hospital until responses to treatmentallow for home administration.

Caution should be used for patients with any of the following: symptomatic peripheral arterial disease,past or present peptic or oesophageal ulcer disease with a history of bleeding, clinically significantrenal disease and stroke within the last 12 months. Where appropriate, consideration should be madeto providing concomitant treatment with a proton pump inhibitor.

Patients with clinically significant infection requiring the use of antibiotics, antifungals, or antivirals,or who have completed prior anti-infectious therapy within 14 days of starting treatment should betreated with caution unless the use of antibiotics and antivirals were for prophylaxis purposes.

Patients with a prior history of autoimmune disease (including systemic lupus, inflammatory boweldisease, psoriasis and rheumatoid arthritis) should be treated with caution.

Monitoring of laboratory test results is recommended including standard haematological and bloodchemistry tests.

Patients receiving the following medicinal products should be treated with caution (see section 4.5):

- Beta-blockers or other anti-hypertensive agents.

- H1 blocking agents and neuroleptics (anti-psychotics) with H1 receptor blocking properties.

- Tricyclic anti-depressants that may have H1 and H2 receptor blocking properties.

- Monoamine oxidase inhibitors and anti-malarial and anti-trypanosomal agents.

- Neuromuscular blocking agents, narcotic analgesics, and various contrast media.

While posology differs, when Ceplene is used in conjunction with IL-2, physicians should also refer tothe Summary of Product Characteristics (SmPC) for IL-2 and observe the respective medicinalproduct interactions.

H2 receptor antagonists with imidazole structures similar to histamine, e.g., cimetidine, systemicsteroids and clonidine, must not be used during treatment with Ceplene (see section 4.3).

Beta-blockers and other anti-hypertensive agents should be used with caution during treatment with

Ceplene. Concurrent administration of medicinal products with cardiotoxicity or blood pressurelowering effects may increase the toxicity of Ceplene.

H1 receptor blocking antihistamines or neuroleptics (anti-psychotics) with H1 receptor blockingproperties that might decrease efficacy of Ceplene should be avoided.

Tricyclic anti-depressants may have H1 and H2 receptor blocking properties and should be avoided.

Monoamine oxidase inhibitors, anti-malarial, and anti-trypanosomal active substances may alter themetabolism of Ceplene and should be avoided (see section 4.4).

It has been noted that neuromuscular blocking agents, narcotic analgesics, and various contrast mediacan induce the release of endogenous histamine; therefore in patients undergoing diagnostic orsurgical procedures, the additive effect of Ceplene treatment should be considered prior to theprocedure (see section 4.4).

Women of childbearing potential and sexually active men must use effective methods of contraceptionduring treatment with Ceplene and IL-2.

For Ceplene, no clinical data on exposed pregnancies are available. Animal studies showedreproductive toxicity but only at maternotoxic doses, and did not indicate direct harmful effects withrespect to pregnancy, embryonal/foetal development, parturition or postnatal development (seesection 5.3). Ceplene in conjunction with IL-2 must not be used during pregnancy.

It is unknown whether histamine is excreted in human breast milk. The excretion of histamine in milkhas not been studied in animals, but at maternotoxic doses in rats, offspring showed slight toxicityduring early lactation (see section 5.3). Ceplene in conjunction with IL-2 must not be used duringbreast-feeding.

Refer to the IL-2 SmPC for information on pregnancy and breast-feeding with IL-2.

No clinical data are available on the effects of Ceplene on fertility. Animal studies revealed noadverse effects on fertility apart from a slight reduction in implantations and viable foetuses (seesection 5.3).

Ceplene has moderate influence on the ability to drive and use machines. Administration of Ceplenecan cause hypotension and may result in dizziness, light-headedness and blurred vision. Patientsshould not drive or operate machines for at least 1 hour after receiving Ceplene.

Adverse reactions were reported to be at least possibly related to IL-2 and Ceplene treatment in almostall patients in studies in AML.

The most common adverse reactions experienced by 30% or more of patients receiving IL-2 and

Ceplene (listed in descending order of frequency) were: flushing, headache, fatigue, injection sitegranuloma, pyrexia and injection site erythema.

The adverse reactions considered at least possibly related to the treatment of low-dose IL-2 with

Ceplene in AML studies (n=280 for the IL-2 and Ceplene treatment arm) are listed below by bodysystem organ, class and frequency. Within each frequency grouping, undesirable effects are presentedin order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common( 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare(< 1/10,000), or not known (cannot be estimated from the available data).

System organ class Adverse reaction Frequency

Infections and infestations upper respiratory tract Very commoninfectionspneumonia Common

Blood and lymphatic system eosinophilia, thrombocytopenia Very commondisorders leucopenia, Commonneutropenia

Metabolism and nutrition anorexia Commondisorders

Psychiatric disorders insomnia Common

Nervous system disorders headache, dizziness, dysgeusia Very common

Cardiac disorders tachycardia Very commonpalpitations Common

Vascular disorders flushing, hypotension Very common

Respiratory, thoracic, and cough, dyspnoea Very commonmediastinal disordersnasal congestion Common

Gastrointestinal disorders nausea, dyspepsia, diarrhoea Very commonvomiting, abdominal pain Commonupper, dry mouth, gastritis,abdominal distention

Skin and subcutaneous tissue rash Very commondisorderserythema, hyperhidrosis, night Commonsweats, pruritus

Musculoskeletal and arthralgia, myalgia Very commonconnective tissue disorders pain in extremity, back pain Common

General disorders and injection site granuloma, Very commonadministration site conditions fatigue, pyrexia, injection siteerythema, feeling hot, injectionsite reaction, injection sitepruritus, influenza like illness,chills, injection siteinflammation, injection sitepaininjection site urticaria, injection Commonsite bruising, injection site rash,injection site swelling,asthenia, chest pain

Other oncology (advanced tumour) studies

Ceplene and low dose IL-2 have been investigated in other clinical studies at different doses (1 mghistamine dihydrochloride twice a day) and with different dose regimens of low-dose IL-2 andinterferon-alfa. The following adverse reactions, not listed above, were at least possibly related to thestudy medicine:

System organ class Adverse reaction Frequency

Blood and lymphatic system anaemia Commondisorders

Endocrine disorders hypothyroidism Common

Metabolism and nutrition decreased appetite Very commondisorders dehydration Common

Psychiatric disorders anxiety Very commondepression Common

Nervous system disorders paraesthesia Common

Ear and labyrinth disorders vertigo Common

Vascular disorders hot flush Common

Respiratory, thoracic, and wheezing Commonmediastinal disorders

Gastrointestinal disorders constipation, abdominal Commondistention, stomatitis

Skin and subcutaneous tissue dry skin Very commondisorders

General disorders and malaise, oedema peripheral Very commonadministration site conditions injection site fibrosis, pain Common

Investigations weight decreased Very common

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Administration of Ceplene or IL-2 by rapid infusion or into vascular spaces, at higher doses than theapproved ones, may exaggerate the adverse reactions associated with Ceplene.

Pharmacotherapeutic group: Immunostimulants, other immunostimulants, ATC code: L03AX14.

Ceplene/IL-2 is an immunotherapy which aims to induce immune-mediated destruction of residualmyeloid leukaemic cells and thereby to prevent relapse of leukaemia. The role of Ceplene is to protectlymphocytes, in particular NK cells and T cells, which are responsible for the immune-mediateddestruction of residual leukaemic cells. The role of IL-2 is to promote the functions of NK cells and Tcells by activating the anti-leukaemic properties of these cells and by expanding these cell populationsby inducing cell cycle proliferation.

The mechanism by which Ceplene improves the anti-leukaemic function of lymphocytes in AML isnot completely established; it is considered to be by inhibition of reactive oxygen species (ROS or‘oxygen free radicals’), which are synthesised by monocytes/macrophages and granulocytes. ROS areknown to limit the anti-leukaemic effects of lymphocyte activators such as IL-2, by triggeringdysfunction and death by apoptosis in NK cells and T cells. Ceplene inhibits NAPDH oxidase whichinitiates the formation and release of ROS from phagocytes. By inhibiting oxidase function andreducing ROS production, Ceplene protects IL-2-activated NK cells and T cells from oxygen freeradical-induced inhibition and apoptosis. The concomitant administration of Ceplene and IL-2therefore aims to optimise the anti-leukaemic functions of NK cells and T cells.

There have been 2 clinical studies to evaluate the use of Ceplene in the maintenance of remission inadult AML patients. Study AML-1 was exploratory, enrolling 39 AML patients in remission todetermine the dose and feasibility of Ceplene administered together with IL-2. Results of this pilotstudy were used to design and implement a multi-national phase 3 trial. The randomised phase 3 trial(0201) compared Ceplene+IL-2 treatment to no treatment in 261 patients in first remission (CR1) andin another 59 patients in subsequent remission after relapse (CR>1). For CR1 patients, the medianduration of leukaemia-free survival increased from 291 days (9.7 months) to 450 days (15 months)after Ceplene/IL-2 versus no maintenance treatment (Intention to Treat [ITT], p=0.01. n=261). Thenumber of CR1 patients remaining leukaemia-free for 3 years was 40% after Ceplene+IL-2 versus26% in patients not receiving this treatment (p=0.01).

Ceplene is indicated for use in adults. There are no data available on pharmacodynamic properties inchildren below 18 years of age.

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct. The European Medicines Agency will review any new information which may becomeavailable every year and this SmPC will be updated as necessary.

Histamine is rapidly absorbed after subcutaneous injection. Maximum plasma concentration isreached approximately 10 minutes after end of subcutaneous infusion. Histamine concentrations and

PK were highly variable across studies, as well as within the normal volunteer and patient groups.

Patients showed a higher degree of variability with respect to systemic exposure as compared tohealthy subjects. Overall systemic exposure of Ceplene was greater in patients versus healthy subjects.

However, this difference was not statistically significant.

It is not known whether histamine crosses the placenta.

Biotransformation/Elimination

Histamine is eliminated by metabolism in kidney, liver and other tissues. The main enzymes involvedin the metabolism of histamine are HNMT (histamine-N-methyltransferase) and DAO (diamineoxidase). The metabolites are mainly excreted in urine. The mean half-life was 0.75 to 1.5 hours inpatients.

There are no significant effects of age or weight on the pharmacokinetic properties of histamine.

Clearance of Ceplene is almost twice as high in females resulting in considerably lower systemicexposure than in males.

The pharmacokinetics of histamine are similar in healthy volunteers with normal renal functioncompared to volunteers with mild, moderate, or severe renal impairment. In subjects with severe renalimpairment, there were decreases in systolic and diastolic blood pressure at plasma histamineconcentrations which caused no appreciable decrease in blood pressure in other subjects. Thus,subjects with severe renal impairment may be more sensitive to the blood pressure lowering effects ofexogenously administered histamine than subjects with normal renal function or subjects with mild ormoderate renal impairment. Although the degree of renal impairment has little effect on the PKdisposition of histamine, caution should be used in the administration of histamine to patients withsevere renal impairment.

A study was performed to measure the PK of histamine in normal volunteers compared to patientswith mild, moderate, and severe hepatic impairment. There were no clinically significant differencesin safety parameters or in pharmacodynamics. Plasma histamine concentrations were highly variableand were considerably higher in the groups of patients with moderate or severe hepatic impairment(medians 10 and 5 times the normal volunteers respectively). Patients with all degrees of hepaticimpairment may have tachycardia or hypotension for 30-60 minutes after Ceplene+IL-2administration.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated-dosetoxicity, local tolerance and genotoxicity. Effects in non-clinical studies were observed only atexposures considered sufficiently in excess of the maximum human exposure, indicating littlerelevance to clinical use. No carcinogenicity studies have been performed on Ceplene.

Histamine dihydrochloride was not teratogenic in rats or rabbits at doses resulting in several hundred-fold greater systemic exposures than the clinical exposure. In female rats dosed before mating togestation day 7, slightly reduced numbers of implantations and viable foetuses were found, but withoutany dose-response and within the range of historical control data. In the peri-post natal developmentstudy, high doses of histamine dihydrochloride caused maternal toxicity, and the offspring showedtoxicity during lactation (fewer live pups at day 21 compared to lactation at day 4) but not afterweaning.

Sodium chloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies this medicinal product should not be mixed with othermedicinal products, diluents or infusion solutions.

3 years

Do not freeze.

2 mL type I glass vial, with bromobutyl rubber stopper and flip-off aluminium over seal, containing0.5 mL of solution (0.70 mL including overfill).

Each carton contains 14 vials.

Ceplene

The vials contain 0.70 mL of solution (including overfill) to facilitate the dose extraction of a single0.5 mL dose.

Patients should be provided with capped polypropylene syringes and instructed to extract 0.5 mL ofsolution into the syringe.

The solution should be visually inspected for particulate matter and discolouration prior toadministration. The solution must be clear and colourless.

Any unused product or waste material should be disposed of in accordance with local requirements.

Interleukin-2 (IL-2; aldesleukin)

Dilute IL-2 dispensed in capped polypropylene tuberculin syringes is to be prepared by the pharmacyin a controlled aseptic environment and stored in a refrigerator at 2°C - 8°C.

For instructions on the initial reconstitution and subsequent dilution to 200 µg/mL of Interleukin-2(aldesleukin) before administration, see commercially available IL-2 SmPC.

Dispensing instructions for IL-2 (aldesleukin)

IL-2 (aldesleukin) should be aseptically reconstituted, diluted and dispensed in capped polypropylenetuberculin syringes by the pharmacy based on the individual patient’s weight (see administration chartfor aldesleukin below) at the recommended dose of 16 400 IU/kg (1 µg/kg). Up to two weeks supplyof pre-filled capped tuberculin syringes may be provided to patients for home administration, withinstructions that the syringes be stored under refrigeration at 2°C - 8°C prior to administration.

Studies have shown chemical stability and sterility of diluted aldesleukin (dispensed in cappedpolypropylene tuberculin syringes) for up to three weeks when prepared in a controlled asepticenvironment and stored under refrigeration at 2°C - 8°C.

NOTE: Dispensing of aldesleukin must be carried out under controlled aseptic conditions.

Dispensing of dilute IL-2 (aldesleukin) for each patient

The diluted IL-2 (aldesleukin) is aseptically drawn up into sterile polypropylene tuberculin syringesand capped for each patient at 1 µg/kg dose, with a minimum standard dosage volume of 0.25 mL(50 µg) and a maximum dose of 0.5 mL (100 µg). Dosing volumes based on patient weight areprovided in Table 3 below. This table also provides the volume required if a 20% dose reduction isprescribed.

Table 3: Administration chart for IL-2 (aldesleukin)

Patient weight Standard dosage Injection volume* 20% dose reduction injection(kg) (µg) (mL) volume (mL)**≤50 50 0.25 0.20>50 to ≤60 60 0.30 0.25>60 to ≤70 70 0.35 0.30>70 to ≤80 80 0.40 0.30>80 to ≤90 90 0.45 0.35>90 to ≤100 100 0.50 0.40>100 100 0.50 0.40

*Injection volume rounded up to the nearest 0.05 mL

** Injection volumes based on 20% reductions are rounded thus actual dose reductions vary from 15%-25%

Laboratoires Delbert49 Rue Rouelle75015 Paris

France

EU/1/08/477/001

AUTHORISATION

Date of first authorisation: 07/10/2008

Date of latest renewal: 26/07/2018

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

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