SIMULECT 20mg powder + solvent for injection / infusion solution medication leaflet

Simulect 20 mg powder and solvent for solution for injection or infusion

Simulect 20 mg powder for solution for injection or infusion

Each vial contains 20 mg basiliximab*.

One ml of the reconstituted solution contains 4 mg basiliximab.

* recombinant murine/human chimeric monoclonal antibody directed against the interleukin-2receptor -chain (CD25 antigen) produced in a mouse myeloma cell line by recombinant DNAtechnology.

For the full list of excipients, see section 6.1.

Simulect 20 mg powder and solvent for solution for injection or infusion

Powder and solvent for solution for injection or infusion

White powder

Simulect 20 mg powder for solution for injection or infusion

Powder for solution for injection or infusion

White powder

Simulect is indicated for the prophylaxis of acute organ rejection in de novo allogeneic renaltransplantation in adult and paediatric patients (1-17 years) (see section 4.2). It is to be usedconcomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression, inpatients with panel reactive antibodies less than 80%, or in a triple maintenance immunosuppressiveregimen containing ciclosporin for microemulsion, corticosteroids and either azathioprine ormycophenolate mofetil.

Simulect should be prescribed only by physicians who are experienced in the use ofimmunosuppressive therapy following organ transplantation. Simulect should be administered underqualified medical supervision.

Simulect must not be administered unless it is absolutely certain that the patient will receive the graftand concomitant immunosuppression.

Simulect is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-basedimmunosuppression. It can be used in a ciclosporin for microemulsion- and corticosteroid-based tripleimmunosuppressive regimen including azathioprine or mycophenolate mofetil.

The standard total dose is 40 mg, given in two doses of 20 mg each.

The first 20 mg dose should be given within 2 hours prior to transplantation surgery. The second20 mg dose should be given 4 days after transplantation. The second dose should be withheld in theevent of a severe hypersensitivity reaction to Simulect or post-operative complications such as graftloss (see section 4.4).

Children and adolescents (1-17 years)

In paediatric patients weighing less than 35 kg, the recommended total dose is 20 mg, given in twodoses of 10 mg each. In paediatric patients weighing 35 kg or more, the recommended dose is theadult dose, i.e. a total dose of 40 mg, given in two doses of 20 mg each.

The first dose should be given within 2 hours prior to transplantation surgery. The second dose shouldbe given 4 days after transplantation. The second dose should be withheld in the event of a severehypersensitivity reaction to Simulect or post-operative complications such as graft loss (seesection 4.4).

Elderly ( 65 years)

There are limited data available on the use of Simulect in the elderly, but there is no evidence thatelderly patients require a different dosage from younger adult patients.

Reconstituted Simulect can be administered as an intravenous bolus injection or as an intravenousinfusion over 20-30 minutes.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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

Pregnancy and lactation (see section 4.6).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Patients receiving Simulect must be managed in facilities equipped and staffed with adequatelaboratory and supportive medical resources, including medications for the treatment of severehypersensitivity reactions.

Immunosuppressive regimens involving combinations of medications increase the susceptibility toinfection, including opportunistic infections, fatal infections and sepsis; the risk increased with totalimmunosuppressive load.

Simulect must not be administered unless it is absolutely certain that the patient will receive the graftand concomitant immunosuppression.

Severe acute (less than 24 hours) hypersensitivity reactions have been observed both on initialexposure to Simulect and on re-exposure to a subsequent course of therapy. These includedanaphylactoid-type reactions such as rash, urticaria, pruritus, sneezing, wheezing, hypotension,tachycardia, dyspnoea, bronchospasm, pulmonary oedema, cardiac failure, respiratory failure andcapillary leak syndrome. If a severe hypersensitivity reaction occurs, therapy with Simulect must bepermanently discontinued and no further dose be administered. Caution should be exercised whenpatients previously given Simulect are re-exposed to a subsequent course of therapy with thismedicinal product. There is accumulating evidence that a subgroup of patients is at an increased riskof developing hypersensitivity reactions. These are patients in whom, following the initialadministration of Simulect, the concomitant immunosuppression was discontinued prematurely due,for example, to abandoned transplantation or early loss of the graft. Acute hypersensitivity reactionswere observed on re-administration of Simulect for a subsequent transplantation in some of thesepatients.

Neoplasms and infections

Transplant patients receiving immunosuppressive regimens involving combinations with or withoutbasiliximab are at increased risk of developing lymphoproliferative disorders (LPDs) (such aslymphoma) and opportunistic infections (such as cytomegalovirus [CMV], BK virus). In clinical trials,the incidence of opportunistic infections was similar in patients using immunosuppressive regimenswith or without Simulect. In a pooled analysis of two five-year extension studies, no differences werefound in the incidence of malignancies and LPDs between immunosuppressive regimens with orwithout combination of basiliximab (see section 4.8).

No data are available on either the effects of live and inactive vaccination or the transmission ofinfection by live vaccines in patients receiving Simulect. Nevertheless, live vaccines are notrecommended for immunosuppressed patients. The use of live attenuated vaccines should therefore beavoided in patients treated with Simulect. Inactivated vaccines may be administered toimmunosuppressed patients; however, response to the vaccine may depend on the degree of theimmunosuppression, therefore vaccination during treatment with Simulect may be less effective.

Use in heart transplantation

The efficacy and safety of Simulect for the prophylaxis of acute rejection in recipients of solid organallografts other than renal have not been demonstrated. In several small clinical trials in hearttransplant recipients, serious cardiac adverse events such as cardiac arrest (2.2%), atrial flutter (1.9%)and palpitations (1.4%) have been reported more frequently with Simulect than with other inductionagents.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially‘sodium-free’.

This medicinal product contains potassium, less than 1 mmol (39 mg) per vial, i.e. essentially‘potassium-free’.

Because basiliximab is an immunoglobulin, no metabolic drug-drug interactions are to be expected.

In addition to ciclosporin for microemulsion, steroids, azathioprine and mycophenolate mofetil, otherconcomitant medications routinely administered in organ transplantation have been administered inclinical trials without any incremental adverse reactions. These concomitant medications includesystemic antiviral, antibacterial and antimycotic medications, analgesics, antihypertensive medicationssuch as beta-blocking agents or calcium channel blockers, and diuretics.

Human antimurine antibody (HAMA) responses were reported in a clinical trial of 172 patients treatedwith basiliximab, without predictive value for clinical tolerability. The incidence was 2/138 in patientsnot exposed to muromonab-CD3 (OKT3) and 4/34 in patients who received muromonab-CD3concomitantly. The use of basiliximab does not preclude subsequent treatment with murineantilymphocyte antibody preparations.

In the original phase III studies during the first 3 months post-transplantation, 14% of patients in thebasiliximab group and 27% of patients in the placebo group had an acute rejection episode treated withantibody therapy (OKT 3 or antithymocyte globulin/antilymphocyte globulin [ATG/ALG]), with noincrease in adverse events or infections in the basiliximab group as compared to placebo.

Three clinical trials have investigated basiliximab use in combination with a triple therapy regimenwhich included either azathioprine or mycophenolate mofetil. The total body clearance of basiliximabwas reduced by an average 22% when azathioprine was added to a regimen consisting of ciclosporinfor microemulsion and corticosteroids. The total body clearance of basiliximab was reduced by anaverage 51% when mycophenolate mofetil was added to a regimen consisting of ciclosporin formicroemulsion and corticosteroids. The use of basiliximab in a triple therapy regimen includingazathioprine or mycophenolate mofetil did not increase adverse events or infections in the basiliximabgroup as compared to placebo (see section 4.8).

Simulect is contraindicated in pregnancy and lactation (see section 4.3). Basiliximab has potentiallyhazardous immunosuppressive effects with respect to the course of gestation and the suckling neonateexposed to basiliximab in breast milk. Women of childbearing potential must use effectivecontraception during and up to 16 weeks after treatment.

There is no animal or human data available concerning excretion of basiliximab into breast milk.

However, based on the IgG1 nature of basiliximab, excretion into milk should be expected. Breast-feeding must therefore be avoided.

Simulect has no influence on the ability to drive and use machines.

Basiliximab has been tested in four randomised, double-blind, placebo-controlled studies in renaltransplant recipients as an induction agent in combination with the following immunosuppressiveregimens: ciclosporin for microemulsion and corticosteroids in two studies (346 and 380 patients),ciclosporin for microemulsion, azathioprine and corticosteroids in one study (340 patients), andciclosporin for microemulsion, mycophenolate mofetil and corticosteroids in another study(123 patients). Safety data in paediatric patients have been obtained from one open-labelpharmacokinetic and pharmacodynamic study in renal transplant recipients (41 patients).

Incidence of adverse events: In the above four placebo-controlled trials, the pattern of adverse eventsin 590 patients treated with the recommended dose of basiliximab was comparable to that observed in595 patients treated with placebo. The overall incidence of treatment-related adverse events among allpatients in the individual studies was not significantly different between the basiliximab (7.1% - 40%)and the placebo (7.6% - 39%) treatment groups.

Adult patients

The most commonly reported (> 20%) events following dual or triple therapy in both treatment groups(basiliximab vs. placebo) were constipation, urinary tract infection, pain, nausea, peripheral oedema,hypertension, anaemia, headache, hyperkalaemia, hypercholesterolaemia, postoperative woundcomplication, weight increase, increase in blood creatinine, hypophosphataemia, diarrhoea and upperrespiratory tract infection.

The most commonly reported (> 20%) events following dual therapy in both (< 35 kg vs.  35 kgweight) cohorts were urinary tract infection, hypertrichosis, rhinitis, pyrexia, hypertension, upperrespiratory tract infection, viral infection, sepsis and constipation.

Incidence of malignant neoplasms: The overall incidence of malignancies among all patients in theindividual studies was similar between the basiliximab and the comparator treatment groups. Overall,lymphoma/lymphoproliferative disease occurred in 0.1% (1/701) of patients in the basiliximab groupcompared with 0.3% (2/595) of patients receiving placebo, both in combination with dual and tripleimmunosuppressive therapy. Other malignancies were reported among 1.0% (7/701) of patients in thebasiliximab group compared with 1.2% (7/595) of placebo patients. In a pooled analysis of two five-year extension studies, the incidence of LPDs and cancer was found to be equal with basiliximab 7%(21/295) and placebo 7% (21/291) (see section 4.4).

Incidence of infectious episodes: The overall incidence and profile of viral, bacterial and fungalinfections among patients treated with basiliximab or placebo in combination with dual and tripleimmunosuppressive therapy was comparable between the groups. The overall incidence of infectionswas 75.9% in the basiliximab group and 75.6% in the placebo group and the incidence of seriousinfections was 26.1% and 24.8%, respectively. The incidence of CMV infections was similar in bothgroups (14.6% vs. 17.3%), following either dual or triple therapy regimen (see section 4.4).

The incidence and causes of deaths following dual or triple therapy were similar in basiliximab (2.9%)and placebo groups (2.6%), with the most common cause of deaths in both treatment groups beinginfections (basiliximab = 1.3%, placebo = 1.4%). In a pooled analysis of two five-year extensionstudies the incidence and cause of death remained similar in both treatment groups, (basiliximab 15%,placebo 11%), the primary cause of death being cardiac-related disorders such as cardiac failure andmyocardial infarction (basiliximab 5%, placebo 4%).

Listing of adverse reactions from post-marketing spontaneous reports

The following adverse reactions have been identified based on post-marketing spontaneous reports andare organised by system organ class. Because these reactions are reported voluntarily from apopulation of uncertain size, it is not always possible to reliably estimate their frequency.

Hypersensitivity/anaphylactoid reactions such as rash, urticaria, pruritus, sneezing, wheezing,bronchospasm, dyspnoea, pulmonary oedema, cardiac failure, hypotension, tachycardia, respiratoryfailure, capillary leak syndrome (see section 4.4). Cytokine release syndrome.

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.

In clinical studies basiliximab has been administered to humans in single doses of up to 60 mg andmultiple doses of up to 150 mg over 24 days with no acute undesirable effects.

For information on preclinical toxicology see section 5.3.

Pharmacotherapeutic group: Interleukin inhibitors, ATC code: L04AC02.

Basiliximab is a murine/human chimeric monoclonal antibody (IgG1) that is directed against theinterleukin-2 receptor -chain (CD25 antigen), which is expressed on the surface of T-lymphocytes inresponse to antigenic challenge. Basiliximab specifically binds with high affinity (KD-value 0.1 nM) tothe CD25 antigen on activated T-lymphocytes expressing the high affinity interleukin-2 receptor (IL-2R) and thereby prevents binding of interleukin-2, a critical signal for T-cell proliferation in thecellular immune response involved in allograft rejection. Complete and consistent blocking of theinterleukin-2 receptor is maintained as long as serum basiliximab levels exceed 0.2 g/ml (usually upto 4-6 weeks after administration). As concentrations fall below this level, expression of the CD25antigen returns to pretherapy values within 1-2 weeks. Basiliximab does not cause myelosuppression.

The efficacy of basiliximab in prophylaxis of organ rejection in de novo renal transplantation has beendemonstrated in double-blind placebo-controlled studies. Results from two pivotal 12-monthmulticentre studies (722 patients in total) comparing basiliximab with placebo show that basiliximab,used concomitantly with ciclosporin for microemulsion and corticosteroids, significantly reduces theincidence of acute rejection episodes both within 6 (31% vs. 45%, p<0.001) and 12 (33% vs. 48%,p<0.001) months after transplantation. There was no significant difference between basiliximab andplacebo-treated patients in graft survival after 6 and 12 months (at 12 months 32 graft losses onbasiliximab (9%) and 37 graft losses on placebo (10%)). The incidence of acute rejection episode wassubstantially lower in patients receiving basiliximab and a triple drug immunosuppressive regimen.

Results from two multicentre double-blind studies comparing basiliximab with placebo (463 patientsin total) show that basiliximab significantly reduces the incidence of acute rejection episodes within6 months after transplantation when used concomitantly with ciclosporin for microemulsion,corticosteroids, and either azathioprine (21% vs. 35%) or mycophenolate mofetil (15% vs. 27%). Graftloss occurred in 6% of basiliximab-treated and 10% of placebo-treated patients by 6 months. Theadverse event profile remained comparable between treatment groups.

In a pooled analysis of two five-year open-label extension studies (586 patients total) the combinedgraft and patient survival rates were not statistically different for the basiliximab and placebo groups.

Extension studies also showed that patients who experienced an acute rejection episode during the firstyear after transplantation experienced more graft losses and deaths over the five-year follow-up periodthan patients who had no rejection. These events were not influenced by basiliximab.

The efficacy and safety of basiliximab were evaluated in two paediatric studies.

Basiliximab was used concomitantly with ciclosporin for microemulsion and steroids in anuncontrolled study in 41 paediatric de novo renal transplant recipients. Acute rejection occurred in14.6% of patients by 6 months post-transplantation, and in 24.3% by 12 months. Overall the adverseevent profile was consistent with general clinical experience in the paediatric renal transplantationpopulation and with the profile in the controlled adult transplantation studies.

A 12-month, randomised, placebo-controlled, double-blind, multicentre study investigated basiliximabin combination with ciclosporin for microemulsion, mycophenolate mofetil and steroids in paediatricrenal allograft recipients. The primary objective of the study was to demonstrate superiority of thiscombination versus treatment with ciclosporin for microemulsion, mycophenolate mofetil and steroidsin the prevention of acute rejections. Of the 202 patients, 104 were randomised to basiliximab and 98to placebo. The primary efficacy endpoint, time to first biopsy-proven acute rejection (BPAR) episodeor treatment failure defined as graft loss, death or presumptive rejection within the first 6 months posttransplantation, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo-treatedpatients. When borderline rejections were included in the primary efficacy endpoint, the rates were26.0% and 23.9% respectively, with no statistically significant difference between the basiliximab-and placebo-treated groups (HR: 1.04, 90% CI: [0.64; 1.68]). The rates of BPAR were 9.4% in thebasiliximab group and 17.4% in the placebo group (HR: 0.50, 90% CI: [0.25; 0.99]). When borderlinerejections were included, the rates were 20.8% and 19.6% respectively (HR: 1.01, 90% CI: [0.59;1.72]). The overall safety profiles were similar in both groups. The incidence rates of adverse eventsand the pattern of adverse events were comparable between the two treatment groups and to beexpected for the treatment regimens and the underlying diseases.

Of 339 renal transplant patients treated with basiliximab and tested for anti-idiotype antibodies, 4(1.2%) developed an anti-idiotype antibody response. In a clinical trial with 172 patients receivingbasiliximab, the incidence of human antimurine antibody (HAMA) in renal transplantation patientstreated with basiliximab was 2/138 in patients not exposed to muromonab-CD3 and 4/34 in patientswho received muromonab-CD3 concomitantly. The available clinical data on the use of muromonab-

CD3 in patients previously treated with basiliximab suggest that subsequent use of muromonab-CD3or other murine anti-lymphocytic antibody preparations is not precluded.

Single-dose and multiple-dose pharmacokinetic studies have been conducted in adult patientsundergoing kidney transplantation. Cumulative doses ranged from 20 mg up to 60 mg. Peak serumconcentration following intravenous infusion of 20 mg over 30 minutes is 7.15.1 mg/l. There is aproportional increase in Cmax and AUC from 20 mg to 60 mg, the range of single-dose administrationstested. The volume of distribution at steady state was 8.64.1 l. The extent and degree of distributionto various body compartments have not been fully studied. In vitro studies using human tissuesindicate that basiliximab binds only to activated lymphocytes and macrophages/monocytes. Theterminal half-life was 7.23.2 days. Total body clearance was 4119 ml/h.

No clinically relevant influence of body weight or gender on distribution volume or clearance has beenobserved in adult patients. Elimination half-life was not influenced by age, gender, or race.

The pharmacokinetics of basiliximab were assessed in 39 paediatric de novo renal transplantationpatients. In infants and children (age 1-11 years, n=25), the steady-state distribution volume was4.82.1 l, half-life was 9.54.5 days and clearance was 176 ml/h. Distribution volume and clearanceare reduced by about 50% compared to adult renal transplantation patients. Disposition parameterswere not influenced to a clinically relevant extent by age (1-11 years), body weight (9-37 kg) or bodysurface area (0.44-1.20 m) in this age group. In adolescents (age 12-16 years, n=14), the steady-statedistribution volume was 7.85.1 l, half-life was 9.13.9 days and clearance was 3119 ml/h.

Disposition in adolescents was similar to that in adult renal transplantation patients. The relationshipbetween serum concentration and receptor saturation was assessed in 13 patients and was similar tothat characterised in adult renal transplantation patients.

No toxicity was observed when rhesus monkeys received intravenous doses of either up to 5 mg/kgbasiliximab twice weekly for 4 weeks followed by an 8-week withdrawal period or 24 mg/kgbasiliximab weekly for 39 weeks followed by a 13-week withdrawal period. In the 39-week study, thehighest dose resulted in approximately 1,000 times the systemic exposure (AUC) observed in patientsgiven the recommended clinical dose together with concomitant immunosuppressive therapy.

No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgous monkeysfollowing injections of up to 5 mg/kg basiliximab administered twice weekly during the organogenesisperiod.

No mutagenic potential was observed in vitro.

Simulect 20 mg powder and solvent for solution for injection or infusion

Potassium dihydrogen phosphate

Disodium phosphate, anhydrous

Sodium chloride

Sucrose

Mannitol (E421)

Glycine

Water for injections

Simulect 20 mg powder for solution for injection or infusion

Potassium dihydrogen phosphate

Disodium phosphate, anhydrous

Sodium chloride

Sucrose

Mannitol (E421)

Glycine

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Powder: 3 years

Chemical and physical stability of the reconstituted solution is demonstrated for 24 hours at 2°C - 8°C

or for 4 hours at room temperature (see section 6.6).

Store and transport refrigerated (2°C - 8°C).

Simulect 20 mg powder and solvent for solution for injection or infusion

Colourless type I glass vial, grey fluor-resin coated butyl rubber stopper, held in place by a flangedaluminium band, blue polypropylene flip-off cap, containing 20 mg basiliximab as powder for solutionfor injection or infusion.

Colourless glass ampoule, type I glass, containing 5 ml water for injections.

Simulect is also available in vials with 10 mg basiliximab.

Simulect 20 mg powder for solution for injection or infusion

Colourless type I glass vial, grey fluor-resin coated butyl rubber stopper, held in place by a flangedaluminium band, blue polypropylene flip-off cap, containing 20 mg basiliximab as powder for solutionfor injection or infusion.

Simulect is also available in vials with 10 mg basiliximab.

Simulect 20 mg powder and solvent for solution for injection or infusion

To prepare the solution for infusion or injection, add 5 ml of water for injections from theaccompanying ampoule aseptically to the vial containing the Simulect powder. Shake the vial gentlyto dissolve the powder, avoiding foaming. It is recommended that after reconstitution the colourless,clear to opalescent solution should be used immediately. Reconstituted products should be inspectedvisually for particulate matter prior to administration. Do not use if foreign particles are present. Afterreconstitution, chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°Cor for 4 hours at room temperature. From a microbiological point of view, the product should be usedimmediately. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user.

Discard the reconstituted solution if not used within 24 hours.

The reconstituted solution is isotonic and may be given as a bolus injection or diluted to a volume of50 ml or greater with normal saline or dextrose 50 mg/ml (5%) for infusion.

Since no data are available on the compatibility of Simulect with other medicinal products intendedfor intravenous administration, Simulect should not be mixed with other medicinal products andshould always be given through a separate infusion line.

Compatibility with a number of infusion sets has been verified.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Simulect 20 mg powder for solution for injection or infusion

To prepare the solution for infusion or injection, add 5 ml of water for injections compliant with the

European Pharmacopoeia and without any additives aseptically to the vial containing the Simulectpowder. Shake the vial gently to dissolve the powder, avoiding foaming. It is recommended that afterreconstitution the colourless, clear to opalescent solution should be used immediately. Reconstitutedproducts should be inspected visually for particulate matter prior to administration. Do not use ifforeign particles are present. After reconstitution, chemical and physical in-use stability has beendemonstrated for 24 hours at 2°C - 8°C or for 4 hours at room temperature. From a microbiologicalpoint of view, the product should be used immediately. If not used immediately, in-use storage timesand conditions prior to use are the responsibility of the user.

Discard the reconstituted solution if not used within 24 hours.

The reconstituted solution is isotonic and may be given as a bolus injection or diluted to a volume of50 ml or greater with normal saline or dextrose 50 mg/ml (5%) for infusion.

Since no data are available on the compatibility of Simulect with other medicinal products intendedfor intravenous administration, Simulect should not be mixed with other medicinal products andshould always be given through a separate infusion line.

Compatibility with a number of infusion sets has been verified.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Simulect 20 mg powder and solvent for solution for injection or infusion

EU/1/98/084/001

Simulect 20 mg powder for solution for injection or infusion

EU/1/98/084/004

Date of first authorisation: 09 October 1998

Date of latest renewal: 09 October 2008

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

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