Novartis Pharmaceuticals UK Ltd

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

Immunosuppressive regimens involving combinations of medications increase the susceptibility to infection, including opportunistic infections, fatal infections and sepsis; the risk increased with total immunosuppressive load.

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

Hypersensitivity reactions

Severe acute (less than 24 hours) hypersensitivity reactions have been observed both on initial exposure to Simulect and on re-exposure to a subsequent course of therapy. These included anaphylactoid-type reactions such as rash, urticaria, pruritus, sneezing, wheezing, hypotension, tachycardia, dyspnoea, bronchospasm, pulmonary oedema, cardiac failure,  and respiratory failure. and capillary leak syndrome. There have been rare reports of such reactions in patients receiving Simulect (< 1/1,000 patients). If a severe hypersensitivity reaction occurs, therapy with Simulect must be permanently discontinued and no further dose be administered. Caution should be exercised when patients previously given Simulect are re-exposed to a subsequent course of therapy with this medicinal product. There is accumulating evidence that a subgroup of patients is at an increased risk of developing hypersensitivity reactions. These are patients in whom, following the initial administration of Simulect, the concomitant immunosuppression was discontinued prematurely due, for example, to abandoned transplantation or early loss of the graft. Acute hypersensitivity reactions were observed on re-administration of Simulect for a subsequent transplantation in some of these patients.

Neoplasms and infections

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

Vaccination

No data are available on either the effects of live and inactive vaccination or the transmission of infection by live vaccines in patients receiving Simulect. Nevertheless, live vaccines are not recommended for immunosuppressed patients. The use of live attenuated vaccines should therefore be avoided in patients treated with Simulect. Inactivated vaccines may be administered to immunosuppressed patients; however, response to the vaccine may depend on the degree of the immunosuppression, therefore vaccination during treatment with Simulect may be less effective.

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 being infections (basiliximab = 1.3%, placebo = 1.4%). In a pooled analysis of two five-year extension studies 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 and myocardial infarction (basiliximab 5%, placebo 4%).

Listing of adverse reactions from Ppost-marketing spontaneous reports adverse reactions

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

Immune System disorders

Hypersensitivity/anaphylactoid reactions such as rash, urticaria, pruritus, sneezing, wheezing, bronchospasm, dyspnoea, pulmonary oedema, cardiac failure, hypotension, tachycardia, respiratory failure,  and capillary leak syndrome (see section 4.4). , and cCytokine release syndrome. have been reported during post-marketing experience with Simulect. The frequency is not known (cannot be estimated from the available data).

Paediatric populations

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

Basiliximab was used concomitantly with ciclosporin for microemulsion and steroids in an uncontrolled study in 41 paediatric de novo renal transplant recipients. Acute rejection occurred in 14.6% of patients by 6 months post-transplantation, and in 24.3% by 12 months. Overall the adverse event profile was consistent with general clinical experience in the paediatric renal transplantation population and with the profile in the controlled adult transplantation studies.

A 12-month, randomised, placebo-controlled, double-blind, multicentre study investigated basiliximab in combination with ciclosporin for microemulsion, mycophenolate mofetil and steroids in paediatric renal allograft recipients. The primary objective of the study was to demonstrate superiority of this combination versus treatment with ciclosporin for microemulsion, mycophenolate mofetil and steroids in the prevention of acute rejections. Of the 202 patients, 104 were randomised to basiliximab and 98 to placebo. The primary efficacy endpoint, time to first biopsy-proven acute rejection (BPAR) episode or treatment failure defined as graft loss, death or presumptive rejection within the first 6 months post transplantation, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo-treated patients. When borderline rejections were included in the primary efficacy endpoint, the rates were 26.0% 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 the basiliximab group and 17.4% in the placebo group (HR: 0.50, 90% CI: [0.25; 0.99]). When borderline rejections 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 events and the pattern of adverse events were comparable between the two treatment groups and to be expected for the treatment regimens and the underlying diseases.

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Section 2:

The following statement has been added:

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

Section 4.2:

The statement below has been moved to  paragraph 2 of this section.

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

Section 4.4:

The following statements have been added:

Immunosuppressive regimens involving combinations of medications increase the susceptibility to infection, including opportunistic infections, fatal infections and sepsis; the risk increased with total immunosuppressive load.

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

Section 4.6

Reworded from:

Simulect is contraindicated (see section 4.3) in pregnancy and lactation. Basiliximab has potentially hazardous pharmacological effects with respect to the course of gestation and the suckling neonate exposed to basiliximab in breast milk. This concern is based on basiliximab’s immunosuppressive action. Women of childbearing potential have to use effective contraception 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.

To:

Simulect is contraindicated in pregnancy and lactation (see section 4.3). Basiliximab has potentially hazardous immunosuppressive effects with respect to the course of gestation and the suckling neonate exposed to basiliximab in breast milk. Women of childbearing potential must use effective contraception 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.

Section 4.8.

Changed from:

Post-marketing adverse reactions

Adverse reactions are listed according the following categories:

Very common: >1/10; common: > 1/100, < 1/10; uncommon: > 1/1,000, < 1/100; rare: > 1/10,000, < 1/1,000; very rare: < 1/10,000.

To:

Post-marketing adverse reactions

Hypersensitivity/anaphylactoid reactions such as rash, urticaria, sneezing, wheezing, bronchospasm, pulmonary oedema, cardiac failure, respiratory failure and capillary leak syndrome (see section 4.4), and cytokine release syndrome have been reported during post-marketing experience with Simulect. The frequency is not known (cannot be estimated from the available data).

Section 4.9

The following statement has been deleted:

In a 39-week study in rhesus monkeys followed by a 13-week recovery period, the no observable effect level was set at the highest dose level of 24 mg/kg week, leading to exposure values greater than 1,000-times the systemic exposure (AUC) in renal transplant patients given the recommended clinical dose together with concomitant immunosuppressive therapy.

And replaced by:

For information on preclinical toxicology see section 5.3.

Section 5.1

The following statement has been deleted:

Soluble IL-2R serum concentrations increase over the first 2–3 weeks following the administration of Simulect, reaching a plateau at levels of 80–120 ng/ml. These levels are maintained while IL-2R sites are saturated by basiliximab. When IL-2R sites are no longer saturated, soluble IL-2R levels fall to pretransplant levels over the following 1–2 weeks.

Section 6.3

Changed from:

After reconstitution the solution may be stored at 2°C - 8°C for 24 hours or at room temperature for 4 hours.

To:

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).

Section 6.6:

 Changed from :

6.6     Special precautions for disposal and other handling

Simulect 10 mg powder and solvent for solution for injection or infusion

To prepare the solution for infusion or injection, take 2.5 ml of water for injections out of the accompanying 5 ml-ampoule aseptically and add this 2.5 ml of water for injections aseptically to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. It is recommended that after reconstitution the colourless, clear to opalescent solution should be used immediately. After reconstitution it may be stored at 2°C - 8°C for 24 hours or at room temperature for 4 hours.

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 of  25 ml or greater with normal saline or dextrose 5% for infusion.

Simulect 20 mg powder and solvent for injection or infusion

To prepare the solution for infusion or injection, add 5 ml of water for injections from the accompanying ampoule aseptically to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. It is recommended that after reconstitution the colourless, clear to opalescent solution should be used immediately. After reconstitution it may be stored at 2°C - 8°C for 24 hours or at room temperature for 4 hours.

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 of 50 ml or greater with normal saline or dextrose 5% for infusion.

Since no data are available on the compatibility of Simulect with other intravenous substances, Simulect should not be mixed with other medications/substances and should always be given through a separate infusion line.

Compatibility with a number of infusion sets has been verified.

To:

6.6     Special precautions for disposal and other handling

Simulect 10 mg powder and solvent for solution for injection or infusion

Reconstitution

To prepare the solution for infusion or injection, take 2.5 ml of water for injections out of the accompanying 5 ml-ampoule aseptically and add this 2.5 ml of water for injections aseptically to the vial containing the Simulect powder. Shake the vial gently to 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 inspected visually for particulate matter prior to administration. Do not use if foreign particles are present. After reconstitution, chemical and physical in-use stability has been demonstrated for 24 hours at 2°C ‑ 8°C or for 4 hours at room temperature. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and 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 of  25 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 intended for intravenous administration, Simulect should not be mixed with other medicinal products and should always be given through a separate infusion line.

Compatibility with a number of infusion sets has been verified.

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

Simulect 20 mg powder and solvent for injection or infusion

Reconstitution

To prepare the solution for infusion or injection, add 5 ml of water for injections from the accompanying ampoule aseptically to the vial containing the Simulect powder. Shake the vial gently to 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 inspected visually for particulate matter prior to administration. Do not use if foreign particles are present. After reconstitution, chemical and physical in-use stability has been demonstrated for 24 hours at 2°C ‑ 8°C or for 4 hours at room temperature. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and 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 of 50 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 intended for intravenous administration, Simulect should not be mixed with other medicinal products and should always be given through a separate infusion line.

Compatibility with a number of infusion sets has been verified.

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

Section 10

Date of revision of the text changed to 08 Oct 2008