Simulect 20 mg Film-coated tablets

SIMULECT is indicated for the prophylaxis of acute organ rejection in de novo renal transplantation in adult and paediatric patients. It is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression or in a triple maintenance immunosuppressive regimen containing ciclosporin for microemulsion, corticosteroids and either azathioprine or mycophenolate mofetil.

Use in Adults: 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. SIMULECT must not be administered unless it is absolutely certain that the patient will receive the graft and concomitant immunosuppression. The second 20 mg dose should be given 4 days after transplantation. The second dose should be withheld if severe hypersensitivity reactions to SIMULECT or graft loss occur (see Warnings and Special Precautions).

Use in Children and adolescents (1-17 years): In paediatric patients weighing less than 35 kg, the recommended total dose is 20 mg, given in two doses of 10 mg each. In paediatric patients weighing 35 kg or more, the recommended dose is the adult 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. SIMULECT must not be administered unless it is absolutely certain that the patient will receive the graft and concomitant immunosuppression. The second dose should be given 4 days after transplantation. The second dose should be withheld if severe hypersensitivity reactions to SIMULECT or graft loss occur (see Warnings and Special Precautions).

Use in the Elderly u2265 65 years: There are limited data available on the use of SIMULECT in the elderly, but there is no evidence that elderly patients require a different dosage from younger adult patients.

Mode of administration: Reconstituted SIMULECT can be administered either as an intravenous infusion over 20 to 30 minutes or as a bolus injection.

Instructions for reconstitution: To prepare the infusion/injection solution, add 5 ml of water for injection aseptically to the vial containing the SIMULECT powder. Shake the vial gently to dissolve the powder. Use the reconstituted, colourless, clear to opalescent solution as soon as possible (see Storage Instructions). 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 is 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.

Known hypersensitivity to basiliximab or any other component of the formulation.

Patients who are using anti-T-cell antibody infusions, can develop a characteristic set of clinical signs and symptoms that occurs as an immediate complication, more frequently with monoclonal or polyclonal lymphocyte-depleting antibodies. Anti-T-cell antibodies bind to the T-cell receptor, which leads to activation of the T-cells prior to their destruction. The cytokines released by the activated T- cells produce a type of systemic inflammatory response similar to that found in severe infection characterised by hypotension, pyrexia, and rigors. CRS can cause life-threatening pulmonary oedema with potential fatal outcome, especially if the patient is fluid overloaded.

General: SIMULECT should be prescribed only by physicians who are experienced in the use of immunosuppressive therapy following organ transplantation.

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

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, respiratory failure and capillary leak syndrome. If severe hypersensitivity occurs, therapy with SIMULECT should be permanently discontinued and no further dose should be administered. Caution should be exercised when patients previously given SIMULECT are re-exposed to a subsequent course of therapy with this medicine. There is evidence that a subgroup of patients is at 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 SIMULECT 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.

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. Inactivated vaccines may be administered to immunosuppressed patients; however, response to the vaccine may depend on the degree of the immunosuppression.

Because SIMULECT is an immunoglobulin, no metabolic drug-drug interactions are to be expected. Concomitant medications routinely administered in organ transplantation: In addition to ciclosporin for microemulsion, steroids, azathioprine and mycophenolate mofetil, other concomitant medications routinely administered in organ transplantation have been administered in clinical trials without any incremental adverse reactions. These concomitant medications include systemic antiviral, antibacterial and antimycotic medications, analgesics, antihypertensive medications such as beta-blocking agents or calcium channel blockers, and diuretics.

In the original phase 3 studies during the first 3 months post-transplantation, 14 % of patients in the SIMULECT group and 27 % of patients in the placebo group had an acute rejection episode treated with antibody therapy (OKT 3 or ATG/ALG), with no increase in adverse events or infections in the SIMULECT group as compared to placebo. Three clinical trials have investigated SIMULECT use in combination with a triple therapy regimen which included either azathioprine or mycophenolate mofetil. The total body clearance of SIMULECT was reduced by an average 22 % when azathioprine was added to a regimen consisting of ciclosporin for microemulsion and corticosteroids. The total body clearance of SIMULECT was reduced by an average 51 % when mycophenolate mofetil was added to a regimen consisting of ciclosporin for microemulsion and corticosteroids. The use of SIMULECT in a triple therapy regimen including azathioprine or mycophenolate mofetil did not increase adverse events or infections in the SIMULECT group as compared to placebo (see Side effects).

Pregnancy: SIMULECT is contraindicated during 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 basiliximabu2019s immunosuppressive action.

Women of Childbearing Potential: Women of child-bearing potential must use adequate contraception to prevent pregnancy and continue its use for an additional 4 months after the last dose of SIMULECT.

Lactation: Since SIMULECT is an immunoglobulin G (IgG1 u03ba) antibody, it may cross the human placenta and may be excreted in human milk. Women receiving SIMULECT should not breastfeed for 4 months following the second dose.

No studies on the effects on the ability to drive and use machines have been performed. SIMULECT is not expected to affect the ability to drive or use machines.

SIMULECT has been tested in four randomised, double-blind, placebo-controlled studies in renal transplant recipients: in two studies patients were concomitantly treated with ciclosporin for microemulsion and corticosteroids (346 and 380 patients), in one study patients were concomitantly treated with ciclosporin for microemulsion, azathioprine and corticosteroids (340 patients), in one study patients were concomitantly treated with ciclosporin for microemulsion, mycophenolate mofetil and corticosteroids (123 patients). SIMULECT has also been compared to a polyclonal anti-T-lymphocyte immunoglobulin preparation (ATG/ALG) in one active-controlled study in renal transplant recipients, all patients were concomitantly treated with ciclosporin for microemulsion, mycophenolate mofetil and corticosteroids (135 patients). Safety data in paediatric patients have been obtained from one open-label pharmacokinetic and pharmacodynamic study in renal transplant recipients (41 patients).

Incidence of Adverse Events: SIMULECT did not appear to add to the background of adverse events seen in organ transplantation patients as a consequence of their underlying disease and the concurrent administration of immunosuppressants and other medications. In the four placebo-controlled trials, the pattern of adverse events in 590 patients treated with the recommended dose of SIMULECT was indistinguishable from that in 595 patients treated with placebo. SIMULECT did not increase the incidence of serious adverse events observed when compared to placebo. The overall incidence of treatment-related adverse events among all patients in the individual studies was not significantly different between the SIMULECT (7,1 % - 40 %) and the placebo (7,6 % - 39 %) treatment groups. In the active-controlled study, fewer SIMULECT (11,4 %) than ATG/ALG (41,5 %) patients experienced treatment-related adverse events.

Adult experience: Adverse events reported in >20 % (very common) of adult patients following dual or triple therapy in both treatment groups (SIMULECT and Placebo or ATG/ALG) Gastrointestinal disorders Infections and infestations Nausea, diarrhoea, constipation Upper respiratory tract infection, urinary tract infection General disorders and administration site conditions Pain, peripheral oedema Vascular disorders Hypertension Blood and lymphatic system disorders Anaemia Nervous system disorders Headache Metabolism and nutrition disorders Hyperkalaemia, hypophosphataemia, hypercholesterolaemia Injury, poisoning and procedural complications Postoperative wound complication Investigations Weight increase, increase in blood creatinine

Paediatric experience: The most commonly reported (> 20 %) events following dual therapy in both (< 35 kg vs. u2265 35 kg weight) cohorts were urinary tract infection, hypertrichosis, rhinitis, pyrexia, hypertension, upper respiratory tract infection and viral infection, sepsis and constipation.

Incidence of Neoplasms: The overall incidence of malignancies among all patients in the individual studies was similar between the SIMULECT and the comparator treatment groups. Overall, lymphoma/lymphoproliferative disease occurred in 0,1 % (1/701) of patients in the SIMULECT group compared with 0,3 % (2/595) of placebo and 0 % of ATG/ALG patients. Other malignancies were reported among 1,0 % (7/701) of patients in the SIMULECT group compared with 1,2 % (7/595) of placebo and 4,6 % (3/65) of ATG/ALG patients. No differences were found in the incidence of malignancies and LPDs between SIMULECT 7 % (21/295) and placebo 7 % (21/291) in a pooled analysis of two five-year extension studies.

Incidence of Infectious Episodes: The overall incidence and profile of infectious episodes among dual and triple therapy patients was similar between the SIMULECT and the placebo treatment groups (SIMULECT = 75,9 %, Placebo or ATG/ALG = 75,6 %). The incidence of serious infections was similar in the SIMULECT and comparator groups (26,1 % vs. 24,8 %). The incidence of CMV-infections was similar in both groups (14,6 % vs. 17,3 %), following either dual or triple therapy regimen. The incidence and causes of deaths following dual or triple therapy were similar in SIMULECT (2,9 %) and placebo or ATG/ALG groups (2,6 %), with the most common cause of deaths in both treatment groups being infections (SIMULECT = 1,3 %, placebo or ATG/ALG = 1,4 %). In a pooled analysis of two five-year extension studies the incidence and cause of death remained similar in both treatment groups (SIMULECT 15 %; placebo 11 %), the primary cause of death being cardiac-related disorders such as cardiac failure and myocardial infarction (SIMULECT 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 and are organised by system organ classes. Because these reactions are reported voluntary from a population of uncertain size, it is not always possible to reliably estimate their frequency.

System organ class Adverse reaction: Immune system disorders hypersensitivity/anaphylactoid reaction such as rash, urticaria, pruritis, sneezing, wheezing, bronchospasm, dyspnoea, pulmonary oedema, cardiac failure, hypotension, tachycardia, respiratory failure, capillary leak syndrome, and cytokine release syndrome (CRS) (see Warnings and Special Precautions).

In clinical studies SIMULECT has been administered to humans in single doses of up to 60 mg and multiple doses of up to 150 mg over 24 days with no untoward acute effects. 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 1000-times the systemic exposure (AUC) in renal transplant patients given the recommended clinical dose together with concomitant immunosuppressive therapy.