Simulect

Simulect also contains the following excipients: SDZ CHI 621 protein, disodium hydrogen phosphate, sodium chloride, potassium dihydrogen phosphate, sucrose, mannitol and glycine.
Each ampule contains water for injection 5 mL as solvent.

Pharmacotherapeutic Group: Specific Immunosuppressant. ATC Code: L04AA02.
Pharmacology: Pharmacodynamics: Simulect is a murine/human chimeric monoclonal antibody (Ig_G1κ) that is directed against the interleukin-2 receptor α-chain (CD₂₅ antigen), which is expressed on the surface of T-lymphocytes in response to antigenic challenge. Simulect specially binds to the CD₂₅ antigen on activated T-lymphocytes expressing the high affinity interleukin-2 receptor and thereby, prevents binding of interleukin-2, the signal for T-cell proliferation. Complete and consistent blocking of the interleukin-2 receptor is maintained as long as serum basiliximab levels exceed 0.2 mcg/mL (which was 4-6 weeks). As concentration fall below this level, expression of the CD₂₅ antigen returns to pre-therapy values within 1-2 weeks. Simulect does not cause cytine release or myelosuppression.
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 pre-transplant levels over the following 1-2 weeks.
Clinical Studies: The efficacy of Simulect in prophylaxis of organ rejection in the Nov renal transplantation has been demonstrated in placebo-controlled studies. Result from 2 pivotal, 12-month multicenter studies comparing Simulect with placebo show that Simulect, used concomitantly with cyclosporin for microemulsion and corticosteroids, significantly reduces the incidence of acute rejection episodes both within 6 and 12 months (at 12 months, 32 graft losses on Simulect (9%) and 37 graft losses on placebo (10%).
Of 268 patients treated with Simulect and tested for anti-idiotype antibodies, only 1 developed an anti-idiotype antibody response. Of 172 patients receiving Simulect in clinical trial, 6 (3.5%) developed a HAMA response.
Pharmacokinetics: Single- and multiple-dose pharmacokinetic studies have been conducted in patient as undergoing kidney transplantation. Cumulative doses ranged from 20-60 mg. Peak serum concentration following IV infusion of 20 mg over 30 min is 7.1±5.1 mg/L. There is a proportional increase in C_max and from 20-60 mg, the range of single-dose administrations tested. The volume of distribution at steady state is 8.6±4.1 L. The extent and degree of distribution to various body compartments have not been fully studied. In vitro studies using human tissues indicate that Simulect binds only to lymphocytes and macrophages/monocytes. The terminal half-life is 7.2±3.2 days. Total body clearance is 41±19 mL/hr.
No clinically relevant influence of body weight or gender on distribution volume or clearance has been observed in adult patients. Elimination half-life was not influenced by age (20-69 years), gender or race.
No data exist on the use of Simulect in neonates or infants <2 years. In 1 clinical study in 12 pediatric de novo renal transplant patients. In children (2-11 years, n=8), the steady-state distribution volume was 5.2±28.1 L, half-life was 11.5±6.3 days and clearance was 17±6 mL/hr. Distribution volume and clearance are reduced by about 50% compared to adult renal transplantation patients. Disposition parameters were not influenced to a clinically relevant extent by age (2-11 years), body weight (9-37 kg) or body surface area (0.44-1.20 m²) in this age group. In adolescents (12-15 years, n=4), the steady-state distribution volume was 10.1±7.6 L, half-life was 7.2±3.6 days and clearance was 45±25 mL/hr. Disposition in adolescents was similar to the adult renal transplantation patients. The relationship between serum concentration and receptor saturation was assessed in 2 patients (2 and 12 years) and was similar to that characterized in adult renal transplantation patients.
Toxicology: Preclinical Safety Data: No toxicity was observed when rhesus monkeys received IV doses of up to 5 mg/kg basiliximab twice weekly for 4 weeks, resulting in approximately 20 times the systemic exposure (C_max) observed in renal transplant patients given the recommended clinical dose together with concomitant immunosuppressive therapy.
No maternal toxicity, embryotoxicity or teratogenicity was observed in cynomolgous monkeys 100 days postcoitum following IV bolus injections of up to 5 mg/kg basiliximab administered twice weekly during the organogenesis period.
No mutagenic potential was observed in vitro.

Prophylaxis of acute organ rejection in de novo renal transplantation and is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression. In patients with panel reactive antibodies <80%.

Adults: Recommended Dose: 40 mg given in 2 doses of 20 mg each. The first 20-mg dose should be given within 2 hrs prior to transplantation surgery. The second 20-mg dose should be given 4 days after transplantation. The 2nd dose should be held if postoperative complications eg, graft loss occur. (See Precautions.)
Children: The safety and efficacy of Simulect in pediatric patients has not been established. Very limited pharmacokinetic data are available.
Elderly: There are limited data available on the use of Simulect in elderly, but there is no evidence that elderly patients require a different dosage from younger adult patients.
Administration: Reconstituted Simulect can be administered either as IV infusion over 20-30 min or as a bolus injection.

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 4-weekly study in rhesus monkeys, the no observable effect level was 5 mg/kg twice weekly, leading to a serum C_max of 170 mcg/mL. Levels in humans are generally <10 mcg/mL with the recommended regimen.

Known hypersensitivity to basiliximab or any other component of Simulect.
Use in pregnancy & lactation: 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 basiliximab's immunosuppressive action. Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for an additional 8 weeks after the last dose of Simulect.

Experience with the use of Simulect with immunosuppressive agents other than ciclosporin for microemulsion and corticosteroids is limited. Control studies using azathioprine or mycophenolate mofetil as part of triple immunosuppressive regimen have not been performed.
Medications for the treatment of severe sensitivity reactions should be available for immediate use following administration of proteins.
Patients on immunosuppressive therapy following transplantation are at risk of developing lymphoproliferative disorders (LPDs) and opportunistic infections have been observed in patients treated with Simulect.
Effects on the Ability to Drive or Operate Machinery: Simulect is not expected to affect the ability to drive or use machines.

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 basiliximab's immunosuppressive action. Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for an additional 8 weeks after the last dose of Simulect.

In 2 controlled trials, the pattern of adverse events in 363 patients treated with the recommended dose of Simulect was indistinguishable from that in 359 patients treated with placebo. Simulect did not appear to add to the background of adverse events seen in organ transplant patients as consequence of their underlying disease and the concurrent administration of immunosuppressant and other medications. Adverse events were reported by 99% of the patients in the Simulect-treated group. Simulect did not increase the incidence of serious adverse events observed when compared to placebo. The most commonly reported (>20%) events in both treatment groups were constipation, urinary tract infection, pain, nausea, peripheral edema, hypertension, anemia, headache and hyperkalemia.
Incidence of Malignancies: The overall incidence of malignancies among all patients in the two 12-month controlled trials was not significantly different between the Simulect and the placebo-treatment groups. Overall, lymphoma/lymphoproliferative disease occurred in 1 patient (0.3%) in the Simulect group compared with 2 patients (0.6%) in the placebo group. Other malignancies were reported among 5 patients (1.4%) in the Simulect group compared with 7 patients (1.9%) in patients treated with placebo.
Incidence of Infectious Episodes: Cytomegalovirus infections were reported in 14% of Simulect-treated patients and 18% of placebo-treated patients. The rates of infections were 81% in both groups; for serious infections, they were 28% in the Simulect and 27% in the placebo group, while for infectious organism, they were similar in both the Simulect- and the placebo-treatment groups.
The incidence and causes of deaths were similar in both groups, with the most common cause of deaths in the both treatment groups being infections (13/26 or 50%).

No metabolic drug-drug interactions are to be expected because Simulect is an immunoglobulin.
In addition to cyclosporin for microemulsion and steroids, other medications have been administered in clinical trials without any incremental adverse reactions in the Simulect group as compared to the placebo group, including systemic antiviral medications (60% Simulect, 66% placebo), systemic antibacterial medications (99% both groups), systemic antimycotic medications (47% Simulect, 42% placebo), analgesics (91% Simulect, 92% placebo), antihypertensive medications eg, β-blocking agents (55% Simulect, 64% placebo) or calcium-channel blockers (91% both groups), diuretics (86% Simulect, 89% placebo).
Other immunosuppressives given in the phase 3 studies included azathioprine, mycophenolate mofetil and antibody preparations. During the first 3 months post-transplantation, 10.5% of Simulect patients and 21.7% of placebo patients in the pooled phase 3 studies received triple therapy including azathioprine or mycophenolate mofetil for at least 1 month, with no increase in adverse events or infections in the Simulect group as compared to the placebo group. During the same period, 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 adverse events or infections in the Simulect group as compared to placebo.
Human antimurine antibody (HAMA) responses in Simulect-treated patients are rare (3.5%). The use of Simulect does not preclude subsequent treatment with murine antilymphocyte antibody preparations.
Incompatibilities: None known.

Store under refrigerated conditions (2°-8°C).

Cancer Immunotherapy

L04AC02 - basiliximab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.

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