Simulect

INDICATIONS AND USAGE Simulect ® (basiliximab) is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED), and corticosteroids. The efficacy of Simulect for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

DOSAGE AND ADMINISTRATION Simulect ® (basiliximab) is used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. Simulect is for central or peripheral intravenous administration only. Reconstituted Simulect should be given either as a bolus injection or diluted to a volume of 25 mL (10-mg vial) or 50 mL (20-mg vial) with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and administered as an intravenous infusion over 20 to 30 minutes. Bolus administration may be associated with nausea, vomiting and local reactions, including pain. Simulect should only be administered once it has been determined that the patient will receive the graft and concomitant immunosuppression. Patients previously administered Simulect should only be re-exposed to a subsequent course of therapy with extreme caution due to the potential risk of hypersensitivity (see WARNINGS). Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. After reconstitution, Simulect should be a clear-to-opalescent, colorless solution. If particulate matter is present or the solution is colored, do not use. Care must be taken to assure sterility of the prepared solution because the drug product does not contain any antimicrobial preservatives or bacteriostatic agents. It is recommended that after reconstitution, the solution should be used immediately. If not used immediately, it can be stored at 2oC to 8oC (36oF to 46oF) for 24 hours or at room temperature for 4 hours. Discard the reconstituted solution if not used within 24 hours. No incompatibility between Simulect and polyvinyl chloride bags or infusion sets has been observed. No data are available on the compatibility of Simulect with other intravenous substances. Other drug substances should not be added or infused simultaneously through the same intravenous line. Adults In adult patients, the recommended regimen is two doses of 20 mg each. The first 20-mg dose should be given within 2 hours prior to transplantation surgery. The recommended second 20-mg dose should be given 4 days after transplantation. The second dose should be withheld if complications, such as severe hypersensitivity reactions to Simulect or graft loss occur. Pediatric In pediatric patients weighing less than 35 kg, the recommended regimen is two doses of 10 mg each. In pediatric patients weighing 35 kg or more, the recommended regimen is two doses of 20 mg each. The first dose should be given within 2 hours prior to transplantation surgery. The recommended second dose should be given 4 days after transplantation. The second dose should be withheld if complications, such as severe hypersensitivity reactions to Simulect or graft loss occur. Reconstitution of 10 mg Simulect ® Vial To prepare the reconstituted solution, add 2.5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 25 mL with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE . Reconstitution of 20 mg Simulect ® Vial To prepare the reconstituted solution, add 5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect powder. Shake the vial gently to dissolve the powder. The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 50 mL with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE .

CONTRAINDICATIONS Simulect ® (basiliximab) is contraindicated in patients with known hypersensitivity to basiliximab or any other component of the formulation. See composition of Simulect under DESCRIPTION. WARNINGS. See Boxed WARNING. General Simulect ® (basiliximab) should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy. While neither the incidence of lymphoproliferative disorders nor opportunistic infections was higher in Simulect-treated patients than in placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing these complications and should be monitored accordingly. Hypersensitivity Severe acute (onset within 24 hours) hypersensitivity reactions, including anaphylaxis have been observed both on initial exposure to Simulect and/or following re-exposure after several months. These reactions may include hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing. Extreme caution should be exercised in all patients previously given Simulect when being administered a subsequent course of Simulect. A subgroup of patients may be particularly at risk of developing severe hypersensitivity reactions on re-administration. These are patients in whom concomitant immunosuppression was discontinued prematurely (e.g., due to abandoned transplantation or early loss of the graft) following the initial administration of Simulect. If a severe hypersensitivity reaction occurs, therapy with Simulect should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis should be available for immediate use.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. The incidence of adverse events for Simulect ® (basiliximab) was determined in four randomized, double-blind, placebo-controlled clinical trials for the prevention of renal allograft rejection. Two of the studies (Study 1 and Study 2), used a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, whereas the other two studies (Study 3 and Study 4) used a triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids, and either azathioprine or mycophenolate mofetil. 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. Adverse events were reported by 96% of the patients in the placebo-treated group and 96% of the patients in the Simulect-treated group. In the four placebo-controlled studies, the pattern of adverse events in 590 patients treated with the recommended dose of Simulect was similar to that in 594 patients treated with placebo. Simulect did not increase the incidence of serious adverse events observed compared with placebo. The most frequently reported adverse events were gastrointestinal disorders, reported in 69% of Simulect-treated patients and 67% of placebo-treated patients. The incidence and types of adverse events were similar in Simulect-treated and placebo-treated patients. The following adverse events occurred in ≥ 10% of Simulect-treated patients: Gastrointestinal System: constipation, nausea, abdominal pain, vomiting, diarrhea, dyspepsia; Body as a Whole-General: pain, peripheral edema, fever, viral infection; Metabolic and Nutritional: hyperkalemia, hypokalemia, hyperglycemia, hypercholesterolemia, hypophosphatemia, hyperuricemia; Urinary System: urinary tract infection; Respiratory System: dyspnea, upper respiratory tract infection; Skin and Appendages: surgical wound complications, acne; Cardiovascular Disorders-General: hypertension; Central and Peripheral Nervous System: headache, tremor; Psychiatric: insomnia; Red Blood Cell: anemia. The following adverse events, not mentioned above, were reported with an incidence of ≥ 3% and < 10% in pooled analysis of patients treated with Simulect in the four controlled clinical trials, or in an analysis of the two dual-therapy trials: Body as a Whole-General: accidental trauma, asthenia, chest pain, increased drug level, infection, face edema, fatigue, dependent edema, generalized edema, leg edema, malaise, rigors, sepsis; Cardiovascular: abnormal heart sounds, aggravated hypertension, angina pectoris, cardiac failure, chest pain, hypotension; Endocrine: increased glucocorticoids; Gastrointestinal : enlarged abdomen, esophagitis, flatulence, gastrointestinal disorder, gastroenteritis, GI hemorrhage, gum hyperplasia, melena, moniliasis, ulcerative stomatitis; Heart Rate and Rhythm: arrhythmia, atrial fibrillation, tachycardia; Metabolic and Nutritional: acidosis, dehydration, diabetes mellitus, fluid overload, hypercalcemia, hyperlipemia, hypertriglyceridemia, hypocalcemia, hypoglycemia, hypomagnesemia, hypoproteinemia, weight increase; Musculoskeletal: arthralgia, arthropathy, back pain, bone fracture, cramps, hernia, myalgia, leg pain; Nervous System: dizziness, neuropathy, paraesthesia, hypoesthesia; Platelet and Bleeding: hematoma, hemorrhage, purpura, thrombocytopenia, thrombosis; Psychiatric: agitation, anxiety, depression; Red Blood Cell: poly …

Drug Interactions No dose adjustment is necessary when Simulect is added to triple-immunosuppression regimens, including cyclosporine, corticosteroids, and either azathioprine or mycophenolate mofetil. Three clinical trials have investigated Simulect use in combination with triple-therapy regimens. Pharmacokinetics were assessed in two of these trials. Total body clearance of Simulect was reduced by an average 22% and 51% when azathioprine and mycophenolate mofetil, respectively, were added to a regimen consisting of cyclosporine, USP (MODIFIED) and corticosteroids. Nonetheless, the range of individual Simulect clearance values in the presence of azathioprine (12-57 mL/h) or mycophenolate mofetil (7-54 mL/h) did not extend outside the range observed with dual therapy (10-78 mL/h). The following medications have been administered in clinical trials with Simulect with no increase in adverse reactions: ATG/ALG, azathioprine, corticosteroids, cyclosporine, mycophenolate mofetil, and muromonab-CD3. Carcinogenesis/Mutagenesis/Impairment of Fertility No mutagenic potential of Simulect was observed in the i n vitro assays with Salmonella (Ames) and V79 Chinese hamster cells. No long-term or fertility studies in laboratory animals have been performed to evaluate the potential of Simulect to produce carcinogenicity or fertility impairment, respectively. There are no adequate and well-controlled studies in pregnant women. No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients. Immunotoxicology studies have not been performed in the offspring. Because IgG molecules are known to cross the placental barrier, because the IL-2 receptor may play an important role in development of the immune system, and because animal reproduction studies are not always predictive of human response, Simulect should only be used in pregnant women when the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should use effective contraception before beginning Simulect therapy, during therapy, and for 4 months after completion of Simulect therapy. Nursing Mothers It is not known whether Simulect is excreted in human milk. Because many drugs, including human antibodies are excreted in human milk, and because of the potential for adverse reactions, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use No randomized, placebo-controlled studies have been completed in pediatric patients. In a safety and pharmacokinetic study, 41 pediatric patients (1-11 years of age [n = 27], 12-16 years of age [n = 14], median age 8.1 years) were treated with Simulect via intravenous bolus injection in addition to standard immunosuppressive agents, including cyclosporine, USP (MODIFIED), corticosteroids, azathioprine, and mycophenolate mofetil. The acute rejection rate at 6 months was comparable to that in adults in the triple-therapy trials. The most frequently reported adverse events were hypertension, hypertrichosis, and rhinitis (49% each), urinary tract infections (46%), and fever (39%). Overall, the adverse event profile was consistent with general clinical experience in the pediatric renal transplantation population and with the profile in the controlled adult renal transplantation studies. The available pharmacokinetic data in children and adolescents are described in CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION. It is not known whether the immune response to vaccines, infection, and other antigenic stimuli administered or encountered during Simulect therapy is impaired or whether such response will remain impaired after Simulect therapy. Geriatric Use Controlled clinical studies of Simulect have included a small number of pa …

DESCRIPTION Basiliximab is a chimeric (murine/human) monoclonal antibody (IgG 1 к ), produced by recombinant DNA technology, that functions as an immunosuppressive agent, specifically binding to and blocking the interleukin-2 receptor α-chain (IL-2Rα, also known as CD25 antigen) on the surface of activated T-lymphocytes. Based on the amino acid sequence, the calculated molecular weight of the protein is 144 kilodaltons. It is a glycoprotein obtained from fermentation of an established mouse myeloma cell line genetically engineered to express plasmids containing the human heavy and light chain constant region genes and mouse heavy and light chain variable region genes encoding the RFT5 antibody that binds selectively to the IL-2Rα. Simulect ® (basiliximab) for injection is a sterile, preservative-free lyophilisate, which is available in single-dose vials and is available in 10 mg and 20 mg strengths for intravenous administration after reconstitution. Each 10-mg vial contains 10 mg of basiliximab, and dibasic sodium phosphate (anhydrous) (0.50 mg), glycine (20.3 mg), mannitol (40.6 mg), monobasic potassium phosphate (3.66 mg), sodium chloride (0.82 mg), and sucrose (10.1 mg) to be reconstituted in 2.5 mL of Sterile Water for Injection, USP. Each 20-mg vial contains 20 mg of basiliximab, and dibasic sodium phosphate (anhydrous) (0.99 mg), glycine (40.1 mg), mannitol (80.1 mg), monobasic potassium phosphate (7.22 mg), sodium chloride (1.61 mg), and sucrose (20 mg) to be reconstituted in 5 mL of Sterile Water for Injection, USP.

OVERDOSAGE A maximum tolerated dose of Simulect ® (basiliximab) has not been determined in patients. During the course of clinical studies, Simulect has been administered to adult renal transplantation patients in single doses of up to 60 mg, or in divided doses over 3-5 days of up to 120 mg, without any associated serious adverse events. There has been one spontaneous report of a pediatric renal transplantation patient who received a single 20-mg dose (2.3 mg/kg) without adverse events.

HOW SUPPLIED Simulect ® (basiliximab) is supplied in a single-dose glass vial. Each carton contains one of the following 1 Simulect 10 mg vial.............................................................NDC 0078-0393-61 1 Simulect 20 mg vial.............................................................NDC 0078-0331-84 Store lyophilized Simulect under refrigerated conditions at 2oC to 8oC (36oF to 46oF). Do not use beyond the expiration date stamped on the vial.