WARNINGS. SEE BOX WARNING.
GENERAL
Simulect® 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 lympho-proliferative 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. 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. Patients previously administered Simulect® should only be re-exposed to a subsequent course of therapy with extreme caution. The potential risks of such re-administration, specifically those associated with immunosuppression, are not known.
PRECAUTIONS
GENERAL
It is not known whether Simulect® use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during SimuIect®-induced immunosuppression.
IMMUNOGENICITY
Of renal transplantation patients treated with Simulect® and tested for anti-idiotype antibodies, 4/339 developed an anti-idiotype antibody response, with no deleterious clinical effect upon the patient. In none of these cases was there evidence that the presence of anti-idiotype antibody accelerated Simulect® clearance or decreased the period of receptor saturation. In Study 2, the incidence of human anti-murine antibody (HAMA) in renal transplantation patients treated with Simulect® was 2/138 in patients not exposed to muromonab-CD3 and 4/34 in patients who subsequently received muromonab-CD3. The available clinical data on the use of muromonab-CD3 in patients previously treated with Simulect® suggest that subsequent use of muromonab-CD3 or other murine anti-lymphocytic antibody preparations is not precluded.
These data reflect the percentage of patients whose test results were considered positive for antibodies to Simulect® in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Simulect® with the incidence of antibodies to other products may be misleading.
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 in 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.
PREGNANCY CATEGORY B
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 six 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 patients 65 years and older (Simulect® 28; placebo 32). From the available data comparing Simulect® and placebo-treated patients, the adverse event profile in patients >/=65 years of age is not different from patients <65 years of age and no age-related dosing adjustment is required. Caution must be used in giving immunosuppressive drugs to elderly patients.
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