Synagis

5 WARNINGS AND PRECAUTIONS Anaphylaxis and anaphylactic shock (including fatal cases), and other severe acute hypersensitivity reactions have been reported. Permanently discontinue Synagis and administer appropriate medications if such reactions occur. ( 5.1 ) As with any intramuscular injection, Synagis should be given with caution to children with thrombocytopenia or any coagulation disorder. ( 5.2 ) Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based assays. ( 5.3 , 12.4 ) 5.1 Hypersensitivity Reactions Cases of anaphylaxis and anaphylactic shock, including fatal cases, have been reported following initial exposure or re-exposure to Synagis. Other acute hypersensitivity reactions, which may be severe, have also been reported on initial exposure or re-exposure to Synagis. Signs and symptoms may include urticaria, pruritus, angioedema, dyspnea, respiratory failure, cyanosis, hypotonia, hypotension, and unresponsiveness. The relationship between these reactions and the development of antibodies to Synagis is unknown. If a significant hypersensitivity reaction occurs with Synagis, its use should be permanently discontinued. If anaphylaxis or other significant hypersensitivity reaction occurs, administer appropriate medications (e.g., epinephrine) and provide supportive care as required. If a mild hypersensitivity reaction occurs, clinical judgment should be used regarding cautious readministration of Synagis. 5.2 Coagulation Disorders Synagis is for intramuscular use only. As with any intramuscular injection, Synagis should be given with caution to children with thrombocytopenia or any coagulation disorder. 5.3 RSV Diagnostic Test Interference Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based assays. In addition, palivizumab inhibits virus replication in cell culture, and therefore may also interfere with viral culture assays. Palivizumab does not interfere with reverse transcriptase-polymerase chain reaction based assays. Assay interference could lead to false-negative RSV diagnostic test results. Therefore, diagnostic test results, when obtained, should be used in conjunction with clinical findings to guide medical decisions [see Microbiology ( 12.4 ) ]. 5.4 Treatment of RSV Disease The safety and efficacy of Synagis have not been established for treatment of RSV disease. 5.5 Proper Administration The single-dose vial of Synagis does not contain a preservative. Administration of Synagis should occur immediately after dose withdrawal from the vial. The vial should not be re-entered. Discard any unused portion.

6 ADVERSE REACTIONS The most serious adverse reactions occurring with Synagis are anaphylaxis and other acute hypersensitivity reactions [see Warnings and Precautions ( 5.1 ) ]. Adverse reactions occurring greater than or equal to 10% and at least 1% more frequently than placebo are fever and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience 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 data described below reflect exposure to Synagis (n=1639) compared with placebo (n=1143) in children 3 days to 24.1 months of age at high risk of RSV-related hospitalization in two clinical trials. Trial 1 was conducted during a single RSV season and studied a total of 1502 children less than or equal to 24 months of age with BPD or infants with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Trial 2 was conducted over four consecutive seasons among a total of 1287 children less than or equal to 24 months of age with hemodynamically significant congenital heart disease. In Trials 1 and 2 combined, fever and rash were each reported more frequently among Synagis than placebo recipients, 27% versus 25%, and 12% versus 10%, respectively. Adverse reactions observed in the 153-patient crossover study comparing the liquid and lyophilized formulations were comparable for the two formulations, and were similar to those observed with Synagis in Trials 1 and 2. Immunogenicity In Trial 1, the incidence of anti-palivizumab antibody following the fourth injection was 1.1% in the placebo group and 0.7% in the Synagis group. In children receiving Synagis for a second season, one of the fifty-six children had transient, low titer reactivity. This reactivity was not associated with adverse events or alteration in serum concentrations. Immunogenicity was not assessed in Trial 2. A trial of high-risk preterm children less than or equal to 24 months of age was conducted to evaluate the immunogenicity of the lyophilized formulation of Synagis (used in Trials 1 and 2 above) and the liquid formulation of Synagis. Three hundred seventy-nine children contributed to the 4 to 6 months post-final dose analysis. The rate of anti-palivizumab antibodies at this time point was low in both formulation groups (anti-palivizumab antibodies were not detected in any subject in the liquid formulation group and were detected in one subject in the lyophilized group (0.5%), with an overall rate of 0.3% for both treatment groups combined). These data reflect the percentage of children whose test results were considered positive for antibodies to palivizumab in an enzyme-linked immunosorbent assay (ELISA) and are highly dependent on the sensitivity and specificity of the assay. The ELISA has substantial limitations in detecting anti-palivizumab antibodies in the presence of palivizumab. Immunogenicity samples tested with the ELISA assay likely contained palivizumab at levels that may interfere with the detection of anti-palivizumab antibodies. An electrochemical luminescence (ECL) based immunogenicity assay, with a higher tolerance for palivizumab presence compared to the ELISA, was used to evaluate the presence of anti-palivizumab antibodies in subject samples from two additional clinical trials. The rates of anti-palivizumab antibody positive results in these trials were 1.1% and 1.5%. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Synagis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: severe thrombocytopenia (platelet count less than 50,000 per microliter) General Disorders and Administration Site Conditions: injection site reactions Limited information from post-marketing reports suggests that, within a single RSV season, adverse events after a sixth or greater dose of Synagis are similar in character and frequency to those after the initial five doses.