Biotechnology Healthcare - July/August 2008 - (Page CB8)

SYNAGIS® (PALIVIZUMAB) for Intramuscular Administration Rx only Table 2 - Adverse Events Occurring at a Rate of 1% or Greater More Frequently in Patients† Receiving Synagis Event Synagis (n=1641) Placebo (n=1148) n (%) n (%) Upper respiratory infection 830 (50.6) 544 (47.4) Otitis media 597 (36.4) 397 (34.6) Fever 446 (27.1) 289 (25.2) Rhinitis 439 (26.8) 282 (24.6) Hernia 68 (4.1) 30 (2.6) SGOT Increase 49 (3.0) 20 (1.7) †Cyanosis (Synagis [9.1%]/placebo [6.9%]) and arrhythmia (Synagis [3.1%]/placebo [1.7%]) were reported during Trial 2 in CHD patients. Immunogenicity In Trial 1, the incidence of anti-Synagis antibody following the fourth injection was 1.1% in the placebo group and 0.7% in the Synagis group. In pediatric patients receiving Synagis for a second season, one of the fifty-six patients 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. These data reflect the percentage of patients whose test results were considered positive for antibodies to Synagis 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 Synagis with the incidence of antibodies to other products may be misleading. With any monoclonal antibody, the possibility exists that a liquid solution may be more immunogenic than a lyophilized formulation. The relative immunogenicity rates between the lyophilized formulation, used in Trials 1 and 2 above, and the liquid solution have not yet been established. Post-Marketing Experience The following adverse reactions have been identified and reported during post-approval use of Synagis. Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. Injection site reactions have been reported. Rare severe acute hypersensitivity reactions (<1 case per 1,000 patients) have been reported on initial or subsequent exposure. Very rare cases of anaphylaxis (<1 case per 100,000 patients) have also been reported following re-exposure (See WARNINGS). None of the reported hypersensitivity reactions were fatal. Hypersensitivity reactions may include dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia and unresponsiveness. The relationship between these reactions and the development of antibodies to Synagis is unknown. Very rare cases (<1 case per 100,000 patients) of severe thrombocytopenia (platelet count < 50,000/uL) have been reported. 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. OVERDOSAGE: No data from clinical studies are available on overdosage. No toxicity was observed in rabbits administered a single intramuscular or subcutaneous injection of Synagis at a dose of 50 mg/kg. DOSAGE AND ADMINISTRATION: The recommended dose of Synagis is 15 mg/kg of body weight. Patients, including those who develop an RSV infection, should continue to receive monthly doses throughout the RSV season. The first dose should be administered prior to commencement of the RSV season. In the northern hemisphere, the RSV season typically commences in November and lasts through April, but it may begin earlier or persist later in certain communities. Synagis serum levels are decreased after cardio-pulmonary bypass (see CLINICAL PHARMACOLOGY). Patients undergoing cardio-pulmonary bypass should receive a dose of Synagis as soon as possible after the cardio-pulmonary bypass procedure (even if sooner than a month from the previous dose). Thereafter, doses should be administered monthly. Synagis should be administered in a dose of 15 mg/kg intramuscularly using aseptic technique, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk of damage to the sciatic nerve. The dose per month = patient weight (kg) x 15 mg/kg ÷ 100 mg/mL of Synagis. Injection volumes over 1 mL should be given as a divided dose. Administration of Synagis • DO NOT DILUTE THE PRODUCT • DO NOT SHAKE OR VIGOROUSLY AGITATE THE VIAL • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration. • Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the Synagis vial, and wipe the rubber stopper with a disinfectant (e.g., 70% isopropyl alcohol). Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution. Administer immediately after drawing the dose into the syringe. • Synagis is supplied as a single-dose vial and does not contain preservatives. Do not re-enter the vial after withdrawal of drug; discard unused portion. Only administer one dose per vial. • To prevent the transmission of hepatitis viruses or other infectious agents from one person to another, sterile disposable syringes and needles should be used. DO NOT reuse syringes and needles. HOW SUPPLIED: Synagis is supplied in single-dose vials as a preservative-free, sterile liquid solution at 100 mg/mL for IM injection. 50 mg vial NDC 60574-4114-1 The 50 mg vial contains 50 mg Synagis in 0.5 mL. 100 mg vial NDC 60574-4113-1 The 100 mg vial contains 100 mg Synagis in 1 mL. There is no latex in the rubber stopper used for sealing vials of Synagis. Upon receipt and until use, Synagis should be stored between 2°C and 8°C (35.6°F and 46.4°F) in its original container. DO NOT freeze. DO NOT use beyond the expiration date. REFERENCES: 1. Press E, and Hogg N. The Amino Acid Sequences of the Fd Fragments of Two Human Gamma-1 Heavy Chains. Biochem. J. 1970; 117:641-660. 2. Takahashi N, Noma T, and Honjo T. Rearranged Immunoglobulin Heavy Chain Variable Region (VH) Pseudogene that Deletes the Second Complementarity-Determining Region. Proc. Nat. Acad. Sci. USA 1984; 81:5194-5198. 3. Bentley D, and Rabbitts T. Human Immunoglobulin Variable Region Genes - DNA Sequences of Two Vκ Genes and a Pseudogene. Nature 1980; 288:730-733. 4. Beeler JA, and Van Wyke Coelingh K. Neutralization Epitopes of the F Protein of Respiratory Syncytial Virus: Effect of Mutation Upon Fusion Function. J. Virology 1989; 63:2941-2950. 5. Johnson S, Oliver C, Prince GA, et al. Development of a Humanized Monoclonal Antibody (MEDI-493) with Potent In Vitro and In Vivo Activity Against Respiratory Syncytial Virus. J. Infect. Dis. 1997; 176:1215-1224. 6. Malley R, DeVincenzo J, Ramilo O, et al. Reduction of Respiratory Syncytial Virus (RSV) in Tracheal Aspirates in Intubated Infants by Use of Humanized Monoclonal Antibody to RSV F Protein. J. Infect. Dis. 1998; 178:1555-1561. 7. The IMpact RSV Study Group. Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-Risk Infants. Pediatrics 1998; 102:531-537. Synagis® is a registered trademark of MedImmune, Inc. DESCRIPTION: Synagis (palivizumab) is a humanized monoclonal antibody (IgG1κ ) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). Synagis is a composite of human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived from the constant domains of human IgG1 and the variable framework regions of the VH genes Cor (1) and Cess (2). The human light chain sequence was derived from the constant domain of Cκ and the variable framework regions of the VL gene K104 with Jκ -4 (3). The murine sequences were derived from a murine monoclonal antibody, Mab 1129 (4), in a process that involved the grafting of the murine complementarity determining regions into the human antibody frameworks. Synagis is composed of two heavy chains and two light chains and has a molecular weight of approximately 148,000 Daltons. Synagis is supplied as a sterile, preservative-free liquid solution at 100 mg/mL to be administered by intramuscular injection (IM). Thimerosal or other mercury containing salts are not used in the production of Synagis. The solution has a pH of 6.0 and should appear clear or slightly opalescent. Each 100 mg single-dose vial of Synagis liquid solution contains 100 mg of Synagis, 3.9 mg of histidine, 0.1 mg of glycine, and 0.5 mg of chloride in a volume of 1 mL. Each 50 mg single-dose vial of Synagis liquid solution contains 50 mg of Synagis, 1.9 mg of histidine, 0.06 mg of glycine, and 0.2 mg of chloride in a volume of 0.5 mL. CLINICAL PHARMACOLOGY: Mechanism of Action: Synagis exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication in laboratory experiments. Although resistant RSV strains may be isolated in laboratory studies, a panel of 57 clinical RSV isolates were all neutralized by Synagis (5). Synagis serum concentrations of ≥ 40 mcg/mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold (5). The in vivo neutralizing activity of the active ingredient in Synagis was assessed in a randomized, placebo-controlled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, Synagis significantly reduced the quantity of RSV in the lower respiratory tract compared to control patients (6). Pharmacokinetics: In pediatric patients < 24 months of age without congenital heart disease (CHD), the mea

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Biotechnology Healthcare - July/August 2008 Openers Contents Editorial/David B. Nash, MD, MBA Drug Track Health Plan Confidential Rheumatoid Arthritis A Decade of Trial, Error, False Starts, and Hope What Path Will Comparative Effectiveness Research Take? RA Therapies in Development: A New Generation of Relief Assessing the Full Impact of RA on Employers and Payers Stem Cells: Health Insurance You Can Bank On Specialty Pharmacy Employer to Employer Personalized Medicine Trends Clinical Briefs

Biotechnology Healthcare - July/August 2008

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