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  • CLASSES

    Respiratory Syncytial Virus (RSV) Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant monoclonal antibody that provides passive immunity against respiratory syncytial virus (RSV)
    Used for the prevention of RSV in high risk infants and children
    More potent and convenient than RespiGam

    COMMON BRAND NAMES

    Synagis

    HOW SUPPLIED

    Palivizumab (Murine)/Synagis Intramuscular Inj Sol: 0.5mL, 1mL, 50mg, 100mg

    DOSAGE & INDICATIONS

    For respiratory syncytial virus (RSV) infection prophylaxis in pediatric patients at high risk of RSV disease.
    Intramuscular dosage
    High-risk Neonates, Infants, and Children <= 2 years

    15 mg/kg/dose IM once monthly. Administer the first dose prior to commencement of RSV season and continue monthly throughout the RSV season. Limit to no more than 5 monthly doses per RSV season. If the patient undergoes cardiopulmonary bypass or extracorporeal membrane oxygenation, administer 15 mg/kg IM of palivizumab as soon as possible after the procedure, even if it has been less than 1 month since the previous dose.

    Intravenous dosage†
    High-risk Neonates, Infants and Children <= 2 years

    Limited data suggest 15 mg/kg IV once monthly may be effective; dilution of the palivizumab liquid solution is necessary prior to administration. In early clinical trials, palivizumab was administered via the intravenous route. However, to improve the ease of administration, subsequent studies were performed using the intramuscular route. In pharmacokinetic studies of infants and children, a dose of 15 mg/kg IV provided therapeutic serum concentrations within 1 hour of administration. The remaining pharmacokinetic profile over 60 days was similar to that seen after intramuscular administration of 15 mg/kg.

    MAXIMUM DOSAGE

    Adults

    Safety and efficacy have not been established. 

    Geriatric

    Safety and efficacy have not been established. 

    Adolescents

    Safety and efficacy have not been established. 

    Children

    > 2 years: Safety and efficacy have not been established.
    <= 2 years: 15 mg/kg/dose IM.

    Infants

    15 mg/kg/dose IM.

    Neonates

    15 mg/kg/dose IM.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments for hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    NOTE: The rubber stopper used to seal vials of palivizumab liquid solution for injection does not contain latex.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Do not shake or vigorously agitate the vial.
    The solution for injection is preservative-free and is supplied as single-use vials. Discard any unused portion.
    Administer the dose immediately after withdrawing from the vial into a sterile syringe.
    Previously, to minimize product wastage when only the 100 mg vials were available, the American Academy of Pediatrics suggested that prescribers arrange for palivizumab administration so that 2 or more eligible patients could receive the injections within the 6-hour period after opening a palivizumab vial.

    Intravenous Administration

    NOTE: Palivizumab is not approved by the FDA for intravenous administration.
    NOTE: In early clinical trials, lyophilized palivizumab was administered via the intravenous route. However, to improve the ease of administration, subsequent studies were performed using the intramuscular route. In pharmacokinetic studies of infants and children, a dose of 15 mg/kg IV provided therapeutic serum concentrations within one hour of administration. The remaining pharmacokinetic profile over 60 days was similar to that seen after intramuscular administration of 15 mg/kg.
    Dilute liquid solution for injection by adding 5 ml of sterile water for injection or D5W to a 100 mg vial or 2.5 ml of sterile water for injection or D5W to a 50 mg vial. The resulting concentration is 20 mg/ml. The use of D5W as the diluent raises the osmolality closer to an isotonic solution. The final osmolality of the 20 mg/ml dilution using D5W is 224 mOsm/kg.
    Use of a filter is not necessary. Administer at a rate of 1—2 ml/min (20—40 mg/min). Flush the IV line with a small amount of D5W prior to and after administration.

    Intramuscular Administration

    Do not dilute the solution for injection prior to intramuscular administration.
    In neonates, infants, and small children: Intramuscular injections should be made into the anterolateral muscles of the thigh. In order to avoid injury to the sciatic nerves, injection into the upper outer quadrant of the gluteus maximus is not recommended.
    Dosages greater than 1 ml should be divided and injected into different sites.
    Aspirate prior to injection to avoid administration into a blood vessel. If a vessel is penetrated, withdraw the needle and use a new syringe and needle at a different injection site.

    STORAGE

    Synagis:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store between 36 to 46 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Palivizumab may interfere with immunological based respiratory syncytial virus (RSV) detection assays and viral culture assays leading to false-negative RSV diagnostic test results. Diagnostic test results for RSV should be used in conjunction with clinical findings to determine treatment decisions. Palivizumab does not interfere with reverse transcriptase-polymerase chain reaction assays.

    Coagulopathy, thrombocytopenia

    Palivizumab should be given as an intramuscular injection (IM). Caution should be used when administering IM injections to patients with thrombocytopenia or other bleeding disorders, or coagulopathy. Palivizumab may be used in such individuals with caution if the potential benefits outweigh the risk of administration. Vaccination of adult populations with palivizumab is not recommended at this time.

    Acute bronchospasm, hypotension, murine protein hypersensitivity

    Palivizumab is contraindicated in patients with a history of a severe prior reaction to palivizumab or to other components of this product. Palivizumab is a composite of human and murine antibody sequences and may be inappropriate for use by patients with known murine protein hypersensitivity. With any biologic product, the prescriber or health care professional should take precautions to prevent allergic reactions. Very rare cases of anaphylaxis have been reported (see Adverse Reactions). If hypotension, acute bronchospasm, anaphylaxis, or a severe allergic reaction occurs, palivizumab should be permanently discontinued. Epinephrine and supportive care should be administered as necessary. If a milder hypersensitivity reaction occurs, caution should be used on readministration of palivizumab. The health care professional should have immediate availability of epinephrine (1:1000) injection and other agents used in the treatment of severe anaphylaxis in the event of a serious allergic reaction to palivizumab.

    Human anti-human antibody (HAHA)

    Studies indicate a low level of immunogenicity of palivizumab. Patients who develop human anti-human antibody (HAHA) titers may have allergic or hypersensitivity reactions when treated with palivizumab or other humanized monoclonal antibodies. In clinical trials with palivizumab, the incidence of anti-humanized antibody was 0.7% in the palivizumab treated group after the fourth monthly dose. The development of the antibody was not associated with adverse events or alterations in palivizumab activity in the first season of use. Anti-palivizumab antibodies were found in one patient who received the lyophilized formulation verses no patients receiving the liquid formulation in a clinical trial of 379 high-risk preterm children <= 24 months of age. Antibodies in this study were detected using an enzyme-linked immunosorbent assay (ELISA) which has limitations in detecting anti-palivizumab antibodies in the presence of palivizumab. Rates of anti-palivizumab antibodies were assessed in 2 additional clinical trials using an electrochemical luminescence (ECL) based immunogenicity assay and were found to be 1.1% and 1.5%.

    Pregnancy

    Palivizumab has been classified as FDA pregnancy risk category C. Studies in animal or human reproduction have not been conducted. It is unknown if palivizumab can cause fetal harm or affect reproductive capacity.

    Breast-feeding

    Palivizumab is not approved for use in women of childbearing age and data regarding its' administration during breast-feeding is unavailable. The manufacturer does not state whether the drug is excreted in human milk.

    Surgery

    Serum concentrations of palivizumab are significantly decreased after cardio-pulmonary bypass. Patients who undergo surgery involving cardio-pulmonary bypass or who undergo extracorporeal membrane oxygenation (ECMO) should receive a dose of palivizumab as soon as possible after the procedure or at the conclusion of ECMO, even if it has been less than a month since their last dose.

    ADVERSE REACTIONS

    Severe

    anaphylactic shock / Rapid / 0-0.1
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    cyanosis / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 2.3-3.6
    antibody formation / Delayed / 0.5-1.5
    erythema / Early / 1.4-1.4
    dyspnea / Early / Incidence not known
    wheezing / Rapid / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    infection / Delayed / 50.6-50.6
    fever / Early / 27.1-27.1
    rhinitis / Early / 26.8-26.8
    rash / Early / 0.9-12.0
    injection site reaction / Rapid / 2.3-2.3
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    cough / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Palivizumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    Palivizumab has been classified as FDA pregnancy risk category C. Studies in animal or human reproduction have not been conducted. It is unknown if palivizumab can cause fetal harm or affect reproductive capacity.

    Palivizumab is not approved for use in women of childbearing age and data regarding its' administration during breast-feeding is unavailable. The manufacturer does not state whether the drug is excreted in human milk.

    MECHANISM OF ACTION

    Palivizumab exhibits neutralizing and fusion-inhibitory activity against RSV. Palivizumab is directed at an epitope in the A antigenic site of the 'F' protein on the surface of RSV. Palivizumab binds to this epitope, which is highly conserved among different RSV isolates. Thus, palivizumab interferes with the ability of RSV to replicate and infect cells. In laboratory studies, palivizumab neutralized 57 strains of RSV tested. Clinically, tracheal isolates from intubated children with RSV infection have shown significantly reduced quantities of RSV in the lower respiratory tract after palivizumab administration when compared to controls. Because palivizumab is not derived from human immune globulin, it is free of potential contamination by infectious agents and does not contain antibodies directed at other viruses or illnesses.
     
    Further data are needed, but the use of palivizumab prophylaxis in the community does not appear to cause palivizumab-resistant RSV strains. Of 371 RSV strains obtained from children hospitalized for RSV in 8 different communities in the U.S., all were found to bind to palivizumab. Also, 25 of the 371 strains were from children that received palivizumab during the current season, although the average exposure duration was only 2 months (range of 1—5 monthly doses). The strains were obtained during the 4 RSV seasons of 1998—2002, which is during the time period that palivizumab was in use.

    PHARMACOKINETICS

    Palivizumab is usually administered via intramuscular injection. In early clinical trials, lyophilized palivizumab was administered via the intravenous route; however, to improve the ease of administration, subsequent studies were performed using the intramuscular route.
     
    While the fate of palivizumab is not clear, the pharmacokinetics appear to be similar to human IgG1. In clinical models of RSV infection, palivizumab serum concentrations of 40 mcg/ml or more are associated with 99% reductions in pulmonary RSV replication. The half-life is approximately 20 days in pediatric patients <= 24 months of age without congential heart disease (CHD).

    Intravenous Route

    In a pharmacokinetic, dose-escalation study of palivizumab in premature infants, infants, and children <= 24 months with bronchopulmonary dysplasia, a dose of 15 mg/kg IV provided therapeutic serum concentrations within one hour of administration. The remaining pharmacokinetic profile over 60 days was similar to that seen after administration of 15 mg/kg IM with mean serum trough concentrations of 60.6 mcg/ml 1 month after the first infusion and 70.7 mcg/ml 1 month after the second infusion (doses given every 30 days).

    Intramuscular Route

    In a population pharmacokinetic analysis in 1800 patients (1684 pediatric and 116 adult patients), the elimination half-life was 24.5 days in pediatric patients. In pediatric patients <= 24 months without congenital heart disease (CHD), the bioavailability was 70% and clearance was 11 ml/day. The inter-patient variability in drug clearance was 48.7%; covariate analysis did not identify any factors that could account for the inter-patient variability. Monthly intramuscular doses of 15 mg/kg IM achieved mean trough serum drug concentrations of 37 +/- 21 mcg/ml after the first injection, 57 +/- 41 mcg/ml after the second injection, 68 +/- 51 mcg/ml after the third injection, and 72 +/- 50 mcg/ml after the fourth injection. In children given palivizumab for a second season, the mean serum concentrations following the first and fourth injections were 61 +/- 17 mcg/ml and 86 +/- 31 mcg/ml, respectively.