SYNAGIS

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intramuscular Administration
Preparation
-Do not dilute the solution prior to intramuscular administration.
-Do not shake or vigorously agitate the vial.
-Administer the dose immediately after withdrawing from the vial into a sterile syringe.
-The solution for injection is preservative-free and is supplied as single-use vials. Discard any unused portion.

IM Injection
-Divide doses greater than 1 mL and inject into different sites.
-Inject into the anterolateral aspect of the thigh. In order to avoid injury to the sciatic nerve, injection into the gluteus maximus is not recommended.

In clinical trials, serious adverse reactions related to palivizumab were rare. The number of patients with any adverse events judged to be related to palivizumab was similar to that of the placebo groups (11% versus 10%, respectively). Limited information from post-marketing reports suggest that, within a single RSV season, adverse reactions occurring after 6 or more doses of palivizumab are similar to those reported after the initial 5 doses.

The most serious adverse reactions occurring with palivizumab are anaphylaxis or anaphylactoid reactions and other acute hypersensitivity reactions. During post marketing surveillance, cases of anaphylaxis and anaphylactic shock have been reported after initial exposure or after re-exposure to palivizumab; some cases have been fatal. Hypersensitivity reactions may include urticaria, pruritus, angioedema, dyspnea, respiratory failure, cyanosis, hypotonia, hypotension, and unresponsiveness. The relationship between these reactions and the development of antibodies to palivizumab is unknown. If hypotension, anaphylaxis, or a severe allergic reaction occurs, palivizumab should be permanently discontinued. Epinephrine and supportive care should be administered as necessary. Rash is a common adverse effect occurring with palivizumab administration. Two clinical trials reported rash (unspecified) in 12% of patients receiving palivizumab (n = 1639) versus 10% of patients receiving placebo (n = 1143).

Injection site reactions may be observed in patients who receive IM administration of palivizumab. In one study of high-risk infants (n = 1002 in palivizumab group), 2.3% of patients who received palivizumab experienced an injection site reaction. These reactions included erythema (1.4% palivizumab vs. 1.2% placebo), pain (0.6% palivizumab vs. 0 placebo), induration/swelling (0.6% palivizumab vs 0.2% placebo), and bruising (0.3% palivizumab vs. 0.4% placebo).

Elevated hepatic enzymes were reported in clinical trials of palivizumab. In all cases these elevations were mild or moderate. Of 1641 patients ages 3 days to 24 months who received palivizumab, 3% experienced an increase in AST compared to 1.7% of those who received placebo (n = 1148). In one study of high-risk infants (n = 1002 in the palivizumab group), elevations in AST occurred in 3.6% of palivizumab treated children, and 1.6% of placebo recipients, respectively. ALT elevations occurred in 2.3% of palivizumab recipients versus 2% of controls. Hepatic and renal adverse events thought to be related to study participation occurred in similar percentages in both groups as judged by a blinded investigator.

Upper respiratory tract infection, otitis media, and fever were the most commonly observed adverse events during palivizumab clinical trials; however, because palivizumab is often studied in infants and young children at high risk for respiratory infections, it is difficult to determine what portion of these events were related to palivizumab therapy and what portion represented background incidences. In clinical trials, there was a slightly higher incidence of upper respiratory infection (50.6% vs. 47.4%), otitis media (36.4% vs. 34.6%), fever (27.1% vs. 25.2%), and rhinitis (26.8% vs. 24.6%) in palivizumab-treated patients (n = 1641) compared to those who received placebo (n = 1148). Other adverse events reported in relation to palivizumab administration include cough and wheezing.

Gastrointestinal side effects of palivizumab are rare and comparable to rates seen with placebo. Hernia was reported in 4.1% of patients receiving palivizumab versus 2.6% of those patients receiving placebo. Other gastrointestinal adverse events reported in relation to palivizumab administration include diarrhea, vomiting, and gastroenteritis.

In clinical trials with palivizumab lyophilized formulation, the incidence of antibody formation, specifically, anti-humanized antibody, was 0.7% in the palivizumab-treated group after the fourth monthly dose. In patients receiving palivizumab for a second season, 1 of 56 patients had transient, low-titer reactivity. The development of the antibody was not associated with adverse events or alterations in palivizumab activity in the first season of use. In addition, the possibility exists that the liquid solution may be more immunogenic than the lyophilized formulation. 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%.

Post-marketing reports of adverse events associated with the use of palivizumab have included reports of severe thrombocytopenia (platelet count < 50,000/microliter). A causal relationship to palivizumab exposure has not been established.

In a clinical trial of pediatric patients < = 24 months of age with congenital heart disease who received palivizumab prophylaxis, cyanosis occurred in 9.1% of patients and arrhythmias or arrhythmia exacerbation occurred in 3.1% of patients compared to 6.9% and 1.7% of patients receiving placebo, respectively.

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.

Palivizumab should be given as an intramuscular injection (IM). Caution should be used when administering IM injections to patients with thrombocytopenia, other bleeding disorders, or coagulopathy. Palivizumab may be used in such individuals with caution if the potential benefits outweigh the risk of administration.

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. Cases of anaphylaxis and anaphylactic shock, including fatal ones, have been reported with initial exposure or re-exposure. Signs and symptoms may include urticaria, pruritis, angioedema, dyspnea, respiratory failure, cyanosis, hypotonia, hypotension, and unresponsiveness. 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.

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%.

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.

Description: Palivizumab is the first recombinant humanized monoclonal antibody approved to provide passive immunity for an infectious disease. Palivizumab is used to prevent respiratory syncytial virus (RSV) infection in high-risk pediatric patients; RSV is the most common cause of pneumonia and bronchiolitis in infancy and early childhood. Palivizumab is produced by recombinant DNA technology and is a composite of human (95%) and murine (5%) antibody sequences. Palivizumab is an IgG1 kappa immunoglobulin that contains a human framework region that surrounds the murine regions responsible for binding to RSV. This type of humanized monoclonal antibody tends to have little immunogenicity. In an early trial, palivizumab administration resulted in a 55% reduction in RSV hospitalizations in high-risk pediatric patients. A lower incidence of RSV-related ICU admissions has also been seen in palivizumab-treated children. In an observational, prospective, case-control study in premature Japanese neonates (gestational age: 33 to 35 weeks), palivizumab prophylaxis given during the first respiratory season significantly lowered the incidence of recurrent wheezing during the first 3 years of life (6.4% in treated group vs. 18.9% in the untreated group; p less than 0.001). The difference remained significant after adjustment for known risk factors for wheezing. Despite the beneficial effect in certain high risk groups, additional data have shown that this benefit does not extend to as many patient populations as previously thought. Based on available data, the American Academy of Pediatrics (AAP) recommends limiting palivizumab administration in the US to certain preterm infants, infants with certain chronic illnesses, immunocompromised children, and some Alaska Native and American Indian infants. Palivizumab is not recommended for the prevention of healthcare-associated RSV disease, and it is not recommended for the treatment of RSV. Palivizumab is FDA-approved in pediatric patients as young as neonates.

General Dosing Information
Centers for Disease Control and Prevention (CDC) recommendations during 2023/2024 RSV season due to limited availability of nirsevimab
-In palivizumab-eligible patients aged 8 to 19 months, suspend using nirsevimab for the 2023/2024 RSV season. These patients should receive palivizumab.
-Continue recommending nirsevimab to American Indian and Alaska Native patients aged 8 to 19 months who are not palivizumab-eligible and who live in remote regions, or in communities with known high rates of RSV among older infants and toddlers.
-Follow American Academy of Pediatrics (AAP) recommendations for palivizumab-eligible patients aged younger than 8 months when appropriate nirsevimab dose is not available.

American Academy of Pediatrics (AAP) recommendations on who should be considered for RSV prophylaxis with palivizumab

-Palivizumab prophylaxis is recommended for:-Patients born before 29 weeks, 0 days gestation who are younger than 12 months postnatal age at start of RSV season
-Patients with chronic lung disease (CLD) of prematurity (defined as birth at younger than 32 weeks, 0 days gestation and a requirement for more than 21% oxygen for at least 28 days after birth) during the first year of life; during the second year of life, consideration of palivizumab prophylaxis is recommended only for those patients who satisfy this definition of CLD of prematurity AND continue to require medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6-month period before the start of the second RSV season

-Palivizumab prophylaxis may be beneficial for:-Patients 12 months of age and younger with hemodynamically significant congenital heart disease (CHD), particularly those with acyanotic heart disease receiving medication to control heart failure and requiring future cardiac surgical procedures and patients with moderate to severe pulmonary hypertension
-Patients younger than 24 months of age who are profoundly immunocompromised during RSV season
-Patients younger than 12 months of age with pulmonary or neurological abnormality that impairs the ability to clear upper airway secretions

-Palivizumab prophylaxis is generally NOT recommended for:-Otherwise healthy patients born at or after 29 weeks, 0 days gestation
-Patients with hemodynamically insignificant heart disease, infants with lesions adequately corrected by surgery (unless they continue to require medication for heart failure), patients with mild cardiomyopathy, and patients in their second year of life
-Patients with Down Syndrome without another qualifying indication
-Patients with cystic fibrosis without another qualifying indication

-Due to differences in RSV epidemiology and burden, selection criteria for Alaska Native patients eligible for palivizumab prophylaxis may differ from the remainder of the United States. Limited data are also available regarding the burden of RSV disease for American Indians; special consideration may be prudent for Navajo and White Mountain Apache patients during the first year of life.
-Discontinue monthly prophylaxis in any infant or child who experiences a breakthrough RSV hospitalization.
-Palivizumab should not be used for the treatment of RSV or for the prevention of healthcare-associated RSV disease.
-Patients in the neonatal intensive care unit who qualify for palivizumab administration may receive the first dose 48 to 72 hours prior to or promptly after discharge.
-Generally, no more than 5 monthly doses of palivizumab are recommended for a given RSV season; however, the AAP supports providing more than 5 consecutive doses of palivizumab to eligible patients in regions with widespread and intense RSV circulation. Patients born during the RSV season may require fewer than 5 doses.
-Typically, in the Northern Hemisphere, RSV season begins in November and continues through April. The season may vary, and administration schedules can be altered accordingly.

For respiratory syncytial virus (RSV) infection prophylaxis in pediatric patients at high risk of RSV disease:
Intramuscular dosage:
Neonates: 15 mg/kg/dose IM once monthly. Administer the first dose prior to commencement of RSV season and continue monthly throughout the RSV season. Generally, limit to 5 monthly doses per RSV season; however, AAP supports providing more than 5 consecutive doses of palivizumab to eligible children in regions with widespread and intense RSV circulation. 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.
Infants and Children 1 to 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. Generally, limit to 5 monthly doses per RSV season; however, AAP supports providing more than 5 consecutive doses of palivizumab to eligible children in regions with widespread and intense RSV circulation. 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.

Maximum Dosage Limits:
-Neonates
15 mg/kg/dose IM.
-Infants
15 mg/kg/dose IM.
-Children
1 to 2 years: 15 mg/kg/dose IM.
3 to 12 years: Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments for hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Palivizumab interferes with the ability of RSV to replicate and infect cells. 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. 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.

Pharmacokinetics: Palivizumab is administered via intramuscular injection. 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 of palivizumab is approximately 20 days in pediatric patients 24 months and younger without congential heart disease (CHD).

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intramuscular Route
In a population pharmacokinetic analysis in 1,800 patients (1,684 pediatric and 116 adult patients), the elimination half-life was 24.5 days in pediatric patients. In pediatric patients 24 months and younger without congenital heart disease (CHD), the bioavailability was 70% and clearance was 11 mL/day. The interpatient variability in drug clearance was 48.7%; covariate analysis did not identify any factors that could account for the interpatient variability. Monthly intramuscular doses of 15 mg/kg 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 after the first and fourth injections were 61 +/- 17 mcg/mL and 86 +/- 31 mcg/mL, respectively.


-Special Populations
Other
Infants and Children Undergoing Cardio-Pulmonary Bypass or Extracorporeal Membrane Oxygenation (ECMO)
In a clinical trial of pediatric patients 24 months and younger with hemodynamically significant congenital heart disease who underwent procedures involving cardio-pulmonary bypass (n = 139), mean palivizumab concentrations declined from 98 mcg/mL prior to bypass to 41 mcg/mL after bypass.