Aetna Palivizumab (Synagis) Form
This procedure is not covered
Background for this Policy
U.S. Food and Drug Administration (FDA)-Approved Indications
Synagis is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients:
Limitations of Use:
The safety and efficacy of Synagis have not been established for treatment of RSV disease.
Compendial Uses
Palivizumab is available as Synagis (Swedish Orphan Biovitrum AB). Palivizumab is a humanized monoclonal antibody (IgG1k) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus. Palivizumab exhibits neutralizing and fusion‐inhibitory activity against respiratory syncytial virus (RSV). The populations at highest risk are premature babies and children with congenital heart disease, patients with chronic lung disease, or immunodeficient patients.
Synagis label carries warnings and precautions for anaphylaxis and anaphylactic shock (including fatal cases), and other severe acute hypersensitivity reactions have been reported. As with any intramuscular injection, Synagis should be given with caution to children with thrombocytopenia or any coagulation disorder. Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based assays. Adverse reactions occurring greater than or equal to 10% and at least 1% more frequently than placebo include fever and rash (Sobi, 2021).
Physicians should arrange for drug administration within six hours after opening a vial as this product does not contain a preservative.
Synagis (palivizumab) received FDA approval in June 1998 for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (≤5 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD).
Randomized placebo controlled clinical trials have demonstrated the safety and efficacy of palivizumab (Impact RSV Study, 1998) in reducing hospitalizations due to RSV infection, and in producing reductions in other measures of severity of RSV infection for a very specific group of infants and children. Epidemiologic data indicate that the risk of severe RSV infection most likely to require hospitalization is greater in the presence of risk factors.
In a phase I/II, multi-center, randomized, double-blind, placebo-controlled, escalating dose clinical trial, Saez-Llorens and colleagues (2004) described the safety, tolerance, pharmacokinetics and clinical outcome of a single intravenous dose of palivizumab in previously healthy children hospitalized with acute RSV infection. A total of 59 subjects less than or equal to 2 years of age received study drug – 16 children received 5 mg/kg of palivizumab (n = 8) or placebo (n = 8); 43 received 15 mg/kg of palivizumab (n = 22) or placebo (n = 21). Adverse events judged to be related to study drug were seen in one 5-mg/kg palivizumab patient and one 15-mg/kg palivizumab patient. These events were transient or consistent with progression of RSV disease. No discontinuations of study drug infusion because of adverse events occurred. Mean serum concentrations of palivizumab in the 5- and 15-mg/kg groups, respectively, were 61.2 and 303.4 microg/ml at 60 mins and 11.2 and 38.4 microg/ml after 30 days. There were no significant differences in clinical outcomes between placebo and palivizumab groups for either dose.
There is no adequate evidence that immune globulins (palivizumab or RSV-IVIG) are effective for treatment of RSV infections. A Cochrane systematic evidence review found no studies demonstrating statistically significant benefits of treatment with immune globulins added to supportive care compared with supportive care alone (Fuller and Del Mar, 2006).
Fernandez and colleagues (2010) stated that RSV is an important pathogen causing annual epidemics of bronchiolitis and pneumonia among infants worldwide. High-risk infants currently receive RSV prophylaxis with palivizumab, a humanized RSV monoclonal antibody (MAb). In pre-clinical in vitro and in vivo (cotton-rat model) studies, motavizumab, a new RSV MAb, was shown to have greater anti-RSV activity than palivizumab. Motavizumab is currently under review for licensing approval. Since both MAbs may be available concurrently, these researchers evaluated their safety and tolerability when administered sequentially during the same RSV season. Between April 2006 and May 2006, 260 high-risk infants were randomly assigned 1:1:1 to receive monthly intra-muscular injections: 2 doses of motavizumab followed by 3 doses of palivizumab (M/P); 2 doses of palivizumab followed by 3 doses of motavizumab (P/M); or 5 doses of motavizumab (control). Adverse events (AEs, serious AEs [SAEs]), development of anti-drug antibody (ADA), and serum drug trough concentrations were assessed. Most children received all 5 doses (246/260 [94.6 %]) and completed the study (241/260 [92.7 %]). While overall AE rates were similar (mostly level 1 or 2 in severity), SAEs and level 3 AEs occurred more frequently in the M/P group (SAEs: 22.9 % M/P, 8.4 % P/M, 11.8 % motavizumab only; level 3 AEs: 15.7 % M/P, 6.0 % P/M, 6.5 % motavizumab only). This trend in AE rates occurred before and after switching from motavizumab to palivizumab, suggesting a cause other than the combined regimen. Frequencies of AEs judged by the investigator to be related to study drug were similar among groups. Two deaths occurred on study (both in the M/P group, before palivizumab administration); neither was considered by the site investigator to be related to study drug. Mean serum drug trough concentrations were comparable among groups; ADA detection was infrequent (5.1 % or less of any group). The authors stated that conclusions drawn from this study are limited by the small sample size per group. However, within this small study, overall AE rates, serum drug trough concentrations, and development of ADA associated with administering motavizumab and palivizumab sequentially to high-risk children appear comparable to administering motavizumab alone during the same RSV season.
Results from clinical trials indicate that palivizumab trough serum concentrations greater than 30 days after the fifth dose will be well above the protective concentration for most infants. If the first dose is administered in November, 5 monthly doses of palivizumab will provide substantially more than 20 weeks of protective serum antibody concentrations for most of the RSV season, even with variation in season onset and end.
The American Academy of Pediatrics (AAP) stated children who qualify for palivizumab prophylaxis for the entire RSV season should receive palivizumab only during the 5 months following the onset of RSV season in their region (maximum of 5 doses), which should provide coverage during the peak of the season, when prophylaxis is most effective. "Because 5 monthly doses of palivizumab at 15 mg/kg per dose will provide more than 6 months (>24 weeks) of serum palivizumab concentrations above the desired level for most children, administration of more than 5 monthly doses is not recommended within the continental United States. For qualifying infants who require 5 doses, a dose beginning in November and continuation for a total of 5 monthly doses will provide protection for most infants through April and is recommended for most areas of the United States. If prophylaxis is initiated in October, the fifth and final dose should be administered in February, which will provide protection for most infants through March. If prophylaxis is initiated in December, the fifth and final dose should be administered in April, which will provide protection for most infants through May. Variation in the onset and offset of the RSV season in different regions of Florida may affect the timing of palivizumab administration. Data from the Florida Department of Health may be used to determine the appropriate timing for administration of the first dose of palivizumab for qualifying infants. Despite varying onset and offset dates of the RSV season in different regions of Florida, a maximum of 5 monthly doses of palivizumab should be adequate for qualifying infants for most RSV seasons in Florida. On the basis of the epidemiology of RSV in Alaska, particularly in remote regions where the burden of RSV disease is significantly greater than the general US population, the selection of Alaska Native infants eligible for prophylaxis may differ from the remainder of the United States. Clinicians may wish to use RSV surveillance data generated by the state of Alaska to assist in determining onset and end of the RSV season for qualifying infants. Limited information is available concerning the burden of RSV disease among American Indian populations. However, special consideration may be prudent for Navajo and White Mountain Apache infants in the first year of life" (AAP, 2014).
The American Academy of Pediatrics (AAP) issued updated guidelines regarding the use of immune prophylaxis for RSV in the AAP Red Book (2014; reaffirmed in 2019). The AAP Red Book was developed by members of the AAP Committee on Infectious Diseases in conjunction with the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and other leading institutions. A summary of the AAP (2014) RSV guidance is as follows:
According to AAP (2014; reaffirmed in 2019), "mean decrease in palivizumab serum concentration of 58% was observed after surgical procedures that involve cardiopulmonary bypass, for children who are receiving prophylaxis and who continue to require prophylaxis after a surgical procedure, a postoperative dose of palivizumab (15 mg/kg) should be considered after cardiac bypass or at the conclusion of extracorporeal membrane oxygenation for infants and children younger than 24 months. Children younger than 2 years who undergo cardiac transplantation during the RSV season may be considered for palivizumab prophylaxis".
Palivizumab prophylaxis is not recommended in the second year of life on the basis of a history of prematurity alone. A second season of palivizumab prophylaxis is recommended only for preterm infants born at <32 weeks, 0 days’ gestation who required at least 28 days of oxygen after birth and who continue to require supplemental oxygen, chronic systemic corticosteroid therapy, or bronchodilator therapy within 6 months of the start of the second RSV season.
Palivizumab reportedly does not interfere with response to vaccines. At this time, the available data do not support the need for supplemental doses of any routinely administered vaccines.
Chronic Lung Disease of Prematurity or Childhood Interstitial Lung Disease (chILD)
Children with more severe chronic lung disease who require medical therapy may benefit from prophylaxis for 2 RSV seasons. Children with less severe underlying disease may benefit only for the first season. The literature also suggests that infants born before 29 weeks of gestation without chronic lung disease of prematurity (CLD) may also benefit from RSV prophylaxis. In these infants, major risk factors to consider are gestational age and chronologic age at the start of the RSV season. Infants born at 28 weeks of gestation or earlier may benefit from prophylaxis up to 12 months of age.
The AAP (2014; reaffirmed in 2019) states that during the second year of life, consideration of palivizumab prophylaxis is recommended only for infants who satisfy the 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. For infants with CLD who do not continue to require medical support in the second year of life prophylaxis is not recommended. CLD of prematurity is defined as gestational age <32 weeks, 0 days and a requirement for >21% oxygen for at least the first 28 days after birth.
Drummond et al (2016) noted that there is a lack of evidence concerning the effectiveness of immunoprophylaxis with palivizumab in children with childhood interstitial lung disease (chILD). In this retrospective study, these researchers evaluated the effectiveness of palivizumab for decreasing the rate of RSV-related hospitalizations in children under the age of 24 months with chILD treated with corticosteroids. A retrospective national study was conducted in France. Patients born between 2007 and 2013, diagnosed with chILD and on corticosteroid treatment were identified through the French online database for pediatric interstitial lung disease (Respirare
®). Data were collected for the etiology and severity of chILD, risk factors and preventive measures for bronchiolitis, palivizumab immunoprophylaxis, and hospitalizations for bronchiolitis and RSV-bronchiolitis. These investigators evaluated 24 children during their first 2 RSV seasons, corresponding to 36 patient-seasons. The observed rate of RSV-related hospitalization (305/1,000 patient-seasons), and the median length of stay (7 days), were higher than those for the general population. However, RSV-related hospitalization rates did not differ significantly between children with and without palivizumab prophylaxis (5/16 versus 4/18, respectively, p = 0.70). The authors concluded that children with chILD on corticosteroid treatment are at high risk of hospitalization for RSV-bronchiolitis, which tends to be more severe in these children than in the general population. Moreover, they stated that the effectiveness of palivizumab prophylaxis in this population remains to be demonstrated.
Congenital Heart Disease
Palivizumab is FDA-approved for prevention of serious lower respiratory tract disease caused by respriatory synctial virus (RSV) in pediatric patients with hemodynamically significant congenital heart disease (CHD) and who are 24 months of age or younger at the beginning of RSV season (Medimmune, 2017).
Chang and Chen (2010) evaluated the impact of palivizumab prophylaxis on RSV hospitalizations among children with hemodynamically significant CHD. In 2003, the AAP revised the bronchiolitis policy statement and recommended palivizumab in children less than 24 months old with hemodynamically significant CHD (HS-CHD). California statewide hospital discharge data from years 2000 to 2002 (pre-AAP policy revision) were compared to those from years 2004 to 2006 (post-AAP policy revision). Hospitalizations due to RSV bronchiolitis for children less than 2 years of age were identified by IDC-9 CM codes 4661.1, 480.1, and 079.6 as the principal diagnosis. Children with CHD and children with HS-CHD were identified by the co-diagnoses. The overall RSV hospitalization rate was 71 per 10,000 children less than 2 years of age. Of all RSV hospitalizations, 3.0 % were among children with CHD, and 0.50 % among children with HS-CHD. HS-CHD patients accounted for 0.56 % of RSV hospitalizations in 2000 to 2002, compared to 0.46 % RSV hospitalizations in 2004 to 2006. That represents a 19 % reduction in RSV hospitalizations among HS-CHD patients after 2003. The 19 % decrease in RSV hospitalizations equates to 7 fewer hospitalizations (76 hospital days) per year among HS-CHD patients. The authors concluded that since the recommendation of palivizumab for children with HS-CHD in 2003, the impact on RSV hospitalizations in California among HS-CHD patients has been limited. Considering the high cost of palivizumab administration, the cost-benefit of RSV prophylaxis with palivizumab warranted further investigation.
A multi-center, prospective, controlled clinical trial demonstrated that palivizumab significantly reduced the rate of hospitalizations, hospital days, and days of increased oxygen usage in children with serious CHD. Children born with serious CHD who have decreased cardiac or pulmonary reserve appear to be at highest risk of serious RSV infection. These children have been shown to require intensive care and use mechanical ventilation more frequently than children who do not have CHD. A 4-year, double-blind, placebo-controlled study was designed to assess the safety and efficacy of palivizumab in children less than 2 years of age with serious CHD. The study was conducted at 76 centers in North America and Europe, and involved 1,287 children who were randomized to receive 5 monthly intramuscular injections (15 mg/kg) of either palivizumab or placebo during the RSV season. Compared to placebo, the palivizumab group had 45 % fewer hospitalizations due to RSV (p = 0.003). The data showed significantly fewer RSV-related hospital days (p = 0.003) and fewer days of increased oxygen usage (p = 0.014) in the treated group than in the placebo group. The proportions of subjects in the placebo and palivizumab groups who experienced any adverse events were similar.
A multi‐center, prospective, controlled, clinical trial demonstrated that palivizumab significantly reduced the rate of hospitalizations, hospital days, and days of increased oxygen usage in children with serious CHD. The data showed significantly fewer RSV‐related hospital days and fewer days of increased oxygen usage, in the treated group than in the placebo group. The proportions of subjects in the placebo and palivizumab groups who experienced any adverse events were similar. Infants and children with hemodynamically insignificant heart disease were not included in this study, as they are not considered to be at increased risk from RSV. Paired palivizumab serum levels were available for 139 children before and after cardiopulmonary bypass surgery. Mean serum concentrations were reduced by 58% (98 mcg/ml [ ±52], to 41.4 mcg/ml [ ±33]) after bypass. Based on this observation, the authors recommended that another dose of palivizumab be administered following cardiopulmonary bypass (Feltes, 2003).
According to the AAP Committee on Infectious Diseases, decisions regarding the use of palivizumab prophylaxis in children with congenital heart disease should be made on the basis of the degree of physiological cardiovascular impairment. Infants most likely to benefit from immunoprophylaxis include those receiving medication to control congestive heart failure, those with moderate to severe pulmonary artery hypertension, and infants with cyanotic heart diseases.
A decrease in the serum concentration of palivizumab by a mean of 58 % has been reported after surgical procedures that use cardiopulmonary bypass. Thus, after surgical procedures that use cardiopulmonary bypass, the AAP recommends a post-operative dose of palivizumab (15 mg/kg) be considered for children 2 years of age or less who continue to require prophylaxis as soon as the patient is medically stable.
The AAP (2014; reaffirmed in 2019) reported that certain children who are 12 months or younger with hemodynamically significant CHD may benefit from palivizumab prophylaxis. The children with CHD who are most likely to benefit from prophylaxis, according to the AAP, include infants with acyanotic heart disease who are on medication to control congestive heart failure and will require cardiac surgical procedures and infants with moderate to severe pulmonary hypertension. In regards to infants with cyanotic heart defects in the first year of life, the AAP states that decisions regarding palivizumab prophylaxis may be made in consultation with a pediatric cardiologist. These AAP recommendations apply to qualifying infants in the first year of life who are born within 12 months of onset of the RSV season.
Decisions regarding prophylaxis with palivizumab in children with CHD should be made on the basis of the degree of physiologic cardiovascular compromise. The AAP Red Book (2014; reaffirmed in 2019) guidelines suggest that the following groups of infants are not at increased risk from RSV and generally should not receive immunoprophylaxis:
Cystic Fibrosis
Routine use of palivizumab prophylaxis in patients with cystic fibrosis, including neonates diagnosed with cystic fibrosis by newborn screening, is not recommended unless other indications are present. An infant with cystic fibrosis and clinical evidence of CLD and/or nutritional compromise in the first year of life may be considered for prophylaxis. Continued use of palivizumab prophylaxis in the second year may be considered for infants with manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest radiography or chest computed tomography that persist when stable) or weight for length less than the 10th percentile.
Giebels and colleagues (2008) stated that in CF patients, RSV infection is associated with significant morbidity. Although passive prophylaxis with palivizumab lowers hospitalization rate for RSV infection in populations at risk of severe infection, its use is not recommended in infants with CF disease. In a retrospective study, these researchers examined the effect of palivizumab prophylaxis on hospitalization for acute respiratory illness in young children with CF during the first RSV season following the diagnosis of CF. Medical records of patients diagnosed with CF between the years 1997 and 2005 inclusively and on whom the diagnosis was made before 18 months of age were reviewed. Collected data included age at diagnosis, palivizumab prophylaxis, occurrence of hospitalization for acute respiratory tract illness during the RSV season and identification of RSV infection. A diagnosis of CF was made in 76 young children and data collected from 75 children. Of those, 40 did not receive RSV prophylaxis while 35 received palivizumab injection monthly during the RSV season. Among non-recipient children, 7 out of 40 were hospitalized for acute respiratory illness during the RSV season. Of these 7 patients, RSV detection was positive in naso-pharyngeal secretions in 3 patients, negative in 1 patient and not requested in the others. Among palivizumab recipients, 3 out of 35 children were hospitalized for acute respiratory illness (p > 0.05 compared to non-recipients group). In these 3 palivizumab recipients, RSV detection was negative in naso-pharyngeal secretions. Palivizumab recipients experienced fewer hospital days per patient for acute respiratory illness (mean +/- SD: 0.8 +/- 3.07 days) as compared to non-recipients (mean +/- SD: 1.73 +/- 4.27 days); but this difference did not reach statistical significance. The authors concluded that CF infants may benefit from RSV immunoprophylaxis with palivizumab.
Speer and associates (2008) noted that the Palivizumab Outcomes Registry collected data on 19,548 high-risk infants who received 1 or more dose(s) of palivizumab and followed prospectively from 2000 through 2004. A total of 91 children with CF were identified who received palivizumab off-label. None of the infants with CF who received prophylaxis was hospitalized as a result of RSV lower respiratory tract infection. The authors concluded that evaluations of palivizumab use in infants with CF could be warranted.
The Cystic Fibrosis Foundation's evidence-based guidelines for management of infants with CF (2009) noted that 2 studies have addressed the use of palivizuma in infants with CF. A chart review of hospitalized infants found that fewer children who received palivizumab were hospitalized and their length of stay was shorter, although these differences did not reach statistical significance. Extrapolation of data from other populations suggested that there could be benefit from the use of RSV prophylaxis in infants with CF. Thus, the Foundation recommended the use of palivizumab be considered for prophylaxis of RSV for infants with CF under 2 years of age (Certainty: low; Benefit: moderate; consensus recommendation). The committee made consensus recommendations for topics not included in the evidence review, for topics where prior guidelines were available, and for topics for which there was limited or no evidence, but the potential benefit was assessed as at least moderate.
A Cochrane review initially published in 2010 and updated in 2014 assessed the use of palivizumab in infants with cystic fibrosis. One randomized controlled trial met the inclusion criteria for both reviews. The study compared 5 monthly doses of palivizumab to placebo in infants up to 2 years of age with cystic fibrosis. The authors of the review concluded that the overall incidence of adverse events was similar in both groups and it was not possible to draw conclusions on the safety and tolerability of RSV prophylaxis and palivizumab in infants with cystic fibrosis because the trial did not specify how adverse events were classified and additional randomized studies are needed.
In a Cochrane review, Robinson et al (2012) examined the safety and effectiveness of palivizumab compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalization and mortality from RSV infection in children with CF. These investigators searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the eligible study and related reviews.Date of last search: October 25, 2011. Randomized and quasi-randomized studies were searched. The authors independently extracted data and assessed risk of bias. One study (186 infants up to 2 years old) comparing 5 monthly doses of palivizumab (n = 92) to placebo (n = 94) over 1 RSV season was identified and met inclusion criteria. At 6 months follow-up, 1 participant in each group was hospitalized due to RSV; there were no deaths in either group. In the palivizumab and placebo groups, 86 and 90 children experienced any adverse event, while 5 and 4 children had related adverse events, respectively. A total of 19 children receiving palivizumab and 16 receiving placebo suffered serious adverse events; 1 participant receiving palivizumab discontinued due to this. At 12 months follow-up, there were no significant differences between groups in number of Pseudomonas bacterial colonisations or change in weight-to-height ratio. The authors identified 1 randomized controlled trial comparing 5 monthly doses of palivizumab to placebo in infants up to 2 years old with CF. While the overall incidence of adverse events was similar in both groups, it is not possible to draw conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF because the trial did not specify how adverse events were classified. Six months after treatment, the authors reported no clinically meaningful differences in outcomes; however no data were provided. The authors stated that additional randomized studies are needed to establish the safety and efficacy of palivizumab in children with CF.
Winterstein and colleagues (2013) evaluated palivizumab effectiveness in children with cystic fibrosis by utilizing Medicaid Extract files provided by the Centers for Medicare and Medicaid Services. A cohort was established consisting of children 0–2 years of age from 27 states with a cystic fibrosis (CF) diagnosis between 1999 and 2006. Eligible children entered the cohort after CF diagnosis and after RSV season onset, and were followed until season end, second birthday, death, or hospitalizations for reasons other than a study outcome. The primary endpoint was hospitalization for RSV‐related infections (RSV‐ha). The secondary endpoint was based on hospitalization for acute respiratory illness (ARI‐ha). Palivizumab exposure was defined based on pharmacy or procedure claims. Both primary and secondary outcomes were examined in a Cox regression model, adjusting for RSV risk factors and CF severity via exposure propensity score. The matched cohort included 1974 infants (2875 infant seasons), who experienced 32 RSV‐ha and 212 ARI‐ha (3.9 and 26.2/1000 season months, respectively). Compared to periods of no use, the adjusted hazard ratio for current use was 0.57 (95% confidence interval [CI]: 0.20–.60) for RSV‐related hospitalization and 0.85 (95% CI: 0.59–.21) for ARI‐related hospitalization. Each month of increasing age reduced the ARI‐ha by 5.8%. The authors concluded that adjusted and unadjusted RSV‐hospitalization incidence rates suggested potentially positive effects of palivizumab, but results were inconclusive due to small event rates. The authors also reported that age greatly affected infection risk with incidence rates for 1‐2 year olds reduced to half when compared to 0‐1 year old infants.
The AAP (2014; reaffirmed in 2019) recommended palivizumab for prevention of RSV in an infant with cystic fibrosis (CF) who has clinical evidence of chronic lung disease (CLD) and/or nutritional compromise in the first year of life. Continued use of palivizumab prophylaxis in the second year may be considered for infants with manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest radiography or chest computed tomography that persist when stable) or weight for length less than the 10th percentile.
Sanchez-Solis et al (2015) noted that infections by RSV are more severe in patients with CF, and many CF units use palivizumab as prophylaxis; however, information about the effectiveness of palivizumab in CF patients is almost lacking. These investigators performed a literature search up to December 2012 on the morbidity of RSV bronchiolitis in CF patients and on the safety and effectiveness of palivizumab in those patients. A random-effects meta-analysis was conducted for those studies meeting pre-specified search criteria. Historical controls were allowed. The number of patients who received palivizumab was 354 and the hospital admission rate was 0.018 (95 % CI: 0.0077 to 0.048). The corresponding number in the non-treated groups was 463 patients with an admission rate of 0.126 (95 % CI: 0.086 to 0.182) (Q = 13.9; p < 0.001). The authors concluded that palivizumab may have a role in the prevention of severe lower airway infection by RSV in CF patients.
However, the updated Cochrane review on "Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis" (Robinson et al, 2013) still maintained that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.
In a Cochrane review, Robinson et al (2014) determined the safety and effectiveness of palivizumab compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalization and mortality from RSV infection in children with CF. The authors concluded that they identified 1 randomized controlled trial (RCT) comparing 5 monthly doses of palivizumab to placebo in infants up to 2 years old with CF. While the overall incidence of adverse events was similar in both groups, it is not possible to draw firm conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF. They reported no clinically meaningful differences in outcomes 6 months after treatment. They stated that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.
In a Cochrane review, Robinson and colleagues (2016) evaluated the safety and effectiveness of palivizumab (Synagis) compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalization and mortality from RSV infection in children with CF. The authors identified 1 RCT comparing 5 monthly doses of palivizumab to placebo in infants up to 2 years old with CF. While the overall incidence of AEs was similar in both groups, it is not possible to draw firm conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF. The authors reported no clinically meaningful differences in outcomes 6 months after treatment. They stated that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.
McGirr and associates (2017) evaluated the cost-effectiveness of palivizumab (PMB) prophylaxis in CF children less than 2 years of age from the Canadian healthcare payer's perspective. In 2014, a Markov cohort model of CF disease and infant RSV infections in the Canadian setting was developed based on literature data. Infants were treated with monthly PMB injections over the 5-month RSV season. Lifetime health outcomes, quality-adjusted life years (QALYs) and 2013 $CAD costs, discounted at 5 %, were estimated. Findings are summarized as incremental cost-effectiveness ratios (ICERs) and budget impact. Deterministic sensitivity analysis was conducted to assess parameter uncertainty. Implementation of a hypothetical Canadian RSV prophylaxis program resulted in ICERs of C$652,560 (all CF infants) and C$157,332 (high-risk CF infants) per QALY gained and an annual budget impact of C$1,400,000 (all CF infants) and C$285,000 (high-risk CF infants). The analysis was highly sensitive to the probability of severe RSV, the degree of lung deterioration following infection, and the cost of PMB. The authors concluded that these findings suggested that PMB is not cost-effective in Canada by commonly used thresholds. However, given the rarity of CF and relatively small budget impact, consideration may be given for the selective use of PMB for immunoprophylaxis of RSV in high-risk CF infants on a case-by-case scenario basis.
Buchs and colleagues (2017) noted that RSV infections may worsen CF lung disease and favor Pseudomonas aeruginosa (Pa) or Staphylococcus aureus (Sa) acquisition, which is of particular importance in the youngest patients. These researchers determined the effectiveness of palivizumab (PVZ) on microbiological outcomes in young children with CF. They conducted a retrospective case-control study to compare these outcomes in children who systematically received PVZ (PVZ+; n = 40) or not (PVZ-; n = 140); 1 case was matched with at least 3 same-gender controls born the same year and month. Median (range) age at first Pa isolation was not statistically different between PVZ- (12.3 [3.8 to 32.6] months) and PVZ+ (10.4 [1.2 to 33.0] months; p = 0.953) patients. A similar trend was found for Sa (PVZ+: 6.4 [2.0 to 59.0] months; PVZ-: 3.8 [0.1 to 74.1] months; p = 0.191). The proportion of Pa isolations by 3 years of age did not differ between groups (PVZ+ 40 % versus PVZ- 41.4 %), but this proportion was higher for Sa in the PVZ+ group (97 %) than in the PVZ- group (85 %; p = 0.001). Healthcare consumption and growth outcomes did not significantly differ between groups. The authors concluded that systematic PVZ use did not delay key pathogen acquisition in young children with CF. Whether or not palivizumab is useful in infants with CF remains controversial. Palivizumab did not delay key pathogens (Pseudomonas aeruginosa, Staphylococcus aureus) first isolation in young children with CF; it did not reduce healthcare consumption or improve growth during the first 3 years of life of young children with CF.
Kua and associates (2017) stated that RSV is a common pathogen in infants with CF. The use of PVZ prophylaxis for RSV infection as the standard of care for infants with CF remains controversial. These investigators evaluated the efficacy of PVZ in reducing the incidence of RSV hospitalization in children with CF who are younger than 2 years. Four electronic databases (PubMed, Embase, CINAHL, and CENTRAL) were searched from inception until January 31, 2017, for clinical studies investigating the use of PVZ in infants with CF aged less than 2 years. The primary outcome was hospitalization rate due to RSV infection. Secondary outcomes included hospitalization for respiratory illness, length of hospital stay, safety (adverse effects), and cost-effectiveness of PVZ prophylaxis. The review included a total of 10 studies (6 cohort studies, 2 before-and-after studies, 1 cross-sectional study, and 1 RCT) involving 3,891 patients with CF; 7 studies reported that PVZ prophylaxis had a positive impact on the rate of RSV hospitalization; 5 studies (n = 3,404) reported that PVZ prophylaxis significantly reduced the rate of hospitalization due to RSV infection compared to no prophylaxis. One study (n = 5) demonstrated patients with CF who received PVZ had no RSV hospitalization. Another study showed infants with CF receiving PVZ (n = 117) had a lower risk of hospitalization for RSV infection compared with premature infants (gestational age less than 35 completed weeks) who received PVZ (n = 4,880). The authors concluded that evidence from the literature suggested that PVZ may have a potential role in reducing RSV hospitalization in children aged less than 2 years with CF. moreover, they stated that given the lack of overall data, additional research is needed to better understand the safety and efficacy of prophylactic PVZ in infants with CF.
Fink and colleagues (2019) noted that the AAP does not recommend routine use of palivizumab prophylaxis for infants with CF but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain. These researchers used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary-related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. They created propensity scores to adjust for potential confounding by indication (i.e., sicker infants were more likely to receive palivizumab). For each outcome, these investigators performed regression analyses adjusted by propensity scores. The sample included 4,267 infants; 1,588 (37 %) received palivizumab. Mean percent forced expiratory volume in 1 second (FEV1) predicted at 7 years old was similar among those who did (98.2; 95 % CI: 96.9 to 99.5) and did not (97.3; 95 % CI: 96.1 to 98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab. The authors concluded that at the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.
Down Syndrome
The available limited data indicates a slight increase in RSV hospitalization rates for children with Down syndrome. However, the AAP (2014) reports: "data are insufficient to justify a recommendation for routine use of prophylaxis in children with Down syndrome unless a qualifying heart disease, CLD, airway clearance issues, or prematurity (<29 weeks, 0 days' gestation) is present."
Hematopoietic Stem Cell Transplants (HSCTs)
Boeckh et al (2001) stated that intravenous palivizumab (15 mg/kg) was investigated in 2 phase I studies among recipients of hematopoietic stem cell transplants (HSCTs). Study 1 included 6 HSCT patients without active RSV infection. Study 2 included 15 HSCT patients with RSV upper respiratory tract infection (URTI; n = 3) or RSV interstitial pneumonia (IP; n = 12), all of whom also received aerosolized ribavirin. Peak serum concentrations of palivizumab in the 2 studies were similar. The mean serum half-life was 22.4 days in study 1, which mainly included autologous HSCT recipients, and 10.7 days in study 2, which mainly included allogeneic HSCT recipients. No antibodies to palivizumab were detected in study 1. No adverse events were attributed to palivizumab in the 2 studies. In study 2, all 3 patients with RSV URTI recovered without progression to lower respiratory tract disease, and 10 (83 %) of the 12 patients with RSV IP survived the 28-day study period. Thus, palivizumab appears to be safe and well-tolerated in HSCT recipients. Well-designed studies are needed to validate the findings of these phase I studies.
Shah and Chemaly (2011) noted that RSV is a common cause of seasonal respiratory viral infection in patients who have undergone HSCT. Respiratory syncytial virus usually presents as an URTI in this patient population but may progress rapidly to lower respiratory tract infection. Available therapies that have been used for the treatment of RSV infections are limited to ribavirin, intravenous immunoglobulin (IVIG), and palivizumab. The use of aerosolized ribavirin, alone or in combination with either palivizumab or IVIG, remains controversial.
Seo et al (2013) evaluated the effect of transplant and treatment factors on overall survival, mortality from respiratory failure, and pulmonary function among 82 HSCT recipients who had RSV lower respiratory tract disease (LRD) between 1990 and 2011. All patients received aerosolized ribavirin. In multi-variable analyses, only the use of marrow or cord blood as graft source (adjusted hazard ratio [aHR], 4.1; 95 % confidence interval [CI]: 1.8 to 9.0; p < 0.001) and oxygen requirement (aHR, 3.3; 95 % CI: 1.5 to 6.7; p = 0.003) remained independently associated with overall mortality and death due to respiratory failure (aHR, 4.7; 95 % CI: 1.8 to 13; p = 0.002 and aHR, 5.4; 95 % CI: 1.8 to 16; p = 0.002, respectively). Antibody-based treatments, including IVIG and palivizumab, were not independently associated with improved outcome and did not alter the associations of the graft source and oxygen requirements in statistical models. The authors concluded that use of peripheral blood stem cells as graft source and lack of oxygen requirement at diagnosis appear to be important factors associated with improved survival of HSCT recipients with RSV LRD. These results may explain differences in outcomes reported from RSV infection over time and may guide the design of future interventional trials.
Immunocompromised Adults
: Requires Precertification:
Precertification of palivizumab (Synagis) is required of all Aetna participating providers and members in applicable plan designs. For precertification of palivizumab call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see
Specialty Pharmacy Precertification.
Exclusion
Criteria for Initial Approval
Aetna considers palivizumab (Synagis) medically necessary for up to 5 doses per respiratory syncytial virus (RSV) season for the prevention of serious lower respiratory tract disease caused by RSV when a member has
anyof the following diagnoses and when associated criteria are met:
Prematurity
When
allof the following criteria are met:
Chronic Lung Disease (CLD) of Prematurity
When
allof the following criteria are met:
Congenital Heart Disease (CHD)
When
allof the following criteria are met:
Congenital Airway Abnormality
When
allof the following criteria are met:
The condition compromises handling of respiratory secretions; and Member’s chronological age at the start of RSV season is less than 12 months;Neuromuscular Condition
When
allof the following criteria are met:
Immunocompromised Children
When
allof the following criteria are met:
Cystic Fibrosis
When
eitherof the following criteria is met:
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Other
For all off-season Synagis requests, authorization of 1 dose per request, up to a maximum of 5 doses per RSV season, may be granted if the RSV activity for the requested region is greater than or equal to 10% (with rapid antigen testing) or greater than or equal to 3% (with real-time polymerase chain reaction (PCR) test) within 2 weeks of the intended dose according to the CDC National Respiratory and Enteric Virus Surveillance System (NREVSS). The local health department or the CDC NREVSS will be consulted to assess the RSV activity for that region or state, see
CDC Respiratory Syncytial Virus (RSV) Surveillance.
Aetna considers Synagis season to be from November 1
stto March 31
st. Other health plans may differ.
Dosage and Administration
The dosage and administration information are based on the FDA-approved Prescribing Information. See
Appendix Afor recommendations from the American Academy of Pediatrics (AAP).
Palivizumab is available as Synagis for injection as 50 mg per 0.5 mL and 100 mg per 1 mL single-dose liquid solution vials for intramuscular use.
The recommended dose of Synagis is 15 mg per kg of body weight given monthly by intramuscular injection. The first dose of Synagis should be administered prior to commencement of the RSV season and the remaining doses should be administered monthly throughout the RSV season. Children who develop an RSV infection should continue to receive monthly doses throughout 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. Children undergoing cardio-pulmonary bypass should receive an additional 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 as scheduled.
The efficacy of Synagis at doses less than 15 mg per kg, or of dosing less frequently than monthly throughout the RSV season, has not been established.
Source: Sobi, 2021
Experimental and Investigational
Aetna considers palivizumab experimental and investigational for all other indications (not an all-inclusive list):