1. Aetna considers palivizumab (Synagis™) medically necessary for use in protection against lower respiratory tract infection with respiratory syncytial virus (RSV), in infants and children who are less than 2 years of age at the start of RSV season with chronic lung disease of prematurity (CLD [formerly known as bronchopulmonary dysplasia or BPD]) who have required medical therapy (supplemental oxygen, bronchodilator, and diuretic or corticosteroid therapy) for their CLD within 6 months before the anticipated RSV season†. 

2. Aetna considers palivizumab medically necessary for use in protection against lower respiratory tract infection with RSV in infants and children with any of the following conditions:

   1. Infants born at 32 weeks' gestation or earlier (with or without CLD)*:

      1. Infants born at 28 weeks of gestation or earlier** and who are younger than 12 months of age at the start of RSV season; or 

      2. Infants born at 29 to 32 weeks of gestation and who are younger than 6 months of age at the start of RSV season; or

   2. Infants born between 32 to 35 weeks of gestation and who are younger than 3 months of age at the start of RSV season*** when at least one of the following two risk factors is present:

      • Child care attendance outside the home (defined as a home or facility where care is provided for any number of infants or young toddlers in the child care facility); or 

      • Sibling younger than 5 years of age at the start of RSV season.

   3. Infants born before 35 weeks of gestation who have either congenital abnormalities of the airway or a neuromuscular condition that compromises handling of respiratory secretions during the first year of life.† 
   4. Infants and children with severe immunodeficiencies who are less than 2 years of age at the start of the RSV season (e.g., severe combined immunodeficiency or severe acquired immunodeficiency syndrome); or

   5. Infants and children with hemodynamically significant cyanotic or acyanotic congenital heart disease who are 2 years of age or younger at the onset of the RSV season†, including the following: 

      1. Infants receiving medication to control congestive heart failure; or
      2. Infants with moderate to severe pulmonary artery hypertension; or

      3. Infants with cyanotic congenital heart disease.

3. Aetna considers an additional dose of palivizumab medically necessary after surgical procedures that require cardiopulmonary bypass for children 2 years of age or younger who still require prophylaxis. 

4. Aetna considers palivizumab experimental and investigational for all other indications (e.g., cystic fibrosis prophylaxis, active RSV infection treatment; not an all inclusive list).

5. Aetna considers home administration of palivizumab a medically necessary alternative to office- or clinic-based administration.

6. Palivizumab has no proven value for infants with the following congenital heart disease conditions:

   1. Hemodynamically insignificant heart disease (e.g., secundum atrial septal defect; small ventricular septal defect (VSD); pulmonic stenosis; uncomplicated aortic stenosis; mild coarctation of the aorta; and patent ductus arteriosus); or
   2. Infants with lesions adequately corrected by surgery unless they continue to require medication for congestive heart failure; or

   3. Infants with cardiomyopathy who are not receiving medical therapy for the condition.
      

   According to the AAP (2009), these infants generally should not receive immunoprophylaxis because they are not at increased risk of RSV.

7. Administration of palivizumab more frequently than monthly (every 30 days) is considered not medically necessary.

Notes:

*For infants born at 32 weeks of gestation or earlier (with or without CLD) and who are less than 12 months of age at the start of RSV season, administration should continue throughout the season and not stop at the point an infant reaches either 6 months (infants born at 29 to 32 weeks of gestation) or 12 months of age (infants born at 28 weeks of gestation or earlier).  A maximum of 5 monthly doses is recommended for infants in this category.

** For purposes of this policy, 28 weeks' gestation refers to an infant born on or before the 28th week of gestation (i.e., 28 weeks, 0 days).

***Infants born between 32 to 35 weeks of gestation and who are younger than 3 months of age at the start of RSV season and who qualify for initiation, should receive a maximum of 3 monthly doses and administration should stop at the point the infant reaches 3 months of age.

**** AAP (2009) stated "passive household exposure to tobacco smoke has not been associated with an increased risk of RSV hospitalization on a consistent basis.  Furthermore, exposure to tobacco smoke is a risk factor that can be controlled by the family of an infant at increased risk of RSV disease, and preventive measures will be far less costly than palivizumab prophylaxis.”

***** In most areas of the United States, the usual time for the beginning of RSV outbreaks is November or December, with RSV activity peaking in January or February, and RSV outbreaks ending by the end of March or sometime in April, but regional differences occur (AAP, 2009). The onset of RSV season occurs earlier in southern states than in northern states (see appendix). To determine if there is an RSV outbreak in a geographic area, please refer to CDC surveillance summaries for RSV published in the Morbidity and Mortality Weekly Report at http://www.cdc.gov/mmwr/.

†A maximum of 5 monthly doses is recommended for infants in this category (AAP, 2009).

According to AAP (2009), hospitalized infants who qualify for prophylaxis during the RSV season should receive the first dose of palivizumab 48 to 72 hours before discharge or promptly after discharge.  Thus, any palivizumab doses received prior to discharge from a hospital stay (e.g., NICU, nursery) count as one of the seasonal doses.

Palivizumab (Synagis), a humanized monoclonal antibody, is administered by intramuscular injection in monthly doses of 15 mg/kg body weight. Palivizumab is administered once a month (i.e., every 30 days) during the RSV season.

Results from clinical trials indicate that palivizumab trough serum concentrations >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 AAP (2009) stated "[c]hildren who qualify for palivizumab prophylaxis for the entire RSV season (infants and children with chronic lung disease of prematurity or congenital heart disease or preterm infants born before 32 weeks’ gestation) 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." The onset of the RSV season typically occurs in November.

The Center for Disease Control and Prevention (CDC) National Respiratory and Enteric Virus Surveillance System (NREVSS) is a laboratory-based system that monitors temporal and geographic patterns associated with the detection of respiratory syncytial virus (RSV) and other viruses. Annual summaries and alerts based on NREVSS data have been published periodically in CDC's Morbidity and Mortality Weekly Report at http://www.cdc.gov/mmwr/. CDC surveillance summaries of weekly RSV laboratory test result data for each region of the United States are posted at: http://www.cdc.gov/surveillance/nrevss/rsv/state.html.

In a review, Meissner, et al. (2004) explained that strategies that focus administration of palivizumab during months when RSV infection is most likely to occur should protect the patient from RSV disease and avoid unnecessary waste.

Meissner, et al. (2004) explained that most hospitalizations for bronchiolitis occur during the RSV season: "Data on likely RSV-associated hospitalizations suggest that RSV disease matches the conclusions from RSV-detection data; 81% of hospitalizations due to bronchiolitis in infants and young children occur from November through April. Bronchiolitis outbreaks are correlated closely with RSV detection, and many prospective studies have found that most hospitalizations for bronchiolitis are caused by RSV."

Meissner, et al. (2004) cited evidence supporting the AAP position that 5 monthly doses of palivizumab will provide effective protection during the RSV season, even with variations in the onset and end of the season: "The recommendation for 5 monthly doses of palivizumab was derived from the design of clinical trials with both RespiGam and palivizumab. In the IMpact-RSV trial and in the trial involving children with hemodynamically significant congenital heart disease, 5 monthly doses of palivizumab resulted in serum concentrations 30 µg/mL for over 20 weeks in almost all subjects. A serum palivizumab concentration 30 µg/mL is the proposed serologic correlate of protection, derived from animal models, in which this concentration results in a decrease in pulmonary RSV replication by more than 100-fold. One month after the fourth monthly dose of palivizumab, the mean serum trough concentration was 72 µg/mL among subjects in the IMpact-RSV trial and 90 µg/mL in subjects in the cardiac trial, indicating that the trough serum level more than 30 days after the fifth dose will be greater than 30 µ g/mL for most children. Thus for most infants, 5 monthly doses of palivizumab will provide substantially over 20 weeks of serum antibody levels, which should be protective and cover most of the RSV season even with variation in season onset and end."

Meissner, et al. (2004) stated that "it is important to remember that results from antigen detection assays do not provide an adequate basis for determination of onset and offset of the RSV season."  Meissner, et al. explained that RSV antigen detection assays may overestimate the risk of RSV outside of the RSV season, as the positive predictive value of a test decreases as disease incidence goes down.  Because the sensitivity and specificity of antigen-detection assays are low both at the onset and the end of the season, the risk to the child in these periods will be less than that predicted by RSV detection using antigen-based assays.

Although there have been reports of year-round prevalence of RSV in certain localities (e.g., Chattanooga, TN, South Florida), these reports are based on antigen detection assays, which are only reliable during periods of extremely high population prevalence (Meissner, 2005).  During periods of relatively low RSV prevalence, antigen detection assays are associated with false positive rates greater than 50 percent, and no good correlation with actual disease prevalence in the community or with clinical risk to patients. 

Children with more severe chronic lung disease may benefit from prophylaxis for two RSV seasons, especially those who require medical therapy.  Children with less severe underlying disease may benefit only for the first season.  Decisions regarding individual patients may need additional input from neonatologists, intensivists, or pulmonologists.

The literature also suggests that infants born at 32 weeks of gestation or earlier without 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. Infants born at 29 to 32 weeks gestation may benefit most from prophylaxis up to 6 months of age.

Palivizumab is not approved by the FDA for patients with congenital heart disease (CHD).  However, a recent 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 congenital heart disease (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 four-year, double blind, placebo controlled study was designed to assess the safety and efficacy of palivizumab in children less than two years of age with serious congenital heart disease (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 (15mg/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.  According to the American Academy of Pediatrics 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 still require prophylaxis as soon as the patient is medically stable.  The AAP (2009) concluded that the following groups of infants are not at increased risk of RSV and generally should not receive immunoprophylaxis: infants with hemodynamically insignificant heart disease (e.g., secundum atrial septal defect), small ventricular septal defect (VSD), pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus.  In addition, prophylaxis is not necessary in infants with lesions adequately corrected by surgery unless they continue to require medication for congestive heart failure, and infants with cardiomyopathy who are not receiving medical therapy for their condition.

Palivizumab prophylaxis has not been evaluated in randomized trials in immunocompromised children.  Although specific recommendations for immunocompromised patients cannot be made, the literature indicates that children with severe immunodeficiencies (e.g., severe combined immunodeficiency or severe acquired immunodeficiency syndrome) may benefit from prophylaxis.

RSV is known to be transmitted in the hospital setting and to cause serious disease in high-risk infants.  In high-risk hospitalized infants, the major means to prevent RSV disease is strict observance of infection control practices, including the use of rapid means to identify and cohort RSV-infected infants.  If an RSV outbreak is documented in a high-risk unit (e.g., pediatric intensive care unit), accepted guidelines indicate that primary emphasis should be placed on proper infection control practices.  The need for and efficacy of prophylaxis in these situations has not been evaluated.

The AAP guidelines (2003) stated that one of the risk factors for complications from RSV infection is exposure to environmental air pollutants.  This was meant to refer only to indoor air pollutants (i.e., wood stoves, indoor combustion of unprocessed solid fuels). The AAP Red Book (2009) stated "passive household exposure to tobacco smoke has not been associated with an increased risk of RSV hospitalization on a consistent basis. Furthermore, exposure to tobacco smoke is a risk factor that can be controlled by the family of an infant at increased risk of severe RSV disease, and preventive measures will be far less costly than palivizumab prophylaxis. High-risk infants never should be exposed to tobacco smoke." 

The AAP guidelines (2009) noted that limited studies suggest that some patients with cystic fibrosis (CF) may be at increased risk of RSV infection.  However, there are insufficient data to determine the effectiveness of palivizumab use in this patient population.  Therefore, a recommendation for routine prophylaxis in patients with CF cannot be made.  Furthermore, the European Cystic Fibrosis Society Vaccination Group (Malfroot, et al., 2005) stated that there are no recommendations for palivizumab in CF as an alternative but expensive prophylaxis.

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.

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.

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 & Del Mar, 2006).

In a phase I/II, multi-center, randomized, double-blind, placebo-controlled, escalating dose clinical trial, Sáez-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.

Note on RespiGam Respiratory Syncytial Virus Immune Globulin (RSV-IVIG):  On October 1, 2003, MedImmune and Massachusetts Public Health & Biologics Laboratory (MPHBL), the manufacturers of RespiGam, announced that production of RespiGam will be discontinued. As of March 15, 2004 all current inventory levels of RespiGam had been depleted and no product is available for sale from MedImmune or MPHBL. 

Appendix

Maximum Number of Monthly Doses of Palivizumab for Respiratory Syncytial Virus Prophylaxis

Maximum Number of Palivizumab Doses for RSV Prophylaxis of Preterm Infants Without Chronic Lung Disease, on the Basis of Birth Date, Gestational Age, and Presence of Risk Factors (Shown for Geographic Areas Beginning Prophylaxis on November 1)^a

aIf infant is discharged from the hospital during RSV season, fewer doses may be required.
bFor risk factors, see policy section.
cSome of these infants may have received 1 or more doses of palivizimab in the previous RSV season if discharged from the hospital during that season; if so, they still qualify for up to 5 doses during their second RSV season.
dZero doses because infant will be older than 6 months of age at start of RSV season.
eZero doses because infant will be older than 90 days of age at start of RSV season.
fOn the basis of the age of patients at the time of discharge from the hospital, fewer doses may be required, because these infants will receive 1 dose every 30 days until the infant is 90 days of age. 

Adapted from the American Academy of Pediatrics (AAP) 2009 Red Book.