Coverage Policy Manual
Policy #: 1998155
Category: Pharmacy
Initiated: August 2017
Last Review: September 2018
  Respiratory Syncytial Virus, Immune Prophylaxis with Palivizumab (Synagis)

Description:
Respiratory syncytial virus (RSV) infections typically occur in the winter months, starting from late October to mid-January and ending anywhere from March to May (MMWR, 2014). Considerable variation in the timing of community outbreaks is observed from year to year. According to U.S. Centers for Disease Control and Prevention, onset of the RSV season occurs when the median percentage of specimens testing positive for RSV is 10% higher over a 2-week period. Annually in the United States, RSV infection has been associated with an estimated 57,527 hospitalizations and 2.1 million outpatient visits among children aged less than 5 years (Hall, 2009). While RSV is a near-ubiquitous infection, infants with underlying medical issues, especially a history of prematurity with associated lung problems, are at risk of developing serious complications from bronchiolitis secondary to RSV.
 
Chronic lung disease (CLD) of prematurity (formerly known as bronchopulmonary dysplasia) is a general term for long-term respiratory problems in premature infants. CLD results from lung injury to newborns who consequently must use a mechanical ventilator and supplemental oxygen for breathing. With injury, lung tissues become inflamed, and scarring can result. Causes of lung injury include the following: prematurity, low amounts of surfactant, oxygen use, and mechanical ventilation. Risk factors for developing CLD include birth at less than 34 weeks of gestation; birth weight less than 2000 grams (4 pounds, 6.5 ounces); hyaline membrane disease; pulmonary interstitial emphysema; patent ductus arteriosus; Caucasian race; male sex; maternal womb infection (chorioamnionitis); and family history of
asthma.
 
Palivizumab (Synagis) is a humanized monoclonal antibody made using recombinant DNA technology, which is directed against a site on the antigenic site of the F protein of RSV (FDA, 1999). It was originally approved by the U.S. Food and Drug Administration (FDA) for RSV prevention in 1998.
 
Other RSV preventive agents, including vaccines, have been under development (Fallon, 2016). A recombinant RSV fusion protein nanoparticle vaccine has been shown to induce an immune response in a phase 2 trial (Glenn, 2016). This evidence review does not address therapies to treat RSV infection.
 
Regulatory Status
In June 1998, the biologic drug palivizumab (Synagis®; MedImmune, Gaithersburg, MA) was approved for marketing by FDA through a biologics license application (BLA) for use in the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease. In 2004, FDA approved a liquid formulation of Synagis®, supplied as a sterile solution ready for injection, thus providing improved convenience for administration. This formulation is used in the physician office or home setting. There are no therapeutic equivalents to this drug. FDA application number: (BLA) 103770.

Policy/
Coverage:
Effective September 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Monthly administration of immune prophylaxis for respiratory syncytial virus (RSV) during the RSV season with palivizumab meet member benefit certificate primary coverage criteria in the following infants and children in accordance with current (2014) guidelines from the American Academy of Pediatrics (“Updated guidance”, 2014):
 
1. In the first year of life, ie, younger than 12 months at the start of the RSV season or born during the RSV season in:
 
a. Infants born before 29 weeks, 0 days’ gestation;
 
b. Preterm infants with chronic lung disease (CLD) of prematurity, defined as birth at less than 32 weeks, 0 days’ gestation and a requirement for more than 21% oxygen for at least the first 28 days after birth;
 
c. Certain infants with hemodynamically significant heart disease (eg, infants with acyanotic heart disease who are receiving medication to control congestive heart failure and will require cardiac surgical procedures; infants with moderate to severe pulmonary hypertension; infants with lesions adequately corrected by surgery who continue to require medication for heart failure);
 
i. Decisions regarding palivizumab prophylaxis for infants with cyanotic heart defects in the first year of life may be made in consultation with a pediatric cardiologist.
 
d. Children with pulmonary abnormality or neuromuscular disease that impairs the ability to clear secretions from the upper airways (eg, ineffective cough, recurrent gastroesophageal tract reflux, pulmonary malformations, tracheoesophageal fistula, upper airway conditions, or conditions requiring tracheostomy);
 
e. Children with cystic fibrosis who have at least one of the following conditions:
 
i. Clinical evidence of CLD; and/or
 
ii. Nutritional compromise.
 
 2. In the second year of life, ie, younger than 24 months at the start of the RSV season in:
 
a. Children who were born at less than 32 weeks, 0 days’ gestation and required at least 28 days of supplemental oxygen after birth and who continue to require medical intervention (supplemental oxygen, chronic corticosteroid, or diuretic therapy) during the 6-month period before the start of the second RSV season.
 
b. Children with cystic fibrosis who have either:
 
i. 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
 
ii. Weight for length less than the 10th percentile.
 
3. In the first or second year of life in:
 
a. Children who will be profoundly immunocompromised (eg, will undergo solid organ or hematopoietic stem cell transplantation or receive chemotherapy) during the RSV season.
 
 4. After surgical procedures that use cardiopulmonary bypass, for children who still require prophylaxis, a postoperative dose of palivizumab meets member benefit certificate primary coverage criteria as soon as the patient is medically stable after cardiac bypass or at the conclusion of extracorporeal membrane oxygenation for infants and children younger than 24 months.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Immunoprophylaxis for respiratory syncytial virus does not meet member benefit certificate primary coverage criteria or is considered not medically necessary for members with contracts without primary coverage criteria in:
 
1. Infants and children with hemodynamically insignificant heart disease (eg, secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus);
 
2. Infants with lesions adequately corrected by surgery, unless they continue to require medication for heart failure;
 
3. Infants with mild cardiomyopathy who are not receiving medical therapy for the condition; or
 
4. Children with congenital heart disease in the second year of life.
 
5. Infants and children receiving monthly palivizumab prophylaxis who experience a breakthrough RSV hospitalization. (Monthly prophylaxis should be discontinued at the time of breakthrough because of the extremely low likelihood of a second RSV hospitalization in the same season).    
 
Other indications for immune prophylaxis for respiratory syncytial virus does not meet member benefit certificate primary coverage criteria including, but not limited to, controlling outbreaks of health care-associated disease; or use in immunocompromised children or children with cystic fibrosis or Down syndrome without other risk factors; or in children over 2 years of age, unless criteria for medical necessity (outlined above) are satisfied.  .
 
For members with contracts without primary coverage criteria, other indications for immune prophylaxis for respiratory syncytial virus are considered investigational including, but not limited to, controlling outbreaks of health care-associated disease; or use in immunocompromised children or children with cystic fibrosis or Down syndrome without other risk factors; or in children over 2 years of age, unless criteria for medical necessity (outlined above) are satisfied.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Additional Policy Guidelines
Clinicians may administer up to a maximum of 5 monthly doses of palivizumab (15 mg/kg per dose) during the RSV season to infants who qualify for prophylaxis. Qualifying infants born during the RSV season will require fewer doses. For example, infants born in January would receive their last dose in March.
 
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.
 
Initiation of immunoprophylaxis in November and continuation for a total of 5 monthly doses will provide protection into 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.
 
In the temperate climates of North America, peak RSV activity typically occurs between November and March, whereas in equatorial countries, RSV seasonality patterns vary and may occur throughout the year. The inevitability of the RSV season is predictable, but the severity of the season, the time of onset, the peak of activity, and the end of the season cannot be predicted precisely. Substantial variation in timing of community outbreaks of RSV disease from year to year exists in the same community and between communities in the same year, even in the same region. Communities in the southern United States, particularly some communities in the state of Florida, tend to experience the earliest onset of RSV activity.
 
In the continental United States, a total of 5 monthly doses for infants and young children with congenital heart disease, chronic lung disease (CLD) of prematurity, or preterm birth before 32 weeks’ gestation (31 weeks, 6 days) will provide an optimal balance of benefit and cost, even with variation in season onset and end.
 
Children who receive palivizumab prophylaxis for the entire RSV season should receive palivizumab only during the 5 months after 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.
 
Effective September 2014 to September 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Monthly administration of immune prophylaxis for respiratory syncytial virus (RSV) during the RSV season with palivizumab meet member benefit certificate primary coverage criteria in the following infants and children in accordance with current (2014) guidelines from the American Academy of Pediatrics (“Updated guidance”, 2014):
 
1. In the first year of life, ie, younger than 12 months at the start of the RSV season or born during the RSV season in:
 
a. Infants born before 29 weeks, 0 days’ gestation;
 
b. Preterm infants with chronic lung disease (CLD) of prematurity, defined as birth at less than 32 weeks, 0 days’ gestation and a requirement for more than 21% oxygen for at least the first 28 days after birth;
 
c. Certain infants with hemodynamically significant heart disease (eg, infants with acyanotic heart disease who are receiving medication to control congestive heart failure and will require cardiac surgical procedures; infants with moderate to severe pulmonary hypertension; infants with lesions adequately corrected by surgery who continue to require medication for heart failure);
 
i. Decisions regarding palivizumab prophylaxis for infants with cyanotic heart defects in the first year of life may be made in consultation with a pediatric cardiologist.
 
d. Children with pulmonary abnormality or neuromuscular disease that impairs the ability to clear secretions from the upper airways (eg, ineffective cough, recurrent gastroesophageal tract reflux, pulmonary malformations, tracheoesophageal fistula, upper airway conditions, or conditions requiring tracheostomy);
 
e. Children with cystic fibrosis who have at least one of the following conditions:
i. Clinical evidence of CLD; and/or
 
ii. Nutritional compromise.
 
 2. In the second year of life, ie, younger than 24 months at the start of the RSV season in:
 
a. Children who were born at less than 32 weeks, 0 days’ gestation and required at least 28 days of supplemental oxygen after birth and who continue to require medical intervention (supplemental oxygen, chronic corticosteroid, or diuretic therapy) during the 6-month period before the start of the second RSV season.
 
b. Children with cystic fibrosis who have either:
 
i. 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
 
ii. Weight for length less than the 10th percentile.
 
3. In the first or second year of life in:
 
a. Children who will be profoundly immunocompromised (eg, will undergo solid organ or hematopoietic stem cell transplantation or receive chemotherapy) during the RSV season.
 
 4. After surgical procedures that use cardiopulmonary bypass, for children who still require prophylaxis, a postoperative dose of palivizumab meets member benefit certificate primary coverage criteria as soon as the patient is medically stable after cardiac bypass or at the conclusion of extracorporeal membrane oxygenation for infants and children younger than 24 months.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Immunoprophylaxis for respiratory syncytial virus does not meet member benefit certificate primary coverage criteria or is considered not medically necessary for members with contracts without primary coverage criteria in:
 
1. Infants and children with hemodynamically insignificant heart disease (eg, secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus);
 
2. Infants with lesions adequately corrected by surgery, unless they continue to require medication for heart failure;
 
3. Infants with mild cardiomyopathy who are not receiving medical therapy for the condition; or
 
4. Children with congenital heart disease in the second year of life.
 
5. Infants and children receiving monthly palivizumab prophylaxis who experience a breakthrough RSV hospitalization. (Monthly prophylaxis should be discontinued at the time of breakthrough because of the extremely low likelihood of a second RSV hospitalization in the same season).    
 
Other indications for immune prophylaxis for respiratory syncytial virus does not meet member benefit certificate primary coverage criteria including, but not limited to, controlling outbreaks of health care-associated disease; or use in immunocompromised children or children with cystic fibrosis or Down syndrome, unless criteria for coverage as outlined above are satisfied .
 
For members with contracts without primary coverage criteria, other indications for immune prophylaxis for respiratory syncytial virus are considered investigational including, but not limited to, controlling outbreaks of health care-associated disease; or use in immunocompromised children or children with cystic fibrosis or Down syndrome, unless criteria for coverage as outlined above  are satisfied. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Additional Policy Guidelines
Clinicians may administer up to a maximum of 5 monthly doses of palivizumab (15 mg/kg per dose) during the RSV season to infants who qualify for prophylaxis. Qualifying infants born during the RSV season will require fewer doses. For example, infants born in January would receive their last dose in March.
 
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.
 
Initiation of immunoprophylaxis in November and continuation for a total of 5 monthly doses will provide protection into 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.
 
In the temperate climates of North America, peak RSV activity typically occurs between November and March, whereas in equatorial countries, RSV seasonality patterns vary and may occur throughout the year. The inevitability of the RSV season is predictable, but the severity of the season, the time of onset, the peak of activity, and the end of the season cannot be predicted precisely. Substantial variation in timing of community outbreaks of RSV disease from year to year exists in the same community and between communities in the same year, even in the same region. Communities in the southern United States, particularly some communities in the state of Florida, tend to experience the earliest onset of RSV activity.
 
In the continental United States, a total of 5 monthly doses for infants and young children with congenital heart disease, chronic lung disease (CLD) of prematurity, or preterm birth before 32 weeks’ gestation (31 weeks, 6 days) will provide an optimal balance of benefit and cost, even with variation in season onset and end.
 
Children who receive palivizumab prophylaxis for the entire RSV season should receive palivizumab only during the 5 months after 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.
 
Effective February 2012 through September 2014
 
Monthly administration of immune prophylaxis for respiratory syncytial virus with palivizumab (Synagis) (total of 5 doses) may be considered medically necessary in the following infants and children, based on guidelines from the American Academy of Pediatrics:
    • Infants and children younger than 2 years of age with chronic lung disease who have required medical therapy for their chronic lung disease within 6 months before the anticipated RSV season.
    • Infants born at 32 weeks of gestation or earlier without chronic lung disease or who do not meet the criteria in the above bullet according to the following schedule:
        • Infants born at 28 weeks of gestation* or earlier are candidates for prophylaxis during their first RSV season, whenever that occurs during the first 12 months of life.
        • Infants born at 29 to 32 weeks of gestation* are candidates for prophylaxis up to 6 months of age.
    • Infants born at 32 to less than 35 weeks’ gestation (defined as 32 weeks, 0 days through 34 weeks, 6 days). Available data do not enable definition of a subgroup of infants at risk of prolonged hospitalization and admission to the intensive care unit. Therefore, current recommendations are intended to reduce the risk of RSV hospitalization during the period of greatest risk (the first 3 months of life) among infants with consistently identified risk factors for hospitalization. Palivizumab prophylaxis should be limited to infants in this group at greatest risk of hospitalization due to RSV, namely infants younger than 3 months of age at the start of the RSV season or who are born during the RSV season and who are likely to have an increased risk of exposure to RSV. Epidemiologic data suggest that RSV infection is more likely to occur and more likely to lead to hospitalization for infants in this gestational age group when at least one of the following two risk factors is present:
        • infant attends child care, defined as a home or facility where care is provided for any number of infants or young toddlers in the child care facility; or
        • infant has a sibling younger than 5 years of age who is not a birth sibling.
 
Infants, especially high-risk infants, never should be exposed to tobacco smoke. In published studies, passive household exposure to tobacco smoke has not been associated with an increased risk of RSV hospitalization on a consistent basis. However, exposure to tobacco smoke is a known risk factor for many adverse health related outcomes. Exposure to tobacco smoke can be controlled by the family of an infant at increased risk of RSV disease, and preventive measures will be less costly than palivizumab prophylaxis.
 
Infants with congenital abnormalities of the airway or neuromuscular disease.
Immunoprophylaxis may be considered for 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. Infants and young children in this category should receive a maximum of 5 doses of palivizumab during the first year of life.
 
Once a child qualifies for initiation of prophylaxis at the start of the RSV season, administration should continue throughout the season and not stop at the point an infant reaches either 6 or 12 months of age.
 
Monthly administration of immune prophylaxis with palivizumab (i.e. not RespiGam) only may be considered medically necessary for children who are 24 months of age or younger with hemodynamically significant cyanotic and acyanotic heart disease.
 
Decisions regarding prophylaxis with palivizumab in children with congenital heart disease should be made on the basis of the degree of physiologic cardiovascular compromise. Infants younger than 12 months of age with congenital heart disease who are most likely to benefit from immunoprophylaxis include:
  • Infants who are receiving medication to control congestive heart failure
  • Infants with moderate to severe pulmonary hypertension
  • Infants with cyanotic heart disease.
 
For children with heart disease meeting the above criteria for palivizumab meeting any one of the above bullets, an additional postoperative dose of palivizumab may be considered medically necessary after a surgical procedure requiring cardiopulmonary bypass.
 
Patients with more severe CLD may benefit from prophylaxis during a second RSV season if they continue to require medical therapy for respiratory or cardiac dysfunction.
 
Immune prophylaxis is considered not medically necessary for Infants and children with hemodynamically insignificant heart disease, including but not limited to secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta and patent ductus arteriosus.
 
Other indications for immune prophylaxis for respiratory syncytial virus are considered investigational including, but not limited to adults with any diagnosis, patients undergoing stem cell transplantation, or children with immunodeficiencies, or cystic fibrosis, not otherwise addressed by the above criteria.
 
RSV prophylaxis should be initiated at the onset of the RSV season and terminated at the end of the RSV season. In most areas of the United States, the usual time for the beginning of the RSV outbreaks is October to December, and termination is March to May, but regional differences occur. The onset of RSV infection occurs earlier in southern states than in northern states. Plans may wish to contact their state health departments or diagnostic virology laboratories to determine the optimal time to begin administration.
 
Typically, a total of 5 monthly dosages are given during the RSV winter season. Once a child qualifies for initiation of prophylaxis at the start of the RSV season, administration should continue throughout the season and not stop at the point an infant reaches either 6 months or 12 months of age.
 
 
Effective prior to 2/24/2012
 
Monthly administration for five (5) months during the anticipated RSV season with palivizumab meets primary coverage criteria for effectiveness and is covered for the following infants and children, based on guidelines from the American Academy of Pediatrics:
    • Infants and children younger than 2 years of age with chronic lung disease who have required medical therapy for their chronic lung disease within 6 months before the anticipated RSV season.
    • Infants born at 32 weeks of gestation or earlier without chronic lung disease or who do not meet the criteria in the above bullet according to the following schedule:
      • Infants born at 28 weeks of gestation (up to and including 28 weeks, 6 days) or earlier are candidates for prophylaxis during the RSV season, whenever that occurs during the first 12 months of life; or
      • Infants born at 29 to 32 weeks (29 weeks 0 days through 31 weeks 6 days)of gestation are candidates for prophylaxis up to 6 months of age
    • Infants born between 32 weeks and 35 weeks gestation  (32 weeks 0 days through 34 weeks 6 days) and are younger than 6 months at the start of the RSV season with at least 2 OR MORE of the following high risk factors:
      • Child care attendance;
      • School-aged sibling;
      • Exposure to environmental air pollutants;
    • Infants born less than 35 weeks gestation who have either congenital malformations of the airway or a neuromuscular condition that compromises handling of respiratory secretions. (Revised 12/2011)
    • Monthly administration of immune prophylaxis with palivizumab (i.e. not RespiGam) for 5 months during the anticipated RSV season  is  covered for children who are 24 months of age or younger with hemodynamically significant cyanotic and acyanotic heart disease.
 
Decisions regarding prophylaxis with palivizumab in children with congenital heart disease should be made on the basis of the degree of physiologic cardiovascular compromise. Infants younger than 12 months of age with congenital heart disease who are most likely to benefit from immunoprophylaxis include:
    • Infants who are receiving medication to control congestive heart failure;
    • Infants with moderate to severe pulmonary hypertension; and
    • Infants with cyanotic heart disease.
 
For children  with heart disease meeting the above criteria for palivizumab and  any one of the above bullets, an additional postoperative dose of palivizumab is covered  after a surgical procedure requiring cardiopulmonary bypass.
 
The use of palivizumab (Synagis) does not meet benefit certificate primary coverage criteria, based on recommendations for its use promulgated by the American Academy of Pediatrics for, but not limited to:
    • Immune prophylaxis for infants and children with hemodynamically insignificant heart disease, including but not limited to secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta and patent ductus arteriosus.
    • Other indications for immune prophylaxis for respiratory syncytial virus including, but not limited to adults with any diagnosis, patients undergoing stem cell transplantation, and immunocompromised children or children with cystic fibrosis, not otherwise addressed by the above criteria.
 
For those individual contracts without Primary Coverage Criteria the use of palivizumab (Synagis) would be considered investigational and is not covered based on recommendations for its use promulgated by the American Academy of Pediatrics for, but not limited to:
    • Immune prophylaxis for infants and children with hemodynamically insignificant heart disease, including but not limited to secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta and patent ductus arteriosus.
    • Other indications for immune prophylaxis for respiratory syncytial virus including, but not limited to adults with any diagnosis, patients undergoing stem cell transplantation, and immunocompromised children or children with cystic fibrosis, not otherwise addressed by the above criteria
are considered investigational.  Investigational services are an exclusion in the member certificate of coverage.
 
RSV prophylaxis should be initiated at the onset of the RSV season and terminated at the end of the RSV season. In most areas of the United States, the usual time for the beginning of the RSV outbreaks is October to December, and termination is March to May, but regional differences occur.
 
Typically, a total of 5 monthly dosages are given during the RSV winter season. Once a child qualifies for initiation of prophylaxis at the start of the RSV season, administration should continue throughout the season and not stop at the point an infant reaches either 6 months or 12 months of age.
 
Patients with more severe CLD may benefit from prophylaxis during a second RSV season if they continue to require medical therapy for respiratory or cardiac dysfunction.

Rationale:
Several randomized clinical trials have demonstrated the success of immune prophylaxis of RSV. In 1997, the PREVENT Study Group reported on a trial that randomized 510 infants with prematurity or bronchopulmonary dysplasia to receive either placebo or RSV-IVIg infusions monthly for 5 months. The authors reported a 41% reduction in hospitalization due to RSV infection, and reductions in other measures of severity of RSV infection when it did occur.  In 1998, the Impact RSV Study Group reported similar results with palivizumab. There was a 55% reduction in hospitalization and similar reductions in other measures of RSV severity in breakthrough infections. It is anticipated that palivizumab will be preferred over the IV immunoglobulin product due to the convenience of IM administration, safety concerns regarding immunoglobulin pooled from multiple donors, and the unlimited supply of a bioengineered product.
 
In 1998, the American Academy of Pediatrics (AAP) published revised guidelines regarding the use of RSV-IVIg or palivizumab for RSV immune prophylaxis, which focused on infants with chronic lung disease and preterm infants.  In 2003, the AAP Red Book, which summarizes immunization recommendations, and the AAP policy statement on the prevention of RSV added indications for children with hemodynamically significant heart disease.  These guidelines form the basis of this policy and are summarized in the policy statement above.
 
Regarding the AAP's more restrictive recommendations for infants born between 32 weeks gestation and up to 35 weeks gestation, the AAP Redbook adds the following:
 
"Although palivizumab and RSV-IVIg have been shown to decrease the likelihood of hospitalizations in infants born between 32 and 35 weeks gestation (i.e., between 32 weeks, 1 day and 35 weeks, 0 days), the cost of administering prophylaxis to this large group of infants must be considered carefully. Therefore, most experts recommend that prophylaxis should be reserved for infants in this group who are at greatest risk of severe infection and who are younger than 6 months of age at the start of the RSV season. Epidemiologic data suggest that RSV infection is more likely to lead to hospitalization for these infants when the following risk factors are present: child care attendance, school-aged siblings, exposure to environmental air pollutants, congenital abnormalities of the airways or severe neuromuscular disease. However, no single risk factor causes a very large increase in the rate of hospitalization, and the risk is additive as the number of risk factors for an individual infant increases. Therefore, prophylaxis should be considered for infants between 32 and 35 weeks gestation only if 2 or more of these risk factors are present."
 
Immune prophylaxis has also been suggested for patients 24 months of age or younger with congenital heart disease (CHD). The AAP guidelines note that children with cyanotic CHD who received RSV-IVIg and underwent cardiac surgery appeared to experience an increased surgical mortality rate. Therefore, according to the AAP guidelines, RSV-IVIg is contraindicated in children with cyanotic CHD. The AAP guidelines indicate the use of palivizumab in children with CHD should be based on the degree of cardiovascular compromise. Infants less than 12 months with CHD may benefit from palivizumab if they are receiving medication for congestive heart failure, have moderate to severe pulmonary hypertension or have cyanotic heart disease.
 
The use of palivizumab in infants with hemodynamically significant heart disease represents an off label indication. This new 2003 recommendation by the AAP is based on the results a double blind, placebo controlled randomized trial of 1,287 children with hemodynamically significant CHD. A total of 9.7% of the placebo group required hospitalization compared to 5.3% of the treatment group.
 
The use of RSV-IVIg or palivizumab in patients with documented immunodeficiencies has also been suggested. The AAP guidelines note, "Palivizumab or RSV-IVIg has not been evaluated in randomized trials in immunocompromised children. Although specific recommendations for immunocompromised patients cannot be made, children with severe immunodeficiencies (e.g., severe combined immunodeficiency or severe acquired immunodeficiency syndrome) may benefit from prophylaxis. If these infants and children are receiving standard immune globulin intravenous monthly, physicians may consider substituting RSV-IVIg during the RSV season."
 
Immunocompromised patients undergoing stem cell transplantation are also at risk for potentially lethal respiratory viral infections. Cortez and colleagues studied whether RSV-IVIg provided sufficient RSV immune prophylaxis to prevent RSV pneumonia in 54 patients undergoing stem cell transplantation.  The authors reported a low-incidence of RSV infection in the 54 RSV-IVIg patients as well as in 31 patients not enrolled in the study and could not determine the preventive effect of RSV-IVIg. No other studies evaluating RSV immune prophylaxis in patients undergoing stem cell transplantation were identified.
 
2009 Update
The total number of injections allowed during a RSV season has been changed to 5 based on FDA  approved labeling and recommendations from the American Academy of Pediatrics.  
 
2010 Update
A search of the MEDLINE database was performed for the period July 2009 through August 2010. None of the articles identified led to a change in the policy statements. Two systematic reviews were identified: one reviewing compliance with palivizumab and one reviewing the use in children with cystic fibrosis.
 
A Cochrane review was published in 2010, assessing the use of palivizumab in children with cystic fibrosis (CF) (Robinson, 2010). One randomized comparative trial met the inclusion criteria of the review. In the study, 186 infants under the age of two with CF were randomized to receive 5 monthly doses of palivizumab (n=92) or placebo (n=94). One member of each group was hospitalized for RSV within the 6-month follow-up period. The rate of adverse event noted in each group was relatively high, with serious adverse events not significantly different between the palivizumab and placebo groups (20.2% and 17.3%, respectively). The authors noted that it was not possible to draw conclusions on the tolerability and safety of RSV immune prophylaxis in CF. The single study reported similar adverse events, but did not specify how adverse events were classified. No clinically meaningful outcome differences were noted at 6-month follow-up. The authors of the review called for additional randomized studies to establish both efficacy and safety of immune prophylaxis in children with CF.
 
Frogel and colleagues reviewed the medical literature on compliance with palivizumab therapy, and the relation between hospitalization rates in fully compliant and less compliant groups (Frogel, 2010). A total of 25 articles and abstracts met review inclusion criteria. Significant heterogeneity was detected due to between-study differences in the population studied, and the definition of compliance used. Differences in compliance definitions led to a compliance rate range of 25% to as high as 100%, compared to rates in licensing studies of 92% and 93%. This led the authors to the conclusion that compliance in practice is far more variable. Minorities and patients on Medicaid were less likely to receive the full complement of palivizumab doses, while patients participating in a home health program tended to have higher compliance and less hospitalization. Home health programs were defined as nurse-delivered injections performed in the home setting.
 
2013 Update
A literature search was conducted through February 2013. There were no new randomized controlled trials identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search was conducted using the MEDLINE database through February 2014. One RCT was identified (Blanken, 2013) but the results of the trial do not prompt a change in the coverage statement.
 
In 2013, Blanken et al performed a multicenter, double-blind, randomized, placebo-controlled MAKI trial to investigate the potential causal role of RSV infection in the pathogenesis of wheezing illness during the first year of life, using palivizumab (Blanken, 2013). The trial randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Premature infants treated with palivizumab had a significant 61% relative decrease in the total number of wheezing days during the first year of life (95% confidence interval [CI], 56 to 65) (Blanken, 2013). Moreover, the effect of RSV prevention on the number of wheezing days persisted in the postprophylaxis period (ie, starting at 2 months after the last injection) for a relative reduction of 73% (95% CI, 66 to 80). In addition, palivizumab treatment reduced hospitalizations related to RSV infection (12.6% in the RSV prevention group, as compared with 21.9% in the placebo group (p=0.04) (Blanken, 2013).
 
September 2014 Update
This update is based on the recently published guidelines from the American Academy of Pediatrics (AAP) (“Updated guidance”, 2014).  The AAP published new guidelines based on a technical report also recently published in 2014 (“Technical report”, 2014). The policy statement has been changed in response to these new guidelines.  
 
In a 2014 article sponsored by MedImmune, manufacturer of palivizumab, Makari et al recommended full-season RSV prophylaxis with palivizumab for preterm infants of 32-34 weeks’ gestational age rather than discontinuation of palivizumab at 3 months of age, as is currently recommended (Makari, 2013). The authors reviewed several studies and concluded that elevated risk of RSV-related hospitalization persists through age 6 months. In contrast, Winterstein et al (2013) in a non-industry-sponsored study found support for a 3-month age limit for RSV prophylaxis among preterm infants of 32-34 weeks’ gestational age (Winterstein, 2013). The authors compared RSV-related hospitalizations among preterm and term infants with siblings using Medicaid databases in Florida and Texas (total N=247,566). In both databases, the risk of RSV-related hospitalization among preterm infants was similar to that for 1-month-old term infants at approximately 4.4 months of age (4.2 months in Florida [95% CI, 2.5 to 5.7] and 4.5 months in Texas [95% CI, 2.8 to 6.4]). Given palivizumab’s 30-day window of effectiveness, prophylaxis to age 3 months would provide coverage until the estimated 4.4-month age threshold. Currently, primary evidence to establish when infants of 32-34 weeks’ gestational age develop lung function and immunologic responses similar to their term counterparts is lacking. Given emerging and contradictory evidence about RSV prophylaxis duration in these infants, modifications of current guidance cannot be recommended.
 
In summary, the policy statements are in agreement with the 2014 American Academy of Pediatrics Guidelines. Current evidence for duration of prophylaxis in preterm infants of 32-34 weeks’ gestational age is inconsistent and insufficient to support deviation from AAP guidelines.
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Cohen and colleagues findings were supported by a 2015 study of 91 infants with CHD who received palivizumab prophylaxis during the 2010-2012 RSV seasons and 96 infants with CHD without prophylaxis during the 2009-2010 RSV season (Ozyurt, 2015). Although the study is described as a case-control study, methods used are more consistent with a retrospective cohort study. LRTI-related hospitalizations were less frequent in the palivizumab-treated group (RR=0.75; p<0.001).
 
In 2014, recommendations from the American Academy of Pediatrics (AAP) on the use of palivizumab narrowed. Grindeland and colleagues retrospectively compared RSV hospitalization data for patients under 2 in the 2 RSV seasons preceding the change in AAP recommendations with the RSV season after the change (Grindeland, 2016).  RSV hospitalization rates did not differ significantly between the pre-2014 (5.37 per 1000 children <2 years) and post-2014 seasons (5.78 per 1000 children <2 years; p=0.622), although the number of palivizumab doses decreased significantly (from 21.7 doses to 10.3 doses per 1000 children <2 years; p<0.001). This study supports a more narrowly defined gestational age range for palivizumab use.
 
Other studies have used health care claims data to evaluate the association between palivizumab use and a variety of outcomes. For example, Carrolland colleagues used claims data to evaluate the association between palivizumab and asthma in later childhood (Cohen, 2016). In a cohort of 6571 children eligible to receive immunoprophylaxis with palivizumab, after propensity score matching, there was no significant association between receipt of palivizumab and asthma risk at ages 4 to 6 (for those ≥70% compliant with doses vs no receipt: adjusted odds ratio [OR], 1.17; 95% CI, 0.98 to 1.39).
 
Groves and colleagues has reported on a retrospective review of a CF center registry of 92 children treated from 1997 to 2007, comparing outcomes for those treated before and after palivizumab prophylaxis became routine in 2002 Grooves, 2016).  In addition to the study’s primary objective (RSV-related hospitalization rates in pre- and post-2002 cohorts), the authors reported on lung function, growth parameters, and bacterial colonization in both cohorts at age 6. Of the total, 45 patients were born after 2002 and all received palivizumab in their first year of life before RSV season. The overall rate of RSV-related hospitalizations was 13%. Palivizumab recipients had a lower risk of RSV infection than non-recipients (RR=4.78; 95% CI, 1.1 to 20.7).
 
Cystic Fibrosis
Some evidence, summarized in systematic reviews, demonstrated reductions in hospitalizations in palivizumab-treated patients with CF. However, studies that used contemporaneous controls did not demonstrate reductions in hospitalizations. In the available RCT, event rates were low and did not differ statistically between palivizumab and placebo. Rates of adverse events were high in both the palivizumab and the placebo groups, making it difficult to draw conclusions about the net benefit of palivizumab difficult. A more recent nonrandomized study using non-contemporaneous controls found reduced RSV infections in palivizumab-treated patients with CF. Additional studies are needed to establish the benefit of palivizumab in patients with CF.
 
Immunodeficiencies
Infants infected with HIV are another subgroup who may be at higher risk for RSV LRTI. Cohen and colleagues evaluated LRTI rates for infants less than 6 months of age who had been HIV infected, HIV exposed but not infected, or HIV uninfected, using data from an active, prospective, hospital-based surveillance system (Cohen, 2016).  From a cohort of 3537 infants who an LRTI meeting the study’s case definition, along with population data, the estimated incidence rate ratio (IRR) for HIV-infected infants compared with HIV-unexposed infants was 1.9 (95% CI ,1.3 to 2.7).
 
A relatively small body of literature addresses the use of some form of RSV immunoprophylaxis in immunodeficient patients. For patients who are status post stem cell transplantation, small cohort studies have reported on the use of RSV immunoprophylaxis, including both RSV-IVIg and palivizumab, but comparative evidence is lacking. At least 1 study in HIV-infected infants has suggested that HIV may predispose infants to RSV infection, but evidence on risk reduction practices is lacking.
 
2017 Update
A literature search conducted using the Medline database did not reveal any new information that would prompt a change in the coverage statement.
 
CYSTIC FIBROSIS
Robinson et al published a Cochrane review (originally published in 2010 and subsequently updated in 2013, 2014 and 2016), which assessed the use of palivizumab in children with cystic fibrosis (CF) based on a literature search through May 2016 (Robinson, 2010; Robinson, 2012; Robinson, 2016). Reviewers identified a single RCT that randomized 186 infants (<2 years old) with CF to palivizumab (n=92) or placebo (n=94). One member of each group was hospitalized for RSV within the 6-month follow-up period. The incidence of adverse events was relatively high in both groups, with serious adverse events not differing significantly between the palivizumab (20.2%) and placebo (17.3%) groups. Robinson et al noted that it was not possible to draw conclusions on the safety and tolerability of RSV immune prophylaxis in CF: Although the trial reported similar incidences of adverse events, it did not specify how adverse events were classified, and no clinically meaningful outcome differences were noted at 6-month follow-up. Reviewers called for additional randomized studies to establish safety and efficacy of immune prophylaxis in children with CF.
 
IMMUNODEFICIENCIES
The use of palivizumab in children with primary immunodeficiency has not been formally evaluated in clinical trials or in nonrandomized comparative studies. Lanari et al (2014) published a literature review on RSV infection in infants with primary immunodeficiency disorders and noted that “RCTs evaluating efficacy of palivizumab prophylaxis in immunocompromised infants have not been conducted probably because of the low incidence of these disorders and the ethical controversies surrounding them” (Lanari, 2014). Further, in the absence of empirical data to support the use of palivizumab prophylaxis in immunocompromised infants, reviewers cited findings of a consensus panel (Gaboli, 2014) of pediatric pulmonologists who would consider off-label use of palivizumab in primary immunodeficiencies and case reports (Manzoni, 2007) of 2 infants with primary immunodeficiencies and 2 infants with acquired immunodeficiencies in whom palivizumab was used with good compliance and efficacy.
 
A relatively small body of literature has addressed the use of palivizumab for RSV immunoprophylaxis in patients with primary or acquired immunodeficiency. Comparative evidence is lacking.  

CPT/HCPCS:
90378Respiratory syncytial virus, monoclonal antibody, recombinant, for intramuscular use, 50 mg, each
J3490Unclassified drugs

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