Subject: Synagis (Palivizumab)

Status	Drug	PR	PR-QL	PR-AL	ST	M EX‡
P	Synagis™  (palivizumab)	X

Policy:

For the purpose of this policy, the criteria below apply to plans that have elected to use Aetna Pharmacy to manage the fulfillment and the precertification of specialty drugs.

1. Precertification Criteria

Under some plans, including plans that use an open or closed formulary, Synagis is subject to precertification. If precertification requirements apply Aetna considers Synagis to be medically necessary for those members who meet  the following precertification criteria: 

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 24 months of age at the start of RSV season with bronchopulmonary dysplasia or other chronic lung disease (CLD) who have required medical therapy (supplemental oxygen, bronchodilator, and diuretic or corticosteroid therapy) for their CLD within 6 months before the anticipated RSV season.

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 of gestation or earlier* (with or without CLD) who are less than 12 months of age at the start of RSV season**; or
2. Infants born between 32 to 35 weeks of gestation who are younger than 6 months of age at the start of RSV season with at least two of the following risk factors for RSV infection:

• Exposure to environmental air pollutants (including tobacco smoke if the family refuses to eliminate the infant's exposure to tobacco smoke in the home**); or 
• Child care attendance; or 
• School-aged siblings; or 
• Severe neuromuscular disease; or
• Congenital anomalies of the airways.
  
  

3. 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

4. Infants and children with hemodynamically significant cyanotic or acyanotic congenital heart disease who are 24 months of age or younger at the onset of the RSV season, including the following:

a. Infants receiving medication to control congestive heart failure; or
b. Infants with moderate to severe pulmonary artery hypertension; or
c. Infants with cyanotic congenital heart disease.

Palivizumab is considered experimental and investigational for all other indications.

 

Palivizumab is not considered medically necessary for infants with the following congenital heart disease conditions:

• 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 
• Infants with lesions adequately corrected by surgery unless they continue to require medication for congestive heart failure; or 
• Infants with cardiomyopathy who are not receiving medical therapy.
  
  According to the AAP (2006), these infants generally should not receive immunoprophylaxis because they are not at increased risk of RSV.
  
  
  

It is considered medically necessary to initiate prophylaxis against RSV just before onset of the RSV season, and to terminate prophylaxis at the end of the RSV season. Administration of RSV prophylaxis beyond the RSV season*** is considered medically necessary only if the Centers for Disease Control and Prevention (CDC) or a local health department reporting to and confirmed by the CDC indicates an outbreak† of RSV in the member's geographic area that persists beyond the RSV season. Note: To determine if there is an RSV outbreak in the member's geographic area, please refer to CDC surveillance summaries of weekly RSV laboratory test result data for each region of the United States, posted at the following website: http://www.cdc.gov/ncidod/dvrd/revb/nrevss/rsvtre1.htm. Surveillance summaries for RSV are also published periodically in the Morbidity and Mortality Weekly Report at http://www.cdc.gov/mmwr/.
Notes:

* For purposes of this policy, 32 weeks' gestation refers to an infant born on or before the 32nd week of gestation (i.e., 32 weeks, 0 days). 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.

** The AAP states that high-risk infants should never be exposed to tobacco smoke, and that "[e]xposure 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 October to December, and termination is March to May, but regional differences occur. The onset of RSV season occurs earlier in southern states than in northern states. 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/.

† RSV activity is considered widespread by the National Respiratory and Enteric Virus Surveillance System (NREVSS) when at least half of participating laboratories report any RSV detections for at least 2 consecutive weeks and when greater than 10 percent of all specimens tested by antigen detection for RSV are positive. RSV community outbreaks are defined similarly (greater than 2 consecutive weeks with greater than 10 percent positive tests, by city) (CDC, 1999). Results of antigen detection assays should be correlated with culture results to determine the onset and offset of the RSV season (Meissner, et al., 2004; Meissner, 2005). Results solely from antigen detection assays do not provide an adequate basis for
determination of onset and offset of the RSV season.

Background

Palivizumab (Synagis), a humanized monoclonal antibody, is administered by intramuscular injection in monthly doses of 15 mg/kg body weight, with a maximum recommended total dosage per monthly infusion of 750 mg/kg. Palivizumab is administered once a month during the RSV season.

In most areas of the United States, the usual time for the beginning of RSV outbreaks is October to December, and termination is March to May, but regional differences occur. The onset of RSV season occurs earlier in southern states than in northern states. 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/ncidod/dvrd/revb/nrevss/rsvtre1.htm.
According to the American Academy of Pediatrics Committee on Infectious Diseases (AAP, 2003), prophylaxis against RSV should be initiated just before onset of the RSV season and terminated at the end of the RSV season. The AAP explains:

In most seasons and in most regions of the Northern Hemisphere, the first dose of palivizumab should be administered at the beginning of November and the last dose should be administered at the beginning of March, which will provide protection into April. To understand the epidemiology of RSV in their area, physicians should consult with local health departments or diagnostic virology laboratories or the Centers for Disease Control and Prevention if such information is not available locally. Decisions about the specific duration of prophylaxis should be individualized according to the duration of the RSV season. Pediatricians may wish to use RSV rehospitalization data from their own region to assist in the decision-making process.

The AAP (2003) states that palivizumab is administered approximately once per month (e.g., every 30 days), beginning just before onset of the RSV season, which typically occurs in November. According to the AAP, 4 subsequent monthly doses (total of 5 doses) are generally sufficient to provide protection during the entire RSV season.

In a recent 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 although there are variations in the precise timing of the RSV season among communities, this variation occurs within the overall pattern of RSV outbreaks:

In the Northern Hemisphere and particularly within the United States, RSV circulates predominantly between November and March …. Within the United States, 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. There can be substantial variation in timing of community outbreaks of RSV disease from year to year in the same community and between communities in the same year even in the same region. This variation, however, occurs within the overall pattern of RSV outbreaks, usually beginning in November or December, peaking in January or February, and ending by March. Communities in the southern region tend to experience the earliest onset of RSV activity, and Midwestern states tend to experience the latest onset, but community-to-community variation in timing precludes using either national or regional data to precisely define or predict individual community RSV outbreaks. The duration of the season for western and northeast regions typically occurs between that noted in the South and the Midwest.

Meissner, et al. (2004) explain that most hospitalizations for bronchiolitis occur during the RSV season:
In recent years, the national median duration of the RSV season has been 15 weeks, and even in the South with seasonal duration of 16 weeks, the range is 13 to 20 weeks. 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) cite 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 µg/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) has 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. explain 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. Decisions regarding duration of prophylaxis should be individualized, according to the duration of the RSV season.

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 five 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. The AAP (2003) 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.

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.

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.
Aetna does not generally consider home administration of palivizumab medically necessary. Individual case exceptions may be made upon showing of medical necessity.

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.

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., particulate matter tobacco smoke and wood stoves).

Place of Service:

Outpatient

The above policy is based on the following references:

1. Drug Facts and Comparisons on-line. (www.drugfacts.com), Wolters Kluwer Health, St. Louis, MO. 200
2. USP DI® Drug Information For The Health Care Professional - 26th Ed. (online from www.statref.com) Thomson Micromedex, Greenwood Village, CO. 2006 .
3. AHFS Drug Information® with AHFSfirstReleases®. (online from www.statref.com), American Society Of Health-System Pharmacists®, Bethesda, MD. 2006.
4.  DRUGDEX® System: Klasco RK (Ed): DRUGDEX® System. Online edition. Thomson Micromedex, Greenwood Village, CO.
5. PDR® Electronic Library, Thomson Micromedex, Greenwood Village, Colorado (Edition expires 2006).
6. Tulloh R, Marsh M, Blackburn M, et al; Working Group of the British Paediatric Cardiac Association. Recommendations for the use of palivizumab as prophylaxis against respiratory syncytial virus in infants with congenital cardiac disease. Cardiol Young. 2003;13(5):420-3.
7. American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics. 2003;112(6 Pt 1):1442-6.
8. Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R; CDC; Healthcare Infection Control Practices Advisory Committee. Guidelines for preventing health-care--associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep. 2004 Mar 26;53(RR-3):1-36.
9. Tulloh RM, Feltes TF. The European Forum for Clinical Management: prophylaxis against the respiratory syncytial virus in infants and young children with congenital cardiac disease. Cardiol Young. 2005;15(3):274-8.
10. Embleton ND, Harkensee C, Mckean MC. Palivizumab for preterm infants. Is it worth it? Arch Dis Child Fetal Neonatal Ed. 2005;90(4):F286-9.
11. Lozano JM. Bronchiolitis. In: Clinical Evidence, Issue 12.
12. Nakazawa M, Saji T, Ichida F, Oyama K, Harada K, Kusuda S. Guidelines for the use of palivizumab in infants and young children with congenital heart disease. Pediatr Int. 2006;48(2):190-
    

Copyright Aetna Inc. All rights reserved. Pharmacy Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

January 01, 2007