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1 MP Immune Prophylaxis for Respiratory Syncytial Virus Medical Policy Section Prescription Drug Issue 12:2013 Original Policy Date 12:2013 Last Review Status/Date Reviewed with literature search/12:2013 Return to Medical Policy Index Disclaimer Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. Description Respiratory syncytial virus (RSV) is the most common cause of lower respiratory infections in children. At highest risk are those younger than 2 years of age with prematurity, chronic lung disease (CLD, [formerly known as bronchopulmonary dysplasia]), congenital heart disease, or multiple congenital anomalies. Immune prophylaxis against RSV is a prevention strategy to reduce the incidence of infection and its associated morbidity, including hospitalization, in highrisk infants. Background Respiratory syncytial virus (RSV) infections typically occur in the winter months, starting from October to December and ending from March to May. Considerable variation in the timing of community outbreaks is observed year to year. According to the Centers for Disease Control and Prevention (CDC), onset of the RSV season occurs when the median percentage of specimens testing positive for RSV is 10% higher over a 2-week period. In the U.S., RSV is associated with approximately 75, ,000 pediatric hospitalizations annually. (1) Chronic lung disease (CLD, [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, the lung tissues become inflamed and scarring can result. Some of the causes of the lung injury include the following: prematurity, low amounts of surfactant, oxygen use, mechanical ventilation. Risk factors for developing CLD include: birth at less than 34 weeks gestation, birth weight less than 2,000 grams (4 pounds 6.5 ounces), hyaline membrane disease, pulmonary interstitial emphysema (PIE), patent ductus arteriosus (PDA), Caucasian, male infants, maternal womb infection (chorioamnionitis), and family history of asthma. In contrast to the well-documented beneficial effect of breastfeeding against many viral illnesses, existing data are conflicting regarding the specific protective effect of breastfeeding against RSV infection. Breastfeeding should be encouraged for all infants in accordance with recommendations of the American Academy of Pediatrics (AAP). High-risk infants should be

2 kept away from crowds and from situations in which exposure to infected people cannot be controlled. Participation in group child care should be restrictedduring the RSV season for highrisk infants whenever feasible. Parents should be instructed on the importance of careful handhygiene. In addition, all high-risk infants 6 months of ageand older and their contacts should receive influenza vaccine,as well as other recommended age-appropriate immunizations. This policy does not address therapies to treat RSV infection. Regulatory Status In June 1998, the biologic Synagis (palivizumab; MedImmune, Inc, Gaithersburg, MA) was approved for marketing by the U.S. Food and Drug Administration (FDA) through the biologics licensing application for use in the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. In July 2004, the 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. RespiGam RSV-IVIG for intravenous use was available from 1993 to It is no longer manufactured. In August 2010, Motavizumab (proposed to be marketed as Rezield, MedImmune, Inc) received a complete response letter from the FDA requesting additional clinical data on its biologics license application. Subsequently, AstraZeneca suspended Motavizumab development and upon the manufacturer s request, the FDA withdrew its biological license application. Policy Monthly administration of immune prophylaxis for respiratory syncytial virus during the RSV season with palivizumab may be considered medically necessary in the following infants and children in accordance with current (2009) guidelines from the American Academy of Pediatrics: 1. Infants with chronic lung disease of prematurity (CLD, [formerly known as bronchopulmonary dysplasia]). Infants and children younger than 24 months of age who receive medical therapy (supplemental oxygen, bronchodilator, diuretic or chronic corticosteroid therapy) for chronic lung disease within 6 months before the start of the RSV season. 2. Infants born before 32 weeks gestation (31 weeks, 6 days or less). Infants in this category may benefit from RSV prophylaxis, even if they do not have CLD. For these infants, major risk factors to consider include gestational age and chronologic age at the start of the RSV season. Infants born at 28 weeks of gestation or earlier (up to and including 28 weeks, 6 days)may benefit from prophylaxis during the RSV season, wheneverthat occurs during the first 12 months of life. Infants born at 29 to 32 weeks of gestation may benefit most from prophylaxis if younger than 6 months of age at the start of the RSV season. In this setting, 32 weeks gestation refers to an infant born before the 32nd week of gestation (31 weeks, 6 days or less).

3 3. Infants born at 32 to less than 35 weeks gestation (defined as 32 weeks, 0 days through 34 weeks, 6 days). Infants younger than 3 months of age at the start of or born during RSV season, or who are likely to have an increased risk of exposure to RSV when at least one of the following 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. Infants in this gestational age category should receive prophylaxis only until they reach 3 months of age, maximum of 3 monthly doses. 4.Infants with congenital abnormalities of the airway or neuromuscular disease. Infants who have either congenital malformations of the airway or a neuromuscular condition that compromises handling of respiratory secretions. 5. Infants and children with congenital heart disease. Children who are 24 months of age or younger with hemodynamically significant cyanotic or acyanotic congenital heart disease may benefit from palivizumab prophylaxis. Decisions regarding prophylaxis with palivizumab in children with congenital heart disease should be made on the basis of the degree of physiologic cardiovascular compromise. Children younger than 24 months of age with congenital heart disease who are most likely to benefit from immunoprophylaxis include: Infants who are receiving medication to control heart failure; Infants with moderate to severe pulmonary hypertension; Infants with cyanotic heart disease. After surgical procedures that use cardiopulmonary bypass, for children who still require prophylaxis, a postoperative dose of palivizumab may be considered medically necessary as soon as the patient is medicallystable. Immunoprophylaxis for respiratory syncytial virus is considered not medically necessary in: Infants and children with hemodynamically insignificant heart disease (e.g., secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus); Infants with lesions adequately corrected by surgery, unless they continue to require medication for heart failure; Infants with mild cardiomyopathy who are not receiving medical therapy for the condition. Other indications for immune prophylaxis for respiratory syncytial virus are considered investigationalincluding, but not limited to, immunocompromised children; patients with cystic fibrosis; or for use in controlling outbreaks of health care-associated disease. Policy Guidelines

4 Palivizumab is administered by intramuscular injection in a dose of 15 mg/kg of body weight per month. The anterolateral aspect of the thigh is the preferred injection site. Routine use of the gluteal muscle for the injection site can cause sciatic nerve damage. 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. If an infant or child, who is receiving palivizumab immunoprophylaxis experiences a breakthrough respiratory syncytial virus (RSV) infection, they should continue monthly prophylaxis until a maximum of 5 doses for infants with congenital heart disease, chronic lung disease (CLD, [formerly known as bronchopulmonary dysplasia]), or preterm birth before 32 weeks gestation. This recommendation is based on the observation that high-risk infants may be hospitalized more than once in the same season with RSV lower respiratory tract disease and the fact that more than one RSV strain often co-circulates in a community. Infants who qualify for prophylaxis in the 32 to 35 weeks' gestation age group should receive prophylaxis only until they reach 90 days of age or a maximum of 3 doses (whichever comes first). RSV is known to be transmitted in the hospital setting and to cause serious disease in high-risk infants. Among hospitalized infants, the major means to reduce RSV transmission is strict observance of infection control practices, including prompt initiation of precautions for RSVinfected infants. If an RSV outbreak occurs in a high-risk unit (e.g., pediatric or neonatal intensive care unit or stem-cell transplantation unit), primary emphasis should be placed on proper infection control practices, especially hand hygiene. No data exist to support palivizumab use in controlling outbreaks of health care-associated disease, and palivizumab use is not recommended for this purpose. Palivizumab does not interfere with response to vaccines. Palivizumab may interfere with RSV diagnostic tests that are immunologically-based (e.g., some antigen detection-based assays). 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. Initiation and Termination of Immunoprophylaxis 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

5 year to year exists in the same community and between communities in the same year, even in the same region. These variations occur within the overall pattern of RSV outbreaks, usually beginning in November or December, peaking in January or February, and ending by the end of March or sometime in April. Communities in the southern United States, particularly some communities in the state of Florida, tend to experience the earliest onset of RSV activity. In recent years, the national median duration of the RSV season has been 17 weeks or less. Results from clinical trials indicate that palivizumab trough serum concentrations more than 30 days after the fifth dose will be well above the protective concentration for most infants. Five monthly doses of palivizumab will provide more than 20 weeks of protective serum antibody concentration. In the continental United States, a total of 5 monthly doses for infants and young children with congenital heart disease or chronic lung disease 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. Data from the Centers for Disease Control and Prevention (CDC) have identified variations in the onset and offset of the RSV season in the state of Florida that should affect the timing of palivizumab administration. Northwest Florida has an onset in mid-november, which is consistent with other areas of theunited States. In north central and southwest Florida, the onset of RSV season typically is late September to early October. The RSV season in southeast Florida (Miami-Dade County) typically has its onset in July. Despite varied onsets, the RSV season is of equal duration in the different regions of Florida. Children who receive palivizumab prophylaxis for the entire RSV season should receive palivizumab only during the 5 months following the onset of RSV season in their region (maximum of 5 doses), which should provide coverage during the peak of the season, when prophylaxis is most effective. Rationale This policy was originally created in 1999 and was regularly updated with searches of the MEDLINE database. The most recent literature search was performed for the period of August 2011 through July The following is a summary of the key findings to date. High-risk Infants Several randomized clinical trials have demonstrated the success of immune prophylaxis of respiratory syncytial virus (RSV). A systematic review was conducted in the United Kingdom to evaluate the effectiveness of palivizumab for the prevention of RSV in children. (2) Two randomized controlled trials (RCTs) were identified in the review. (3, 4) In the 1998 Impact-RSV Study Group, prophylaxis with palivizumab for preterm infants without chronic lung disease (CLD) or children with CLD resulted in a 55% reduction in RSV hospital admission; 4.8% (48/1,002) in the palivizumab group and 10.6% (53/500) in the no prophylaxis group. (3) Similar reductions in other measures of RSV severity in breakthrough infections were also reported. In a 2003 double-blind, placebo-controlled randomized trial of 1,287 children with hemodynamically significant CHD, Feltes et al. reported prophylaxis with palivizumab was associated with a 45% reduction in hospitalization rate for RSV among children with congenital heart disease (CHD). (4) Hospitalization rates for RSV were 5.3% (34/639) in the palivizumab group and 9.7% (63/648) in the no prophylaxis group. The authors concluded that prophylaxis with palivizumab is clinically effective for reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalization in high-risk children.

6 In 1997, the PREVENT Study Group reported on a trial that randomly assigned 510 infants with prematurity or chronic lung disease (CLD) to receive either placebo or RSV-intravenous immunoglobulin (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. (5) Palivizumab eventually became the preferred product over the IVIg product due to the convenience of intramuscular 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. (6) 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. (7) 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 with CHD who are younger than 12 months may benefit from palivizumab if they are receiving medication for heart failure, have moderate-to-severe pulmonary hypertension, or have cyanotic heart disease. The 2003 recommendation by the AAP (6) was based on the results of the Feltes RCT noted above. (4) In 2009, AAP updated its guidelines regarding the use of immune prophylaxis for respiratory syncytial virus (RSV). The updated guidelines were published in the new AAP Red Book 2009 in the chapter on RSV. (8) The following is a summary, provided by the AAP, of the major changes to the guidelines: 1. Recommendations for initiation and termination of prophylaxis are modified to reflect current CDC descriptions of RSV seasonality in different geographic locations within the United States. 2. The recommendations remain unchanged for infants with congenital heart disease, chronic lung disease of prematurity and birth before 32 weeks' gestation. 3. Regardless of the month when the first dose is administered, the recommendation for a maximum number of 5 doses for all geographic areas is emphasized for infants with hemodynamically significant congenital heart disease, chronic lung disease of prematurity or birth before 32 weeks' gestation and for a maximum number of 3 doses for infants with a gestational age of 32 to 35 weeks without hemodynamically significant congenital heart disease or chronic lung disease. 4. Risk factors for severe RSV lower respiratory tract disease among infants born between 32 to 35 weeks' gestation have been modified to include only: a. Infant attends child care b. Siblings living in the household are less than 5 years of age

7 5. Infants 32 to 35 weeks' gestation age who are born within the 3 months before the onset of RSV season and throughout the RSV season will qualify for prophylaxis if they have at least one [of the modified] risk factors. Earlier recommendations required 2 of 5 [different] risk factors. 6. Infants who qualify for prophylaxis in the 32 to 35 weeks' gestation age group should receive prophylaxis only until they reach 90 days of age or a maximum of 3 doses (whichever comes first). This is a change from the previous recommendation for 5 months of prophylaxis. 7. The AAP's definition of gestational age is used throughout this document. For example, 32 to 35 weeks' gestation is defined as 32 weeks, 0 days through 34 weeks, 6 days. In August 2009, AAP released a policy statement (including references and evidence grading) that supported their revised indications for the use of palivizumab for the prevention of respiratory syncytial virus infections. (9) In commenting on their 2009 recommendations, the AAP policy statement indicates, "they [the 2009 AAP recommendations] specifically target infants in this [32 to less than 35 weeks' gestational age] with consistently identified risk factors for RSV hospitalization during the period of greatest risk, which is the first 3 months of life. In 2008, Cohen and colleagues evaluated the characteristics of patients (n=19,548) enrolled in The Palivizumab Outcomes Registry with CHD over the 4 RSV seasons. (10) The Palivizumab Outcomes Registry prospectively collected data on patients who received RSV prophylaxis with palivizumab during the RSV seasons. The percentage of registry subjects with CHD increased from 4.8% (102/2,116) in the first season to 11.4% (688/6,050) in the last season. Across all 4 seasons, 1,500 subjects with CHD were enrolled; 71% of whom had acyanotic CHD. The proportion with cyanotic CHD increased from 19.6% (20/102) in the season to 37.5% (258/688) in the season, while the proportion of all CHD in the registry more than doubled during this time. The cumulative RSV hospitalization rate was 1.9% among patients with CHD who received prophylaxis. Among subjects with cyanotic and acyanotic CHD, hospitalization rates were 2.6% and 1.6%, respectively. The authors concluded, the prospective data collected in the Palivizumab Outcomes Registry provides the largest published dataset available on infants with CHD receiving palivizumab; shows low hospitalization rates, use consistent with prelicensure clinical trial data and the revised American Academy of Pediatrics guidelines. A review article discussed the development of a second-generation humanized monoclonal antibody (mab), motavizumab, which is no longer under study in Phase III clinical trials, and most recently, a third generation mab, Numax-YTE. (11) Cystic Fibrosis A Cochrane review was published in 2010 and updated in 2012, assessing the use of palivizumab in children with cystic fibrosis. (12, 13) One randomized comparative trial met the inclusion criteria of both reviews. In the study, 186 infants younger than 2 years with cystic fibrosis were randomly assigned 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 cystic fibrosis. 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

8 called for additional randomized studies to establish both efficacy and safety of immune prophylaxis in children with cystic fibrosis. Immunodeficiencies 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. (14) 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. In a literature review, Hynicka and Ensor found data are limited on RSV prophylaxis in immunocompromised adult patients. (15) The only prospective study identified in the review was by Kassis et al. (16) in which intravenous pavilizumab was given to 16 high-risk stem-cell transplant patients to prevent the nosocomial spread of RSV infection from 5 stem-cell transplant patients. After one week, no further RSV cases occurred, but whether controlling the spread of RSV on the stem-cell transplant unit was related to RSV prophylaxis versus implementation of strict quarantine and infection control practices cannot be determined. Duration of Prophylaxis The RSV season typically occurs from November to April. Within the United States, the inevitability of the RSV season is predicable, but the severity of the season and time of onset are variable from year to year and also between geographic areas within a given year. This has led to requests for either earlier or later immunoprophylaxis, or greater than 5 monthly doses. Nevertheless, as pointed out by Meissner and colleagues from the Centers of Disease Control and Prevention (CDC), this yearly and regional variation still 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 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. The authors point out that the recommendation for 5 monthly doses is derived from the randomized studies of palivizumab. A serum palivizumab concentration of greater than 30 μg/ml is the target level for protection, and in randomized studies, the trough level of palivizumab exceeded 30 μg/ml for at least 30 days after the fifth dose. This indicates that 5 monthly doses will provide substantially more than 20 weeks of protective serum antibody levels, covering most of the RSV season even with variation in season onset and end. (17) Compliance

9 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. (18) 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. Ongoing Clinical Trials A search of online site ClinicalTrials.gov in August 2012 identified 2 active observational studies addressing pavilizumab in infants 2 years or younger. Clinical Input Received through Physician Specialty Societies and Academic Medical Centers In response to requests, input was received through 3 physician specialty societies (7 responders) while this policy was under review in While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. Almost all of those providing input agreed with the policy statements approved in October 2009; these statements are in agreement with the 2009 AAP guidelines. Summary Respiratory syncytial virus (RSV) is the most common cause of lower respiratory infections in children. At highest risk are those younger than 2 years of age with prematurity, chronic lung disease (CLD, [formerly known as bronchopulmonary dysplasia]), congenital heart disease, or multiple congenital anomalies. Immune prophylaxis against RSV is a prevention strategy to reduce the incidence of infection and its associated morbidity, including hospitalization, in highrisk infants. Based on the weight of the clinical evidence from randomized clinical trials, systematic reviews and strong clinical consensus, immune prophylaxis for RSV has demonstrated reductions in RSV-related hospitalizations in select populations of susceptible infants and children. Therefore, immune prophylaxis for RSV may be considered medically necessary for the patients listed in the policy statement above. For all other uses of immune prophylaxis, the clinical evidence is not convincing that RSV hospitalizations will decrease. Therefore, the policy statements above note indications which are considered investigational or not medically necessary. The policy statements are in agreement with the 2009 AAP Guidelines. Practice Guidelines and Position Statements In 2003, the AAP released a policy statement with revised indications for the use of palivizumab and RSV-IVIg for the prevention of RSV infections. (7)

10 In June 2009, the AAP released updated guidelines regarding the use of immune prophylaxis for RSV. The updated guidelines were published in the new AAP Red Book 2009 in the chapter on RSV. (8) In August 2009, the AAP released a policy statement (including references and evidence grading) with revised indications for the use of palivizumab for the prevention of RSV infections. (9) In 2008, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK, released a Health Technology Assessment on immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children. (2) The authors concluded that prophylaxis with palivizumab is clinically effective for the reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalization in high-risk children. Medicare National Coverage No National Coverage Determination References: 1. Respiratory syncytial virus--united States, July 2007-June MMWR Morb Mortal Wkly Rep 2011; 60(35): Wang D, Cummins C, Bayliss S et al. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation. Health Technol Assess 2008; 12(36):iii, ix-x, Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact- RSV Study Group. Pediatrics 1998; 102(3 Pt 1): Feltes TF, Cabalka AK, Meissner HC et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr 2003; 143(4): Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. The PREVENT Study Group. Pediatrics 1997; 99(1): Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. American Academy of Pediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Pediatrics 1998; 102(5):

11 7. Meissner HC, Long SS. 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): Red Book. Report of the Committee on Infectious Disease. Respiratory Syncytial Virus. Vol Elk Grove Village, IL: American Academy of Pediatrics. 9. From the American Academy of Pediatrics: Policy statements--modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics 2009; 124(6): Cohen SA, Zanni R, Cohen A et al. Palivizumab use in subjects with congenital heart disease: results from the Palivizumab Outcomes Registry. Pediatr Cardiol 2008; 29(2): Wu H, Pfarr DS, Losonsky GA et al. Immunoprophylaxis of RSV infection: advancing from RSV-IGIV to palivizumab and motavizumab. Curr Top Microbiol Immunol 2008; 317: Robinson KA, Odelola OA, Saldanha I et al. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev 2010; 2:CD Robinson KA, Odelola OA, Saldanha IJ et al. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev 2012; 2:CD Cortez K, Murphy BR, Almeida KN et al. Immune-globulin prophylaxis of respiratory syncytial virus infection in patients undergoing stem-cell transplantation. J Infect Dis 2002; 186(6): Hynicka LM, Ensor CR. Prophylaxis and treatment of respiratory syncytial virus in adult immunocompromised patients. Ann Pharmacother 2012; 46(4): Kassis C, Champlin RE, Hachem RY et al. Detection and control of a nosocomial respiratory syncytial virus outbreak in a stem cell transplantation unit: the role of palivizumab. Biol Blood Marrow Transplant 2010; 16(9): Meissner HC, Anderson LJ, Pickering LK. Annual variation in respiratory syncytial virus season and decisions regarding immunoprophylaxis with palivizumab. Pediatrics 2004; 114(4): Frogel MP, Stewart DL, Hoopes M et al. A systematic review of compliance with palivizumab administration for RSV immunoprophylaxis. J Manag Care Pharm 2010; 16(1): Codes Number Description CPT Respiratory syncytial virus immune globulin for intramuscular use, 50 mg, each Respiratory syncytial virus

12 immune globulin, human, for intravenous use Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour Each additional hour (list separately in addition to code for primary procedure) Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular ICD-9 Procedure Injection or infusion of other therapeutic or prophylactic substance ICD-9 Diagnosis 396 Diseases of mitral and aortic valves (code range) 417 Other disease of pulmonary circulation (code range) 424 Other diseases of endocardium (code range) 425 Cardiomyopathy (code range) 428 Heart failure (code range) 491 Chronic bronchitis (code range) 745 Bulbus cordis anomalies and anomalies of cardiac septal closure (code range) 746 Other congenital anomalies of the heart (code range) 747 other congenital anomalies of the circulatory system (code range) Weeks of gestation (5th digit indicates specific weeks of gestation) V07.2 Prophylactic immunotherapy V46.2 Supplemental oxygen HCPCS J1565 Injection, respiratory syncytial virus immune

13 globulin, intravenous, 50mg (i.e., RespiGam) ICD-10-CM (effective 10/1/13) I08.0 I08.9 Multiple valve diseases code range I28.0 I28.9 Other diseases of pulmonary vessels code range I34.0 I34.9 Nonrheumatic mitral valve disorders code range I35.0 I35.9 Nonrheumatic aortic valve disorders code range I36.0 I36.9 Nonrheumatic tricuspid valve disorders code range I37.0 I37.9 Nonrheumatic pulmonary valve disorders code range I42.0 I42.9 Cardiomyopathy code range I43 Cardiomyopathy in diseases classified elsewhere I50.1 I50.9 Heart failure code range J41.0 J42 Chronic bronchitis code range J44.0 J44.9 Other chronic obstructive pulmonary disease code range P07.00-P07.32 Disorders of newborn related to short gestation and low birth weight, not elsewhere classified code range P27.0-P27.9 Chronic respiratory disease originating in the perinatal period (includes bronchopulmonary dysplasia P27.1) P28.0 P28.9 Other respiratory conditions originating in the perinatal period code range Q20.0 Q28.9 Congenital malformations of the circulatory system code range ICD-10-PCS (effective 10/1/13) ICD-10-PCS codes are only used for inpatient services. 3E0234Z Administration, physiological systems and anatomical

14 Type of Service Place of Service 3E0334Z Prescription Drug Outpatient regions, introduction, muscle, percutaneous, serum, toxoid and vaccine Administration, physiological systems and anatomical regions, introduction, peripheral vein, percutaneous, serum, toxoid and vaccine Index Palivizumab RespiGam Respiratory Syncytial Virus RSV-IVIg Synagis