Synagis Congential Heart Disease

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Subject:       palivizumab for intramuscular injection (Synagis®)

Date revised: 11/18/2009; selected revision 02/24/2010


Description
Palivizumab is a humanized monoclonal antibody (IgG1K) that has neutralizing and fusion-
inhibitory activity against respiratory syncytial virus (RSV). It is approved by the Food and
Drug Administration (FDA) for the following indication.
        For the prevention of serious lower respiratory tract disease caused by RSV in pediatric
        patients at high risk of RSV disease.

The American Academy of Pediatrics (AAP) revised their policy statement and modified their
recommendations for use of palivizumab for prevention of RSV infections in 2009.1-2 These
recommendations differ from the FDA approved labeling. The AAP recommendations for
starting and stopping prophylaxis were modified to reflect the seasonality of RSV in different
geographic locations in the US. A maximum of 5 doses for all geographic locations is
recommended regardless of the month when prophylaxis is started for congenital heart disease
(CHD), chronic lung disease of prematurity (CLD, formerly called bronchopulmonary
dysplasia[BPD]) and premature infants/children born before 32 weeks 0 days gestation. For
infants with a gestational age of 32 weeks 0 days to 34 weeks 6 days without CLD or CHD, the
maximum number of doses is 3. Risk factors for severe disease in infants born between 32
weeks 0 days and 34 weeks 6 days were modified to only include infants attending child care or
if the child is living with other children who are < 5 years of age. These infants qualify for
prophylaxis if they were born within 3 months before the RSV season or at any time during the
RSV season. Additionally these infants only receive prophylaxis until they are 90 days of age or
have received a maximum of 3 doses whichever comes first. The previous recommendation was
for 5 months. The definition of gestational age defines 32 to 35 weeks gestation as 32 weeks 0
days through 34 weeks 6 days.


Palivizumab is available as preservative-free liquid in single-dose vials containing 50 mg in 0.5
mL or 100 mg in 1 mL.3 Palivizumab is given by intramuscular (IM) injection preferably in the
anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection
site because of the risk of damage to the sciatic nerve. The dose per month is 15 mg/kg. If the
injection volume is over 1 mL, the dose should be divided.




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Indications, Medically Necessary

    1. Prevention of RSV infection in a child with chronic lung disease
    (CLD)/bronchopulmonary dysplasia (BPD): Indicated for the prevention of RSV in
    children with CLD who meet all of the following criteria.

   Child is ≤ 24 months of age,1 and

   The child has required medical therapy (e.g., supplemental oxygen, bronchodilator, diuretic,
    or chronic corticosteroid therapy) for their CLD/BPD within 6 months before the start of the
    anticipated RSV season.1

    Dosing in children with CLD: The dose of palivizumab is 15 mg/kg once monthly given
    IM during the RSV season.1

    Initial approval/extended approval: approve a maximum of 5 months (5 doses) during the
    RSV season (lasting November through March in most areas).1-2,4
        [Example: If the child meets criteria in November, approve for 5 months (5 doses); if
        patient meets criteria in December, approve for 4 months (4 doses) etc.]
        [Note: RSV season in some areas of the US commences earlier than November, such as
        in Florida, where the onset may be as early as July. The RSV season is of the same
        duration (5 months) for Florida therefore, if a patient is eligible in July, approve 5
        monthly doses, if a patient is eligible in August, approve 4 monthly doses etc].

    Duration of therapy in children with CLD: as above under initial approval/extended
    approval. Children with the most severe CLD who continue to require medical therapy may
    benefit from prophylaxis during a second RSV season.1-2 These patients must still meet the
    criteria above if they are treated during a second RSV season.

    Labs/Diagnostics required: Chest x-ray confirms diagnosis of CLD.

    Waste management: The dose is 15 mg/kg with the dose being adjusted each month as the
    child’s weight changes.

    Exclusions: Infants/children with CLD. See more below.
        Children with asthma or reactive airway disease.




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    2. Prevention of RSV infection in a child with congenital heart disease (CHD):
    Indicated for the prevention of RSV in children with CHD who meet all of the following
    criteria.

   Child is ≤ 24 months of age,1 and

   A cardiologist or intensivist has evaluated the child and considers the CHD (acyanotic or
    cyanotic) hemodynamically significant.

    Dosing in children with CHD: The dose of palivizumab is 15 mg/kg once monthly given
    IM during the RSV season.3

    Initial approval/extended approval: approve a maximum of 5 months (5 doses) during the
    RSV season (lasting November through March in most areas).1-2,4 Exceptions can be made
    for children who undergo surgical procedures that use cardiopulmonary bypass and who
    continue to need prophylactic palivizumab.1-2 They should receive a postoperative dose of
    pavilizumab as soon as they are medically stable, even if this is sooner than when the next
    monthly dose is due. This could be an additional dose to allow coverage during the RSV
    season.
        [Example: If the child meets criteria in November, approve for 5 months (5 doses); if
        patient meets criteria in December, approve for 4 months (4 doses) etc.]
        [Note: RSV season in some areas of the US commences earlier than November, such as
        in Florida, where the onset may be as early as July. The RSV season is of the same
        duration (5 months) for Florida therefore, if a patient is eligible in July, approve 5
        monthly doses, if a patient is eligible in August, approve 4 monthly doses etc].

    Duration of therapy in children with CHD: as above under initial approval/extended
    approval.

    Labs/Diagnostics required: none.

    Waste management: The dose is 15 mg/kg with the dose being adjusted each month as the
    child’s weight changes.

    Exclusions: Infants/children with CHD. See more below.
        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
           arterious).1
        Infants with lesions adequately corrected by surgery, unless they continue to require
           medication for congestive heart failure.1
        Infants with mild cardiomyopathy who are not receiving medical therapy for the
           condition.1

    3. Prevention of RSV infection in children born prematurely: Indicated for the
    prevention of RSV in children born prematurely who meet all of the following criteria.

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   If the child is ≤ 12 months of age at the start of the RSV season and was born at 28 weeks, 6
    days gestation or earlier1
    OR
   If the child is < 6 months of age at the start of the RSV season and was born at between 29
    weeks, 0 days gestation and < 32 weeks (≤ 31 weeks, 6 days) gestation1
    OR
   If the infant is < 3 months of age at the start of the RSV season or was born during the RSV
    season AND was born between 32 weeks, 0 days gestation and < 35 days (≤ 34 weeks, 6
    days) gestation AND has one of the following risk factors:1
          Is attending 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
          Child lives permanently in a household with a child such as a sibling or another child
             who is < 5 years of age.

    Dosing in children born prematurely: The dose of palivizumab is 15 mg/kg once monthly
    given IM during the RSV season.3

    Initial approval/extended approval:
         Child ≤ 12 months of age and was born at 28 weeks 6 days gestation or earlier:
            approve a maximum of 5 months (5 doses).1 See Table 1 for number of doses. These
            children continue throughout the RSV season and do not stop if they reach 12 months
            of age.1
    Table 1. Chronological age: ≤ 12 months at Start of Season and Gestational age ≤ 28 weeks 6 days.1
      Birth Month                                      Maximum number of doses (months) for areas
                                                           beginning prophylaxis on November 1
      November 1 to March 31 of previous RSV                                    5a
      season
      April, May, June, July, August, September,                                5
      October, or November
      December                                                                  4
      January                                                                   3
      February                                                                  2
      March                                                                     1
    If infant is discharged from the hospital during RSV season, fewer doses may be required.
    a
      Some of these infants may have received 1 or more doses of palivizumab in the previous RSV season
    if discharged from the hospital during that season; if so, they still qualify for up to 5 doses during
    their second RSV season.


         Child < 6 months of age and was born at between 29 weeks 0 days gestation and
          < 32 weeks (≤ 31 weeks 6 days) gestation: approve a maximum of 5 months (5
          doses).1 See Table 2 for number of doses. These children continue throughout the
          RSV season and do not stop if they reach 6 months of age.1
    Table 2. Chronological age: < 6 months at Start of RSV Season and Gestational age: 29 weeks to
             < 32 weeks (≤31 weeks 6 days).1

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    Birth Month                                               Maximum number of doses (months) for
                                                            areas beginning prophylaxis on November 1
    November 1 to March 31 of previous RSV season                               0b
     April                                                                       0b
     May, June, July, August, September, October, or                              5
     November
     December                                                                     4
     January                                                                      3
     February                                                                     2
     March                                                                        1
   If infant is discharged from the hospital during RSV season, fewer doses may be required.
   b
     Zero doses because infant will be older than 6 months of age at start of RSV season.


        Child < 3 months of age at the start of the RSV season or who was born during
         the RSV season and who were born between 32 weeks 0 days gestation and < 35
         days (≤ 34 weeks 6 days) gestation: a maximum of 3 months (3 doses) during the
         RSV season (lasting November through March in most areas).1 See Table 3 for
         number of doses. These infants only receive prophylaxis until they reach 3 months of
         age.
   Table 3. Chronological age: < 3 months of age and Gestational age: 32 weeks to < 35 weeks
                gestation (≤ 34 weeks 6 days), AND has one of the two risk factors.1,c
     Birth Month                                                Maximum number of doses (months) for
                                                              areas beginning prophylaxis on November 1
     November 1 to March 31 of previous RSV season                                   0d
     April, May, June, or July                                                       0d
     August                                                                          1e
     September                                                                       2e
     October, November, December or January                                          3e
     February                                                                        2e
     March                                                                           1e
   If infant is discharged from the hospital during RSV season, fewer doses may be required.
   c
     Risk factors: infant attends child care or has sibling younger than 5 years of age.
   d
     Zero doses because infant will be older than 90 days of age at start of RSV season.
   e
     On the basis of the age of patients at the time of discharge from the hospital, fewer doses may be
   required, because these infants will receive 1 dose every 30 days until the infant is 90 days of age.

   Duration of therapy in children born prematurely:                        as above under initial
   approval/extended approval.

   Labs/Diagnostics required: none.

   Waste management: The dose is 15 mg/kg with the dose being adjusted each month as the
   child’s weight changes.

   Exclusions: See below.


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    4. Prevention of RSV infection in a child who has congenital abnormalities of the
    airways or a neuromuscular disease: Indicated for the prevention of RSV in children with
    congenital abnormalities of the airways or a neuromuscular disease who meet all of the
    following criteria.

   Child was born < 35 weeks (≤ 34 weeks, 6 days) gestation1 and

   Child is ≤ 12 months of age1 and

   According to the prescribing physician, the patient’s congenital abnormality compromises
    handling of respiratory secretions and the patient is predisposed to respiratory complications
    and.

   The patient does not have CLD or CHD.1


    Dosing in child with congenital abnormalities of the airways or a neuromuscular
    disease: The dose of palivizumab is 15 mg/kg once monthly given IM during the RSV
    season.3

    Initial approval/extended approval: approve a maximum of 5 months (5 doses) during the
    RSV season (lasting November through March in most areas).1
        [Example: If the child meets criteria in November, approve for 5 months (5 doses); if
        patient meets criteria in December, approve for 4 months (4 doses) etc.]
        [Note: RSV season in some areas of the US commences earlier than November, such as
        in Florida, where the onset may be as early as July. The RSV season is of the same
        duration (5 months) for Florida therefore, if a patient is eligible in July, approve 5
        monthly doses, if a patient is eligible in August, approve 4 monthly doses etc].

    Duration of therapy in children with congenital abnormalities of the airways or a
    neuromuscular disease: as above under initial approval/extended approval.

    Labs/Diagnostics required: none.

    Waste management: The dose is 15 mg/kg with the dose being adjusted each month as the
    child’s weight changes.

    Exclusions: see below.


    5. Prevention of RSV infection in an immunocompromised child. Indicated for the
    prevention of RSV infection in immunocompromised infants or children who meet all of the
    following criteria. [NOT FDA-APPROVED INDICATION]

   Prescribed by an immunologist or an infectious disease specialist or a pediatrician and

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   Child has a severe immunodeficiency (e.g., severe combined immunodeficiency, advanced
    acquired immune deficiency disease (AIDS)) as determined by the prescribing physician that
    puts the child at significant risk of RSV infection and

   Child is ≤ 24 months of age.


    Dosing in severely immunocompromised children: The dose of palivizumab is 15 mg/kg
    once monthly given IM during the RSV season.

    Initial approval/extended approval: approve a maximum of 5 months (5 doses) during the
    RSV season (lasting November through March in most areas).
        [Example: If the child meets criteria in November, approve for 5 months (5 doses); if
        patient meets criteria in December, approve for 4 months (4 doses) etc.]
        [Note: RSV season in some areas of the US commences earlier than November, such as
        in Florida, where the onset may be as early as July. The RSV season is of the same
        duration (5 months) for Florida therefore, if a patient is eligible in July, approve 5
        monthly doses, if a patient is eligible in August, approve 4 monthly doses etc].

    Duration of therapy in severely immunocompromised children: as above under initial
    approval/extended approval. These children who continue to require medical therapy may
    benefit from prophylaxis during a second RSV season. These patients must still meet the
    criteria above if they are treated during a second RSV season.

    Labs/Diagnostics required: none.

    Waste management: The dose is 15 mg/kg with the dose being adjusted each month as the
    child’s weight changes.

    Exclusions: See below.




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     Exclusions for all:
         Treatment of established RSV disease.1,3 However, if a child already on palivizumab
            experiences a breakthrough RSV infection, monthly prophylaxis should continue until
            the maximum number of doses allowed have been given.
         Previous severe reaction to palivizumab.3
         Cystic fibrosis in children. According to AAP recommendations, a recommendation
            for routine prophylaxis in these patients cannot be made.1 There is insufficient data
            to determine the effectiveness of palivizumab in these patients.5-8
         Patients with hematopoietic stem cell transplantation.9-10


REFERENCES
1.  Committee on Infectious Diseases. Policy Statement--Modified Recommendations for Use of Palivizumab for Prevention of
    Respiratory Syncytial Virus Infections. Pediatrics. 2009 Sep 7. [Epub ahead of print] Accessed 10/26/2009 at:
    http://pediatrics.aappublications.org/cgi/reprint/peds.2009-2345v1
2. American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds.
    Red Book:2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of
    Pediatrics. 2009(1):560.
3. Synagis injection [package insert]. Gaithersburg, MD: MedImmune LLC; March 2009.
4. Brief report: respiratory syncytial virus activity – United States, July 2007-December 2008. MMWR Morb Mortal Wkly
    Rep. 2008;57:1355-1358. Accessed 10/26/2009 at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5750a3.htm.
5. Malfroot A, Adam G, Ciofu O, et al. Immunization in the current management of cystic fibrosis patients. J Cyst Fibros.
    2005;4:77-87.
6. Speer ME, Fernandes CJ, Boron M, Groothuis JR. Use of palivizumab for prevention of hospitalization as a result of
    respiratory syncytial virus in infants with cystic fibrosis. Pediatr Infect Dis J. 2008;27(6):559-561. #14
7. Giebels K, Marcotte JE, Podoba J, et al. Prophylaxis against respiratory syncytial virus in young children with cystic
    fibrosis. Pediatr Pulmonology. 2008;43:169-174. #15
8. Giusti R. North American Synagis Prophylaxis survey. Pediatr Pulmonol. 2009;44:96-98.
9. Boeckh M, Berrey MM, Bowden RA, et al. Phase 1 evaluation of the respiratory syncytial virus-specific monoclonal
    antibody palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis. 2001;184:350-354.
10. Dykewicz CA. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients:
    focus on community respiratory virus infections. Biol Blood Marrow Transplant. 2001;7:19S-22S.
11. The Impact RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces
    hospitalization from respiratory syncytial virus infection in high risk infants. Pediatrics. 1998;102:531-537.
12. 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;143:532-540.

OTHER REFERENCES
1.   Romero JR. Palivizumab prophylaxis of respiratory syncytial virus disease from 1998 to 2002: results from four years of
     palivizumab usage. Pediatr Infect Dis J. 2003;22(Suppl 2):S46-54
2.   Heikkinen T, Valkonen H, Lehtonen L, et al. Hospital admission of high risk infants for respiratory syncytial virus
     infection: implications for palivizumab prophylaxis. Arch Dis Child Fetal Neonatal Ed. 2005;90:F64-68.
3.   Grimaldi M, Gouyon B, Michaut F, et al; for the Burgundy Perinatal Network. Severe respiratory synctial virus
     bronchiolitis: epidemiologic variations associated with the initiation of palivizumab in severely premature infants with
     bronchopulmonary dysplasia. Pediatr Infect Dis J. 2004;23:1081-1085.
4.   Meissner HC, Anderson LJ, Pickering LK. Annual variation in respiratory syncytial virus season and decisions regarding
     immunoprophylaxis with palivizumab. Pediatrics. 2004;114:1082-1084.
5.   Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J
     Med. 2009;360:588-598.




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ABBREVIATIONS
AAP = American Academy of Pediatrics
BPD = bronchopulmonary dysplasia, now called CLD
CHD = congenital heart disease
CLD = chronic lung disease of prematurity
FDA = Food and Drug Administration
IM = intramuscular
mL = milliliter
RSV = respiratory syncytial virus
< less than          ≤ less than or equal to


OVERVIEW

INDICATIONS AND USAGE: Palivizumab is indicated for the prevention of serious lower
respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high
risk of RSV disease.3 Safety and efficacy were established in infants with bronchopulmonary
dysplasia (BPD), infants with a history of premature birth (≤ 35 weeks gestational age), and
children with hemodynamically significant congenital heart disease (CHD).

The first pivotal trial for palivizumab was conducted during the 1996 to 1997 RSV season11 and
the second was during 4 consecutive RSV seasons, 1998 through 2002.12 Both studies used a
reduction in hospitalization due to RSV infection as the primary endpoint. In the first study,
monthly doses of palivizumab for 5 months was safe and effective for the prevention of serious
RSV infection in premature children (≤ 35 weeks gestation) and in those with CLD or
prematurity (formerly called BPD).11 In this study, hospitalizations for RSV were reduced when
compared to placebo, i.e., in children with prematurity but not with CLD had a 78% reduction in
RSV hospitalization (8.1% vs. 1.8%). Children with CLD had a 39% reduction (12.8% vs.
7.9%). Children on palivizumab had fewer total RSV hospital days, fewer RSV hospital days
with increased oxygen, fewer RSV hospital days with a moderate/severe lower respiratory tract
illness, and a lower incidence of intensive care unit admission. In the second study, children
with hemodynamically significant CHD received 5 monthly doses of palivizumab or placebo.12
Children on palivizumab had a 45% relative reduction in RSV hospitalizations, a 56% reduction
in total days of RSV hospitalization per 100 children, and a 73% reduction in total RSV hospital
days with increased supplemental oxygen per 100 children.

Children with CHD. The AAP 2009 RSV guidelines recommend prophylactic palivizumab in
children ≤ 24 months of age with cyanotic or acyanotic heart disease.1-2 The children most likely
to benefit are 1) infants receiving medication for congestive heart failure (CHF), 2) infants with
moderate to severe pulmonary hypertension, and 3) infants with cyanotic heart disease. The
following groups of infants are not at increased risk of RSV and generally should not receive
prophylaxis with palivizumab:
    1) 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;


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   2) infants with lesions adequately corrected by surgery, unless they continue to require
   medication for CHF; and
   3) infants with mild cardiomyopathy who are not receiving medical therapy for the condition.

Immunocompromised children.            According to AAP recommendations, specific
recommendations for immunocompromised children cannot be made, but infants and young
children with severe immunodeficiency (e.g., severe combined immunodeficiency or advanced
acquired immune deficiency disease (AIDS)) may benefit from prophylaxis.1




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