Patient
Information
Blue Cross Blue Shield Guidelines on the
use of Palivizumab (Synagis™)
http://www.bluecrossma.com/common/en_US/medical_policies/422%20RSV%20Immunoprophylaxis%20prn.pdf
Palivizumab (Synagis™) in accordance
with the American Academy of Pediatrics Guidelines.3,5,10 Injections
are given once a month during the RSV season.7 The 2003
American Academy of Pediatrics guidelines noted that the first
dose should be administered at the beginning of November and the
last dose should be administered at the beginning of March, which
provides protection into April.10
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FIRST COURSE OF TREATMENT
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•
Prematurity: We cover one course of treatment with
RSV-IVIg or palivizumab for infants and children who were born
prematurely, as follows:3,5
o
Infants born at 28 weeks of gestation or earlier may
benefit if they are less than 12 months of age at start of the RSV
season. 3,5,10
o
Infants born at 29-32 weeks gestation may benefit if
they are less than 6 months of age at the start of the RSV
season.3,5,10
•
Reduced lung reserve: We cover treatment with RSV-IVIg
or palivizumab for infants with reduced lung reserve if they are
less than 2 years of age at the start of the RSV season.10 For
example, this category could include infants with any of the
following circumstances:
o
Bronchopulmonary dysplasia (BPD)10
o
On a ventilator for greater than 5 days10
o
On oxygen therapy greater than 40% concentration for
more than 5 days10
o
Chest X-ray findings indicating lung disease when
they were in the neonatal intensive care unit.10
•
Neuromuscular diseases:10 We cover treatment with
RSV-IVIg or palivizumab for children with neuromuscular diseases
that affect respiratory mechanics if they are less than 2 years of
age at the start of the RSV season.10
•
Congenital heart defects:10 We cover treatment with
RSV-IVIg or palivizumab for infants with either acyanotic or
cyanotic congenital heart defects in the following circumstances
if they are less than 2 years of age at the start of the RSV
season:
o
Infants who have lability in oxygen saturation e.g.,
O2 saturation < 94% if stressed)10
o
Infants with hemodynamically significant heart
defects 10
o
Single ventricle pre or post palliation10
o
A palliated congenital cardiac defect such as those
with pulmonary artery bands or shunts10
o
Dilated or hypertrophic cardiomyopathy.10
SECOND COURSE OF TREATMENT
·
Infants born at 28 weeks of gestation or earlier may
benefit from RSV immunoprophylaxis for a second RSV season if they
are less than 12 months of age at the start of the RSV season.
·
Infants with reduced lung reserve may benefit
from RSV immunoprophylaxis for a second RSV season if they
continue to require medical therapy for respiratory or cardiac
dysfunction. 10
·
Infants with neuromuscular diseases affecting
respiratory mechanics may benefit from RSV immunoprophylaxis
for a second RSV season if they are less than 24 months of age at
the start of the RSV season.10
·
Infants with congenital heart defects may
benefit from RSV immunoprophylaxis for a second RSV season if they
are less than 24 months of age at the start of the RSV season as
noted above.10
1 FDA
labeling, based upon data submitted to the Food and Drug
Administration
2 Prophylactic
administration of RSV immune globulin to high-risk infants and
young children by Groothuis JR 1993 NEJM 329:1524-30. Infants and
young children (n=102, mean age 8 mo) with bronchopulmonary
dysplasia of prematurity (n=102), CHD (n=87), or prematurity alone
(n=60) were studied. High-dose was compared to low-dose and
controls. Of the 64 subsequent episodes of RSV infection, 19 were
in the high-dose group, 16 in the low-dose group, and 29 in the
control group. There were fewer lower tract respiratory infections
in the high-dose group (7) vs. control (20) p=0.01, fewer
hospitalizations (6 vs. 18) p=0.02), fewer ICU days (p=0.05), and
less use of ribavirin (p=0.05). Adverse events during 580
infusions were generally mild: fluid overload (n=5), )2
desaturation (n=8), and fever (n=6). Six children died, 5 of whom
had congenital heart disease: 3 in the high-dose group, three in
the low-dose group, and no control patients. No death was
attributed to use of immune globulin or to RSV. Authors concluded
that RSV Ig is safe and effective in this population.
Also
see the FDA’s response by Ellenberg SS, 1994 NEJM 331:203-4,
regarding the randomization and other procedures used in the above
trial, which might have introduced bias to results. The FDA also
addressed the deaths in the study. The authors reply that in a
subsequent open-label trial of high-dose RSV Ig (n=68 with
bronchopulmonary dysplasia), no deaths occurred to date of that
publications.
3 See
the American Academy of Pediatrics 1997 recommendations about RSV-IVIg
at their web site, http://www.aap.org. Comments include:
• Chronic
Lung Disease (CLD): RSV-IGIV should be considered for infants
and children < 2 years old with BPD who are currently or have
received oxygen therapy within 6 months prior to RSV season. Those
with BPD who have more severe underlying lung disease may benefit
from prophylaxis for two RSV seasons, while those with less severe
underlying lung disease may benefit only for the first season.
• Prematurity:
Infants born <= 32 weeks gestation without BPD or who do
not meet the above criteria may also benefit from RSV-IGIV
prophylaxis. In such infants, major risk factors to consider are
gestational age and chronologic age at start of the RSV season.
• Infants
born >= 28 weeks gestation may benefit from prophylaxis up to
12 months of age.
• Infants
born 29 - 32 weeks gestation may benefit from prophylaxis up to 6
months of age.
• Congenital
Heart Disease: RSV-IGIV is not FDA-approved for patients with
CHD. RSV-IGIV should not be used in patients with cyanotic CHD.
However, those with BPD and/or prematurity who meet criteria (in
first bullet above), who also have asymptomatic, acyanotic CHD
(such as patent ductus arteriosus or ventricular septal defect)
may benefit from prophylaxis.
• Immunocompromise:
RSV-IGIV use has not been evaluated in randomized trials in
immunocompromised pediatric patients. Children with severe
immunodeficiencies (such as severe combined immunodeficiency or
severe AIDS) may benefit from RSV-IGIV. If these infants and
children are receiving IGIV monthly, providers may consider
substituting RSV-IGIV during the RSV season.
• Nosocomial:
RSV transmission is known to occur in the hospital setting and to
cause serious disease in high-risk infants. The major means to
prevent nosocomial RSV disease is strict observance of infection
control practices, including rapid means to identify and cohort
RSV-infected infants. The necessity and efficacy of RSV-IGIV
prophylaxis in these situations has not been documented.
• Timing:
RSV-IGIV prophylaxis should be initiated before onset of RSV
season and terminated at the end of the RSV season. In most areas
of the US, RSV outbreaks begin October-December, and end in
March-May. However, regional differences occur: RSV onset occurs
earlier in southern states than in northern ones.
• Other
vaccines: Immunization with MMR and varicella vaccines should
be deferred until 9 months after the last dose. There is no data
on use of RSV-IGIV and Hep B vaccine response, but there is no
reason to expect interference. RSV-IGIV use should not alter the
primary immunization schedule for diphtheria and tetanus toxoids,
whole-cell or acellular pertussis, HiB, IPV or OPV. At this time,
available data does not support the need for supplemental doses of
routine vaccines.
• Education:
Parents and other care givers should be educated about reducing
exposure to and transmission of RSV. Preventive measures include
limiting exposure to cigarette smoke and contagious settings (such
as child care centers) and emphasis on hand washing in all
settings, especially during times of contact with others who have
respiratory infections.
4 See
the FDA labeling from Palivizumab (Synagis™), approved by the
FDA on June 19, 1998:
Pharmacology:
Palivizumab, is a humanized monoclonal antibody (IgG1k) produced
by recombinant DNA technology, directed to an epitope in the A
antigenic site of the F protein of respiratory syncytial virus
(RSV). Palivizumab is a composite of human (95%) and murine (5%)
antibody sequences. Palivizumab exhibits neutralizing and
fusion-inhibitory activity against RSV. These activities inhibit
RSV replication in laboratory experiments. Although resistant RSV
strains may be isolated in laboratory studies, a panel of 57
clinical RSV isolates were all neutralized by palivizumab.
Indications:
Respiratory syncytial virus (RSV): Prevention of serious lower
respiratory tract disease caused by RSV in pediatric patients at
high risk of RSV disease. Safety and efficacy were established in
infants with bronchopulmonary dysplasia (BPD) and infants with a
history of prematurity (<= 35 weeks gestational age).
Pregnancy:
Category C . Palivizumab is not indicated for adult usage. It is
not known whether palivizumab can cause fetal harm when
administered to a pregnant woman or could affect reproductive
capacity.
Precautions:
Palivizumab is for IM use only. As with any IM injection, give
with caution to patients with thrombocytopenia or any coagulation
disorder. The safety and efficacy of palivizumab have not been
demonstrated for treatment of established RSV disease.
Immunogenicity:
In a clinical trial, the incidence of anti-humanized antibody
following the fourth injection was 1.1% in the placebo group and
0.7% in the palivizumab group. In pediatric patients receiving
palivizumab for a second season, one of 56 patients had transient,
low titer reactivity. This reactivity was not associated with
adverse events or alteration in palivizumab serum concentrations.
Adverse
Reactions:
In
prophylaxis studies of pediatric patients with BPD or prematurity
involving 520 subjects receiving placebo and 1168 subjects
receiving palivizumab, the proportions of subjects in the placebo
and palivizumab groups who experienced any adverse event or any
serious adverse event were similar.
Administration
and Dosage: The recommended dose of palivizumab is 15 mg/kg. Patients,
including those who develop an RSV infection, should receive
monthly doses throughout the RSV season. Administer the first dose
prior to commencement of the RSV season. In the northern
hemisphere, the RSV season typically commences in November and
lasts through April, but it may begin earlier or persist later in
certain communities. The dose per month = [patient weight (kg) x
15 mg/kg ÷ 100 mg/ml of palivizumab]. Give injection volumes >
1 ml as a divided dose.
5 See
the American Academy of Pediatrics 1998 Guidelines for the use of
palivizumab for RSV prophylaxis at www.aap.org.
The FDA
approved this drug based upon a large, randomized study showing a
55% reduction in the risk of hospitalization due to RSV infections
in high-risk pediatric patients, including those with chronic lung
disease (CLD) (bronchopulmonary dysplasia), and infants with
prematurity.
RSV-IVIg
vs. Palivizumab: The AAP noted that palivizumab is preferred for most high-risk
children due to ease of administration (IM), lack of interference
with MMR and varicella vaccines, and lack of complications
associated with IV administration of human immune globulin
products. However, they noted that RSV-IGIV provides added
protection against other respiratory viral illnesses; hence it may
be preferable for selected high-risk children. Examples include
patients receiving replacement intravenous immune globulin due to
underlying immune deficiency or HIV infection. For those premature
infants who are about to be discharged from the hospital during
the RSV season, the AAP encouraged physicians to consider
administering RSV-IGIV for the first month of prophylaxis. . The
AAP noted that only limited cost-benefit data are available for
RSV-IGIV, and currently no peer-reviewed data are available for
palivizumab; they noted that for many infants qualifying for the
FDA-approved indications, risk of rehospitalization for serious
respiratory illness is low, and that the cost and logistics
associated with prophylaxis may outweigh potential benefits. For
children with cyanotic congenital heart disease, RSV-IGIV is
contraindicated, and palivizumab is not recommended.
Indications
and Recommendations:
The AAP
concluded that palivizumab is shown to provide benefit for infants
32-35 weeks of gestation at time of birth. It appears that adverse
events are similar between palivizumab and placebo, and that
discontinuation of injections due to adverse events related to
palivizumab was rare.
Chronic
Lung Disease (CLD): The AAP recommended consideration of RSV prophylaxis (either
palivizumab or RSV-IGIV) for infants and children younger than 2
years of age with CLD who have required medical therapy for their
CLD within 6 months before the anticipated RSV season. The
considered palivizumab preferable for most high-risk children
because of its ease of administration, safety, and effectiveness.
The AAP noted that those with more severe CLD may benefit from
prophylaxis for two RSV seasons, especially those who require
continued medical therapy. They concluded that there is limited
data on palivizumab’s efficacy during the second year of age;
those with less severe underlying disease may receive some benefit
for the second season, but immunoprophylaxis may not be necessary.
Prematurity:
Infants born at 32 weeks of gestation or earlier without CLD or
who do not otherwise meet the above criteria may also benefit from
RSV prophylaxis. The AAP defined major risk factors to consider:
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- 32 weeks of gestation may benefit most from
prophylaxis up to 6 months of age.
• For
patients born between 32 to 35 weeks gestation, the use of
palivizumab in this population should be reserved for those
infants with additional risk factors until more data is available.
The AAP
recommended that decisions regarding duration of prophylaxis be
individualized.
Congenital
Heart Disease: Palivizumab and RSV-IVIg are not licensed by the FDA for patients
with CHD. The AAP noted, however, that patients with CLD or who
are premature, and who meet the above recommendations and who also
have asymptomatic acyanotic CHD (such as patent ductus
arteriosus or ventricular septal defect) may benefit from
prophylaxis.
Immunocompromise:
Neither palivizumab nor RSV-IVIg prophylaxis has been evaluated in
a randomized trial in immunocompromised children; therefore
specific recommendations for immunocompromised patients cannot be
made. However, the AAP noted that children with severe
immunodeficiencies (such as SCID or severe acquired
immunodeficiency syndrome) may benefit from prophylaxis. If such
infants and children are already receiving standard immune
globulin IV each month, physicians may consider substituting RSV-IVIg
during the RSV season.
Timing:
The AAP noted that prophylaxis should be initiated at the onset of
the RSV season, and end at the end of the RSV season. In most
areas of the US, 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 infection occurs
earlier in southern states than in northern states. Practitioners
should contact their health departments and/or diagnostic virology
laboratories in their geographic areas to determine the optimal
time to begin administration.
Nosocomial:
The AAP concluded that in high-risk hospitalized infants, the
major means to prevent RSV disease is strict observance of
infection control. They noted that if an RSV outbreak is
documented in a high-risk unit (such as the PICU), primary
emphasis should be placed on proper infection control practices.
They noted that the need for and efficacy of prophylaxis in these
situations has not been evaluated.
Vaccines:
The AAP guidelines for modification of immunizations following
RSV-IGIV remain unchanged: they concluded that palivizumab does
not interfere with the response to vaccines.
6 Respiratory
syncytial virus immune globulin for prophylaxis against
respiratory syncytial virus disease in infants and children with
congenital heart disease, by EA Simoes et al and the Cardiac Study
Group, The Journal of Pediatrics v1998 vol. 133, no 4, pp492-9.
This placebo-controlled trial examined the use of RSV-IGIV in
children under age 4 with CHD. Overall, a (non-significant) 31%
reduction in hospitalization for RSV was noted in the treatment
arm (p=0.16); however, in infants younger than age 6 months at
entry, there was a 58% reduction (p=0.01). There was a
significantly higher frequency of unanticipated cyanotic episodes
and also of poor outcomes after surgery among children with
cyanotic CHD in the RSV-IVIG group (28% vs. 8.5%, p=0.009).
Authors concluded that RSV-IGIV should not be used for prophylaxis
of RSV disease in children with cyanotic CHD. RSV-IGIV did not
reduce RSV hospitalization in all children with CHD, but did
appear to prevent RSV hospitalizations in infants under age 6
months at study entry.
7 See
http://www.cdc.gov.mmwr.
8 The
AAP Policy Statement: “Factors other than chronic lung disease
influence the decision about use of prophylaxis, particularly in
children with a gestational age of 32-35 weeks, including other
underlying conditions that predispose to respiratory complications
(e.g., neurologic disease in very low birth weight infants),
number of young siblings, child care center attendance, exposure
to tobacco smoke in the home, anticipated cardiac surgery, and
distance to and availability of hospital care for severe
respiratory illness.” The AAP Policy Statement does not indicate
how many of these additional risk factors need to be present. In
some instances, presence of a single or multiple risk factors may
not be sufficient to warrant coverage of RSV immunoprophylaxis.
These determinations will be based on individual consideration.
9 Note
that asthma or reactive airway disease treated intermittently does
not meet the definition of chronic lung disease for purposes of
this medical policy.
10 The
American Academy of Pediatrics 2003 Guidelines for the use of
palivizumab for RSV prophylaxis. The AAP’s recommendations are
as follows:
• RSV
should be considered for infants and children younger than 2 years
of age with CLD (chronic lung disease) who have required
medical therapy (supplemental oxygen, bronchodilator, diuretic or
corticosteroid therapy) for CLD within 6 months before the
anticipated start of the RSV season.
• 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.
Individual
patient may benefit from decisions made in consultation with
neonatologists, pediatric intensivists, pulmonologists, or
infectious disease specialists. There are limited data regarding
the effectiveness of Synagis during the second year of life,
although children with CLD who require ongoing medical therapy may
experience severe RSV infections.
•
Infants born at 32 weeks of gestation or earlier may
benefit from RSV prophylaxis, even if they do not have CLD.
•
Infants born at 28 weeks of gestation or earlier may
benefit from prophylaxis during their first RSV season.
•
Infants born at 29 to 32 weeks of gestation may benefit
most from prophylaxis up to 6 months of age.
Once
a child qualifies for initiation of prophylaxis at the start of
RSV season, administration should continue throughout the season
and not stop at the point infant reaches either 6 months or 12
months of age.
•
Infants born between 32-35 weeks of gestation. 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.
Prophylaxis should be considered for infants between 32-35 weeks
of gestation only if 2 or more of the following risk factors are
present:
•
Child care attendance
•
School-aged siblings
•
Exposure to environmental air pollutants
•
Congenital abnormalities of the airways
•
Severe neuromuscular disease.
The AAP noted that exposure to tobacco 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 that palivizumab prophylaxis. High-risk infants should
never be exposed to tobacco smoke. High-risk infants should be
kept away from crowds and from situations in which exposure to
infected individuals cannot be controlled. Participation in
childcare should be restricted during the RSV season for high-risk
infants.
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 most likely are 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.
The 2003 AAP guidelines suggest that the following groups of
infants are not at increased risk from RSV and generally should
not receive prophylaxis:
•
Infants and children with hemodynamically insignificant heart
disease (eg secundum atrial septal defects, 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 congestive heart failure.
•
Infants with mild cardiomyopathy who are not receiving medical
therapy.
Immunocompromised children: Palivizumab or RSV IVIG has not been
evaluated in randomized trials. According to the 2003 AAP
guideline, although specific recommendations cannot be made,
children with severe immunodeficiencies (e.g., severe combined
immunodeficiency or severe acquired immunodeficiency syndrome) may
benefit from prophylaxis.
Cystic fibrosis: The 2003 AAP guidelines notes that there is
insufficient data to determine the effectiveness of palivizumab in
this patient population.
This document is designed for informational purposes only and is
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.
SYNAGIS is a registered trademark of MedImmune, Inc.
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