Embed Size (px)
Citation preview
CLI
NIC
AL
BRI
EFS
This publication is funded and written by MedImmune, LLC.
Volume 17, No. 6Supplement 5
June 2008
Supplement to
RSV Virology: Understanding RSV Seasonality and the Importance of Local Data
CLI
NIC
AL
BRI
EFS
RSV Virology: Understanding RSV Seasonality and the Importance of Local Data
This publication is funded and written by MedImmune, LLC.
Volume 5, No. 2Supplement 3
June 2008
Supplement to
data indicate that the onset and duration of the RSV sea-son vary greatly from year to year (Tables 1, 2), region toregion, and even among local communities (Mullins 2003,Panozzo 2007).
Although the American Academy of Pediatricsacknowledges that the inevitability of the RSV season ispredictable, other sources support that the severity of theseason, time of onset, peak of activity, and end of theRSV season cannot be predicted precisely. The AAP, how-ever, states, “There can be substantial variation in timingof community outbreaks of RSV disease from year to yearin the same community and between communities in thesame year, even in the same region. These variations, how-ever, occur within the overall pattern of RSV outbreaks,usually beginning in November or December, peaking inJanuary or February, and ending by the end of March orsometime in April”(AAP 2006). Furthermore, approxi-mately 17 percent of bronchiolitis admissions in children<1 year of age and 19 percent in children <5 years of ageare estimated to occur outside the peak RSV season ofNovember to April (Shay 1999).
Epidemiology of RSV and the importance of earlyplanning
Bronchiolitis due to respiratory syncytial virus (RSV)is a common and easily transmitted disease affectinginfants and young children, and is the leading cause ofhospitalization among infants <1 year of age in the UnitedStates (Leader 2003a, Leader 2002, McLaurin 2005). Upto 125,000 infants are hospitalized each year due to severeRSV disease, and approximately 20 percent of these arepremature infants (Boyce 2000, Horn 2003, Shay 1999).RSV is also responsible for up to 400 deaths annually inchildren <1 year of age (Shay 2001). Most children areinfected before 12 months of age, and by age 2, nearly allchildren become infected at least once (Glezen 1986).RSV, then, presents an enormous cost burden on theU. S. health care system (Leader2003a, Leader 2003b,McLaurin 2005).
RSV hospitalizations have been positively correlatedwith the level of RSV activity (Figure 1). RSV epidemicsin the United States generally occur between late fall andearly spring — November to April. However, surveillance
RSV Virology: Understanding RSV Seasonality and the Importance of Local Data
2
RSV prophylaxis should be tailored to local conditions to help ensure infant protection and avoid hospitalization.
FIGURE 1RSV hospitalizations correspond with RSV seasons
SOURCE: FERGIE J. PEDIATR INFECT DIS J. 2007. REPRINTED WITH PERMISSION.
160
140
120
100
80
60
40
20
0
Tota
l RSV
ho
spit
aliz
atio
ns
Month
July
200
2
Au
gu
st 2
002
Sep
tem
ber
200
2
Oct
ob
er 2
002
No
vem
ber
200
2
Dec
emb
er 2
002
Jan
uar
y 20
03
Feb
ruar
y 20
03
Mar
ch 2
003
Ap
ril 2
003
May
200
3
Jun
e 20
03
July
200
3
Au
gu
st 2
003
Sep
tem
ber
200
3
Oct
ob
er 2
003
No
vem
ber
200
3
Dec
emb
er 2
003
Jan
uar
y 20
04
Feb
ruar
y 20
04
Mar
ch 2
004
Ap
ril 2
004
May
200
4
Jun
e 20
04
July
200
4
Au
gu
st 2
004
Sep
tem
ber
200
4
Oct
ob
er 2
004
No
vem
ber
200
4
Dec
emb
er 2
004
Jan
uar
y 20
05
Feb
ruar
y 20
05
Mar
ch 2
005
Ap
ril 2
005
May
200
5
Jun
e 20
05
Posi
tive
RSV
test
s
Total RSV hospitalizationsPositive RSV tests
70%
60%
50%
40%
30%
20%
10%
0
Total RSV admissions at Driscoll Children’s Hospital in Corpus Christi, Texas, and percentage of RSV-positive tests overthe course of 3 consecutive RSV seasons (2002–2005). RSV positivity was determined by rapid antigen detection or viralculture. RSV, respiratory syncytial virus.
Onset and duration of the RSV season, therefore, arethe most important variables to consider in planning aneffective RSV therapy program (Mullins 2003).
Who conducts RSV surveillance?RSV surveillance data are collected from a broad range
of sources — from local hospitals and laboratories to thefederal government. The Centers for Disease Control andPrevention began collecting RSV surveillance data in1983. In 1989, CDC established the National Respiratoryand Enteric Virus Surveillance System (NREVSS) to coor-dinate the collection of virology data about RSV andother major viruses. NREVSS reports trends in RSV activ-ity at the level of individual states, nine geographic divi-sions, four geographic regions, and the nation as a wholeon CDC’s NREVSS Web site (CDC 2008).
CDC also publishes annual summaries of national andregional RSV activity in the Morbidity and MortalityWeekly Report (CDC 2007). Since 2006, CDC has brokenout RSV trends in Florida separately because of Florida’ssubstantial deviation from trends in the South region(CDC 2006).
Currently, 705 laboratories across the United States arecontributing RSV data to NREVSS as the result of a DataSharing Agreement between CDC and Surveillance Data,Inc. (SDI). Under this agreement, SDI shares RSV surveil-lance data obtained from its Sentinel Laboratory Net-
work, which consists of private or teaching hospitals (75percent) and children’s hospitals, public health laborato-ries, public hospitals, and reference laboratories (25 per-cent) throughout the country.
SDI also supports and administers, under the sponsor-ship of MedImmune, LLC, RSVAlert, a comprehensivesurveillance program that tracks the increase, peak, anddecline of RSV levels throughout the U. S. and providesaccurate RSV data (updated weekly) that characterizeRSV activity at the local as well as regional and nationallevels. These data include the number of tests and thepercentage that were positive during the previous 7 daysat the national level and within most metropolitan statis-tical areas (MSAs) throughout the country.
MSAs are defined by the U. S. Office of Managementand Budget and are based on census data. There are 363MSAs in the United States, and 8 MSAs are assigned toPuerto Rico. RSVAlert encompasses 95 percent of the 200largest MSAs (in terms of population) and 52 percent(189/363) of all U. S. MSAs and collects hospital datafrom participating hospital laboratories within each MSA.By providing data at the MSA level, RSVAlert comple-ments and expands CDC’s data reporting.
Two changes are important to highlight as a result of thecollaboration between SDI and CDC NREVSS: 1) CDCpreviously lacked data below the regional level, but nowreports at the state, division, and regional levels (CDC
3
TABLE 1Range of RSV season onset by region 2004 -2007
Seasons Northeast Midwest South West
2004–2005 22 Oct 2004 to 3 Dec 2004 to 3 Sept 2004 to 3 Sept 2004 to25 Feb 2005 4 Mar 2005 21 Jan 2005 17 Dec 2005
2005–2006 7 Oct 2005 to 4 Nov 2005 to 16 Sept 2005 to 16 Sept 2005 to3 Jan 2006 20 Jan 2006 13 Jan 2006 13 Jan 2006
2006–2007 12 Oct 2006 to 29 Sept 2006 to 4 Aug 2006 to 16 Oct 2006 to 19 Jan 2007 9 Mar 2007 16 Feb 2007 16 Feb 2007
SOURCE: DATA DERIVED FROM CDC MMWR 2005, 2006, 2007
TABLE 2Range of RSV season offset by region 2004 -2007
Seasons Northeast Midwest South West
2004–2005 4 Mar 2005 to 18 Mar 2005 to 31 Dec 2005 to 18 Feb 2005 to6 May 2005 6 May 2005 6 May 2005 6 May 2005
2005–2006 10 Mar 2006 to 17 Mar 2006 to 3 Feb 2006 to 31 Mar 2006 to5 May 2006 5 May 2006 5 May 2006 5 May 2006
2006–2007 2 Feb 2006 to 26 Jan 2007 to 16 Feb 2007 to 9 Mar 2007 to4 May 2007 4 May 2007 4 May 2007 4 May 2007
SOURCE: DATA DERIVED FROM CDC MMWR 2005, 2006, 2007
Please see important safety and full prescribing information on pages 7 and 8.
2008); and 2) the expansion of participating laboratoriesto more than 700 has significantly increased the dataavailable for reporting and analysis of RSV epidemiology.Noting that RSV activity can vary among local commu-nities as well as regions, CDC recommends that physiciansconsult their local laboratories for the latest data (CDC2008).
Defining the RSV seasonNREVSS defines the national and regional RSV season
onset as the first of 2 consecutive weeks during which themedian percentage of specimens testing positive for RSVantigen is >10 percent; RSV season offset is defined as thelast of 2 consecutive weeks during which the median per-centage of positive specimens is >10 percent (CDC 2007).
The limited variation in national RSV epidemiologydata disguises greater variation in regional trends (Tables1, 2), which in turn disguises variation in local trends(Figure 2). At the national level, analysis of CDC data forJuly 1990 through June 2000 shows moderate variationfrom year to year (Mullins 2003). In Florida, however, RSVvariations differ so much from trends in the rest of theSouth region that CDC reports that state separately (CDC2006).
Florida resembles other tropical locales in the northernhemisphere (CDC 2006), with RSV circulation occurringvirtually year round and with regional variations. In a 54-month (1999 through 2003 RSV seasons) statewide studyby Bauman (2007), there were only 4 months duringwhich the percentage of positive laboratory tests failed toreach the 10 percent epidemic threshold (May twice andJune twice). In southeast Florida, this trend was con-firmed by another study (Light 2007) using 48-monthdata (January 2003 through December 2006) from three
emergency departments. Throughout calendar years 2003and 2006, the percentage of positive RSV tests was ≥10percent, and during all 48 months studied, it was <10percent in only 6 months.
South Texas also differs substantially from the rest of theSouth region — only one RSV season among 11 (1996through 2006 RSV seasons) matched the duration of sea-sons for the CDC South region. All others were longer (upto 36 weeks), with a median of 21 weeks (5 weeks longerthan CDC South) — 2 seasons started on week 48, 8began earlier than week 47, and all 11 began earlier thanthe national median (Fergie 2007, Mullins 2003).
Contrasting national and regional findings, a samplingof local data taken from 18 laboratories nationwideshowed greater variation (Figure 3). Notably, in 21 percentof the 177 regional RSV seasons studied (1990 through
TABLE 3RSV activity during the September – October“shoulder months” over 3 RSV seasons
Metropolitan statistical area laboratories (MSAs) participating in the RSVAlert surveillance program duringSeptember and October demonstrated significant RSVactivity prior to the traditional season start in November.
Number of MSAs reporting >10% RSV activity for any 2 consecutive weeks during September andOctober 2004–2007
2004–2005 2005–2006 2006–2007
16 19 30
SOURCE: MEDIMMUNE DATA ON FILE
FIGURE 2U.S. regional RSV trends, July 2000 through July 2006
SOURCE: PANOZZO CA. PEDIATR INFECT DIS J. 2007. REPRINTED WITH PERMISSION.
7/1/
2000
8/26
/200
0
10/2
1/20
00
12/1
6/20
00
2/10
/200
1
4/7/
2001
6/2/
2001
7/28
/200
1
9/22
/200
1
11/1
7/20
01
1/12
/200
2
3/9/
2002
5/4/
2002
6/29
/200
2
8/24
/200
2
10/1
9/20
02
12/1
4/20
02
2/8/
2003
4/5/
2003
5/31
/200
3
7/26
/200
3
9/20
/200
3
11/1
5/20
03
1/10
/200
4
3/6/
2004
5/1/
2004
6/26
/200
4
8/21
/200
4
10/1
6/20
04
12/1
1/20
04
2/5/
2005
4/2/
2005
5/28
/200
5
7/23
/200
5
9/17
/200
5
11/1
2/20
05
1/7/
2006
3/4/
2006
4/29
/200
6
6/24
/200
6
50
40
30
20
10
0
Posi
tive
RSV
test
s (%
)
South North West Midwest
4
1999 RSV seasons), local onset occurred 5or more weeks earlier than the regionalmedian onset weeks (Mullins 2003).
In addition, RSVAlert data collected since2004 show that significant RSV activityoccurs during the so-called “shouldermonths,” the 2 months before or after anRSV season — September/October andApril/May (Tables 3, 4).
RSV is a local eventStudies of RSV seasonality show substan-
tial variations in the timing and duration ofRSV outbreaks across the United States(Fergie 2007, Peret 1998, Peret 2000,Panozzo 2007). More important, surveil-lance data show that RSV virology is local— not only does the RSV season vary tem-porally and geographically, it also variesamong communities in any one locale(Mullins 2003, Peret 1998, Peret 2000).
The data strongly support that ManagedCare Organizations should use at least 3years of historical data to define the onsetand duration of the RSV season in theirrespective geographic areas as a basis for
FIGURE 3Frequency distribution of local vs. regional median values for RSV seasonality
5 33
16
7 6
38
30
17
11
11
9
22
32
29
5
9
20
38
18
TABLE 4States with RSV activity during the September – October“shoulder months” over 4 RSV seasons
2004–2005 2005–2006 2006–2007 2007–2008
AlabamaArizona Arizona Arizona
Delaware DelawareFlorida Florida Florida FloridaGeorgia Georgia Georgia GeorgiaHawaii Hawaii Hawaii
KentuckyMaryland
Mississippi MississippiNebraska
New Jersey New JerseyNevada Nevada
Rhode IslandSouth Carolina
TexasVirginia VirginiaWest Virginia
SOURCE: MEDIMMUNE DATA ON FILE
The columns show the percentages of local measurements of RSV seasonality (onset, peak, duration) that vary by agiven number of weeks from the regional median RSV season values. The dark and light orange segments at the top of each column show the percentage of local measurements that are 5 or fewer weeks later/longer than the regionalmedian. The dark and light red segments at the bottom of each column show the percentage of local measurementsthat are 5 or more weeks earlier/shorter than the regional median. SOURCE: ADAPTED FROM MULLINS JA. PEDIATR INFECT DIS J. 2003
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0
9 or more5–8 more1–4 moreNo change1–4 fewer5–8 fewer9 or fewer
Onset week (%) Peak week (%) Duration weeks (%)
Variance in local values from regional medians (in weeks)
5
ReferencesAAP (American Academy of Pediatrics). Respiratory syncytial virus.
In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Redbook: 2006 report of the committee on infectious diseases.27th ed. Elk Grove Village:American Academy of Pediatrics;2006:560–566.
Bauman J, Eggleston M, Oquist N, Malinoski F. Respiratory syncytialvirus: seasonal data for regions of Florida and implications forpalivizumab. South Med J. 2007;100(7):669–676.
Boyce TG, Mellen BG, Mitchel EF, et al. Rates of hospitalization forrespiratory syncytial virus infection among children inMedicaid. J Pediatr. 2000;137(6):865–870.
CDC (Centers for Disease Control and Prevention). Brief report:respiratory syncytial virus activity–United States, 2004-2005.MMWR Morb Mortal Wkly Rep. 2005;54(49):1259–1260.«www.cdc.gov/mmwr/preview/mmwrhtml/mm5449a3.htm».Accessed May 15, 2008.
CDC (Centers for Disease Control and Prevention). Brief report:respiratory syncytial virus activity–United States, 2005-2006.MMWR Morb Mortal Wkly Rep. 2006;55(47):1277–1279.«www.cdc.gov/mmwr/preview/mmwrhtml/mm5547a5.htm».Accessed May 15, 2008.
CDC (Centers for Disease Control and Prevention). Brief report:respiratory syncytial virus activity–United States, July 2006-November 2007. MMWR Morb Mortal Wkly Rep.2007;56(48):1263–1265.«www.cdc.gov/mmwr/preview/mmwrhtml/mm5648a3.htm».Accessed May 15, 2008.
CDC (Centers for Disease Control and Prevention). National Respi-ratory and Enteric Virus Surveillance System (NREVSS).«www.cdc.gov/surveillance/nrevss/rsv-data.htm». Accessed May15, 2008.
Fergie J, Purcell K. Respiratory syncytial virus laboratory surveillanceand hospitalization trends in South Texas. Pediatr Infect Dis J.2007;26(11):S51–S54.
RSV coverage policies. Local virology data can also beused to further refine those policies to achieve maximumvalue and protection of infants and children covered bythe policies.
Clinicians, too, should use local data, in addition to his-torical RSV seasonal data, to ascertain RSV activity intheir respective communities so that appropriateimmunoprophylaxis can begin before the epidemic levelof >10 percent is reached. In this way, clinicians can helpprevent severe RSV disease and better manage theirpatients to avoid unnecessary and costly hospitalization.
SummarySubstantial variations in RSV seasonality across the
United States make it a challenge to predict the onset andduration of an RSV season from year to year and fromlocality to locality. Delaying immunoprophylaxis untilRSV is widespread in a community places infants andchildren at risk of severe RSV disease.
Local trends are more precise indicators of RSV out-breaks. SDI and CDC, through their Data Sharing Agree-ment, along with the RSVAlert surveillance program, pro-vide local RSV virology data that can be used to augmenthistorical data. These data can be used to guide RSVimmunoprophylaxis prevention and management pro-grams to avoid unnecessary and costly hospitalizations.
Local RSV Virology Data Is Key To A Successful Immunoprophylaxis ProgramA managed care analysis by Barry S. Lachman, MD, MPHMedical Director, Parkland Community Health Plan, Dallas, Texas
Successful intervention byMCOs and clinicians for theprevention and manage-
ment of RSV diseasedepends on a number offactors. UnderstandingRSV epidemiology both inthe population served andin the community are keyfactors in developing apopulation-basedapproach to immunopro-phylaxis. Understandinghow local data are collected is keyin successfully using that data todevelop an RSV managementstrategy. Results of RSV detectiontechniques will vary, depending onthe population that is sampled.
The best systems use ambulatorysamples that include office-basedcommunity sites. Using only hospi-
talized patients or emer-gency room samples willelevate the results, skewingthe length of the seasonand both the beginningand end points.
Several strategies can beused to determine thebeginning and end pointsto an RSV season. Waiting
to reach a threshold to begin theseason can be a costly mistake,since the rise of incidence is oftenrapid after the threshold. Further,compiling, disseminating, and tak-ing action on results takes valuable
time. A more productive strategywould be to set an onset pointbased on historic data and to beprepared to move it back if thethreshold is reached early. Endpoints can be more flexible if localdata are quickly and readily avail-able. The end point can be moreeasily extended or even con-tracted, based on local data.
Development of a limitedadministration network that stillprovides access will facilitate theprocess of responding quickly tothe surveillance data. The need forlocal response poses challenges forMCOs that are more centralized insetting guidelines.
Barry S. Lachman,MD, MPH
6
Important Safety InformationSynagis® (palivizumab) is indicated for the prevention of
serious lower respiratory tract disease caused by respira-tory syncytial virus (RSV) in pediatric patients at high risk ofRSV disease and is administered by intramuscular injection.Safety and efficacy were established in infants with bron-chopulmonary dysplasia (BPD), infants with a history ofpremature birth (≤35 weeks gestational age), and childrenwith hemodynamically significant congenital heart disease(CHD). Synagis has been used in more than one million chil-dren in the U.S. since its introduction in 1998. The first doseof Synagis should be administered prior to commence-ment of the RSV season. Patients, including those whodevelop an RSV infection, should continue to receivemonthly doses throughout the season.
Very rare cases (<1 per 100,000 patients) of anaphylaxisand rare (<1 per 1,000 patients) hypersensitivity reactionshave been reported with Synagis. Cases of anaphylaxiswere reported following re-exposure to Synagis and raresevere hypersensitivity reactions occurred on initial expo-sure or re-exposure. If a severe hypersensitivity reactionoccurs, therapy with Synagis should be permanently dis-continued. If milder hypersensitivity reaction occurs, cau-tion should be used on re-administration of Synagis. Inpost-marketing reports, very rare cases (<1 case per100,000 patients) of severe thrombocytopenia (plateletcount <50,000/microliter) have been reported.
In clinical trials, the most common adverse events occur-ring at least 1% more frequently in Synagis-treated patientsthan controls were upper respiratory infection, otitis media,fever, and rhinitis. Cyanosis and arrhythmia were seen inchildren with CHD. There have also been post-marketingreports of injection site reactions.
Please see Full Prescribing Information on page 8.
Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infectionand reinfection with respiratory syncytial virus. Am J Dis Child.1986;140:543–546.
Horn SD, Smout RJ. Effect of prematurity on respiratory syncytialvirus hospital resource use and outcomes. J Pediatr.2003;143(5):S133–S141.
Leader S, Kohlhase K. Recent trends in severe respiratory syncytialvirus (RSV) among US infants, 1997 to 2000. J Pediatr.2003a;143(5):S127–S132.
Leader S, Yang H, DeVincenzo J, et al. Time and out-of-pocket costsassociated with respiratory synctial virus hospitalization ofinfants. Value in Health. 2003b;6(2):100–106.
Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatrichospitalizations, 1997 to 1999. Pediatr Infect Dis J.2002;21:629–632 .
Light M. Respiratory syncytial virus seasonality in southeast Florida:Results from three area hospitals caring for children. PediatrInfect Dis J. 2007;26(11):S55–S59.
McLaurin KK, Leader S. Growing impact of RSV hospitalizationsamong infants in the US, 1997-2002. Abstract 936. Presented at:Pediatric Academic Societies Annual Meeting, May 14-17, 2005;Washington, D.C.
MedImmune, LLC, Gaithersburg, Md. Data on File. 2008.Mullins JA, Lamonte AC, Bresee JS, Anderson LJ. Substantial variabil-
ity in community respiratory syncytial virus season timing.Pediatr Infect Dis J. 2003;22(10):857–862.
Panozzo CA, Fowlkes AL, Anderson LJ. Variation in timing ofrespiratory syncytial virus outbreaks: Lessons from nationalsurveillance. Pediatr Infect Dis J. 2007;26(11):S41–S45.
Peret TCT, Hall CB, Hammond GW, et al. Circulation patterns ofgroup A and B human respiratory syncytial virus genotypesin 5 communities in North America. J Infect Dis.2000;181:1891–1896.
Peret TCT, Hall CB, Schnabel KC, et al. Circulation patterns ofgenetically distinct group A and B strains of human respiratorysyncytial virus in a community. J Gen Virol. 1998;79:2221–2229.
Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associatedhospitalizations among U S children, 1980–1996. JAMA.1999;282(15):1440–1446.
Shay DK, Holman RC, Roosevelt GE, et al. Bronchiolitis-associatedmortality and estimates of respiratory syncytial virus-associateddeaths among US children, 1979–1997. J Infect Dis.2001;183:16–22.
7
SYNAGIS® (PALIVIZUMAB) Rx onlyfor Intramuscular Administration
DESCRIPTION: Synagis (palivizumab) is a humanized monoclonal antibody (IgG1κ ) produced by recombinant DNAtechnology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). Synagis isa composite of human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived fromthe constant domains of human IgG1 and the variable framework regions of the VH genes Cor (1) and Cess (2). Thehuman light chain sequence was derived from the constant domain of Cκ and the variable framework regions of the VLgene K104 with Jκ -4 (3). The murine sequences were derived from a murine monoclonal antibody, Mab 1129 (4), in aprocess that involved the grafting of the murine complementarity determining regions into the human antibody frame-works. Synagis is composed of two heavy chains and two light chains and has a molecular weight of approximately148,000 Daltons. Synagis is supplied as a sterile, preservative-free liquid solution at 100 mg/mL to be administered by intramuscularinjection (IM). Thimerosal or other mercury containing salts are not used in the production of Synagis. The solution hasa pH of 6.0 and should appear clear or slightly opalescent.Each 100 mg single-dose vial of Synagis liquid solution contains 100 mg of Synagis, 3.9 mg of histidine, 0.1 mg ofglycine, and 0.5 mg of chloride in a volume of 1 mL. Each 50 mg single-dose vial of Synagis liquid solution contains 50 mg of Synagis, 1.9 mg of histidine, 0.06 mg ofglycine, and 0.2 mg of chloride in a volume of 0.5 mL.
CLINICAL PHARMACOLOGY: Mechanism of Action: Synagis exhibits neutralizing and fusion-inhibitory activity against RSV.These activities inhibit RSV replication in laboratory experiments. Although resistant RSV strains may be isolated in labo-ratory studies, a panel of 57 clinical RSV isolates were all neutralized by Synagis (5). Synagis serum concentrations of ≥ 40 mcg/mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold(5). The in vivo neutralizing activity of the active ingredient in Synagis was assessed in a randomized, placebo-controlledstudy of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, Synagis significantlyreduced the quantity of RSV in the lower respiratory tract compared to control patients (6). Pharmacokinetics: In pediatric patients < 24 months of age without congenital heart disease (CHD), the mean half-lifeof Synagis was 20 days and monthly intramuscular doses of 15 mg/kg achieved mean ±SD 30 day trough serum drugconcentrations of 37± 21 mcg/mL after the first injection, 57 ± 41 mcg/mL after the second injection, 68 ± 51 mcg/mLafter the third injection and 72 ± 50 mcg/mL after the fourth injection (7). Trough concentrations following the first andfourth Synagis dose were similar in children with CHD and in non-cardiac patients. In pediatric patients given Synagisfor a second season, the mean ±SD serum concentrations following the first and fourth injections were 61 ± 17 mcg/mLand 86 ± 31mcg/mL, respectively.In 139 pediatric patients ≤ 24 months of age with hemodynamically significant CHD who received Synagis and underwentcardio-pulmonary bypass for open-heart surgery, the mean ± SD serum Synagis concentration was 98± 52 mcg/mL beforebypass and declined to 41± 33 mcg/mL after bypass, a reduction of 58% (see DOSAGE AND ADMINISTRATION). Theclinical significance of this reduction is unknown.Specific studies were not conducted to evaluate the effects of demographic parameters on Synagis systemic exposure.However, no effects of gender, age, body weight or race on Synagis serum trough concentrations were observed in aclinical study with 639 pediatric patients with CHD (≤24 months of age) receiving five monthly intramuscular injectionsof 15 mg/kg of Synagis. The pharmacokinetics and safety of Synagis liquid solution and Synagis lyophilized formulation administered IM at 15 mg/kg were studied in a cross-over trial of 153 pediatric patients ≤6 months of age with a history of prematurity. Theresults of this trial indicated that the trough serum concentrations of palivizumab were comparable between the liquidsolution and the lyophilized formulation, which was the formulation used in the clinical studies described below.
CLINICAL STUDIES: The safety and efficacy of Synagis were assessed in two randomized, double-blind, placebo-controlled trials of prophylaxis against RSV infection in pediatric patients at high risk of an RSV-related hospitalization.Trial 1 was conducted during a single RSV season and studied a total of 1,502 patients ≤ 24 months of age with bron-chopulmonary dysplasia (BPD) or infants with premature birth (≤ 35 weeks gestation) who were ≤ 6 months of age atstudy entry (7). Trial 2 was conducted over four consecutive seasons among a total of 1287 patients ≤ 24 months ofage with hemodynamically significant congenital heart disease. In both trials participants received 15 mg/kg Synagis oran equivalent volume of placebo IM monthly for five injections and were followed for 150 days from randomization. InTrial 1, 99% of all subjects completed the study and 93% completed all five injections. In Trial 2, 96% of all subjectscompleted the study and 92% completed all five injections. The incidence of RSV hospitalization is shown in Table 1.
Table 1: Incidence of RSV Hospitalization by Treatment Group
Difference Relative Trial Placebo Synagis Between Reduction p-ValueGroups
Trial 1Impact-RSV
N 500 1002
Hospitalization 53 (10.6%) 48 (4.8%) 5.8% 55% <0.001
Trial 2CHD
N 648 639
Hospitalization 63 (9.7%) 34 (5.3%) 4.4% 45% 0.003
In Trial 1, the reduction of RSV hospitalization was observed both in patients with BPD (34/266 [12.8%] placebo vs.39/496 [7.9%] Synagis), and in premature infants without BPD (19/234 [8.1%] placebo vs. 9/506 [1.8%] Synagis). InTrial 2, reductions were observed in acyanotic (36/305 [11.8%] placebo versus 15/300 [5.0%] Synagis) and cyanoticchildren (27/343 [7.9%] placebo versus 19/339 [5.6%] Synagis).The clinical studies do not suggest that RSV infection was less severe among RSV hospitalized patients who receivedSynagis compared to those who received placebo.
INDICATIONS AND USAGE: Synagis is indicated for the prevention of serious lower respiratory tract disease caused byrespiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. Safety and efficacy were establishedin infants with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (≤ 35 weeks gestationalage), and children with hemodynamically significant congenital heart disease (CHD) (see CLINICAL STUDIES).
CONTRAINDICATIONS: Synagis should not be used in pediatric patients with a history of a severe prior reaction toSynagis or other components of this product.
WARNINGS: Very rare cases of anaphylaxis (<1 case per 100,000 patients) have been reported following re-exposure toSynagis (see ADVERSE REACTIONS, Post-Marketing Experience). Severe acute hypersensitivity reactions, estimated tobe rare, (<1 case per 1,000 patients) have also been reported on initial exposure or re-exposure to Synagis (seeADVERSE REACTIONS, Post-Marketing Experience). If a severe hypersensitivity reaction occurs, therapy with Synagisshould be permanently discontinued. If milder hypersensitivity reactions occur, caution should be used on readministra-tion of Synagis. If anaphylaxis or severe allergic reactions occur, administer appropriate medications (e.g., epineph-rine) and provide supportive care as required.
PRECAUTIONS: General: Synagis is for intramuscular use only. As with any intramuscular injection, Synagis should begiven with caution to patients with thrombocytopenia or any coagulation disorder. The safety and efficacy of Synagis have not been demonstrated for treatment of established RSV disease. The single-dose vial of Synagis does not contain a preservative. Administration of Synagis should occur immediatelyafter dose withdrawal from the vial. The vial should not be re-entered. Discard any unused portion.Drug Interactions: No formal drug-drug interaction studies were conducted. In Trial 1, the proportions of patients in theplacebo and Synagis groups who received routine childhood vaccines, influenza vaccine, bronchodilators or cortico-steroids were similar and no incremental increase in adverse reactions was observed among patients receiving theseagents. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis, mutagenesis and reproductive toxicity studieshave not been performed. Pregnancy: Pregnancy Category C: Synagis is not indicated for adult usage and animal reproduction studies have notbeen conducted. It is also not known whether Synagis can cause fetal harm when administered to a pregnant woman orcould affect reproductive capacity.
ADVERSE REACTIONS: The most serious adverse reactions occurring with Synagis treatment are anaphylaxis and otheracute hypersensitivity reactions (see WARNINGS). The adverse reactions most commonly observed in Synagis-treatedpatients were upper respiratory tract infection, otitis media, fever, rhinitis, rash, diarrhea, cough, vomiting, gastroenteri-tis, and wheezing. Upper respiratory tract infection, otitis media, fever, and rhinitis occurred at a rate of 1% or greaterin the Synagis group compared to placebo (Table 2).Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trialsof a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observedin practice. The adverse reaction information does, however, provide a basis for identifying the adverse events thatappear to be related to drug use and a basis for approximating rates.The data described reflect Synagis exposure for 1641 pediatric patients of age 3 days to 24.1 months in Trials 1 and 2.Among these patients, 496 had bronchopulmonary dysplasia, 506 were premature birth infants less than 6 months ofage, and 639 had congenital heart disease. Adverse events observed in the 153 patient crossover study comparing theliquid and lyophilized formulations were similar between the two formulations, and similar to the adverse eventsobserved with Synagis in Trials 1 and 2.
Table 2 - Adverse Events Occurring at a Rate of 1% or Greater More Frequently in Patients† Receiving Synagis
Event Synagis (n=1641) Placebo (n=1148)n (%) n (%)
Upper respiratory infection 830 (50.6) 544 (47.4)Otitis media 597 (36.4) 397 (34.6)
Fever 446 (27.1) 289 (25.2)Rhinitis 439 (26.8) 282 (24.6)Hernia 68 (4.1) 30 (2.6)
SGOT Increase 49 (3.0) 20 (1.7)†Cyanosis (Synagis [9.1%]/placebo [6.9%]) and arrhythmia (Synagis [3.1%]/placebo [1.7%]) were reported duringTrial 2 in CHD patients.
ImmunogenicityIn Trial 1, the incidence of anti-Synagis antibody following the fourth injection was 1.1% in the placebo group and 0.7%in the Synagis group. In pediatric patients receiving Synagis for a second season, one of the fifty-six patients had tran-sient, low titer reactivity. This reactivity was not associated with adverse events or alteration in serum concentrations.Immunogenicity was not assessed in Trial 2. These data reflect the percentage of patients whose test results were considered positive for antibodies to Synagis in anELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidenceof antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medica-tions, and underlying disease. For these reasons, comparison of the incidence of antibodies to Synagis with the inci-dence of antibodies to other products may be misleading.With any monoclonal antibody, the possibility exists that a liquid solution may be more immunogenic than a lyophilizedformulation. The relative immunogenicity rates between the lyophilized formulation, used in Trials 1 and 2 above, andthe liquid solution have not yet been established.Post-Marketing Experience The following adverse reactions have been identified and reported during post-approval use of Synagis. Because thereports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably esti-mate the frequency of the reaction or establish a causal relationship to drug exposure.Injection site reactions have been reported.Rare severe acute hypersensitivity reactions (<1 case per 1,000 patients) have been reported on initial or subsequentexposure. Very rare cases of anaphylaxis (<1 case per 100,000 patients) have also been reported following re-exposure(See WARNINGS). None of the reported hypersensitivity reactions were fatal. Hypersensitivity reactions may includedyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia and unresponsiveness. The relation-ship between these reactions and the development of antibodies to Synagis is unknown. Very rare cases (<1 case per 100,000 patients) of severe thrombocytopenia (platelet count < 50,000/uL) have beenreported. Limited information from post-marketing reports suggests that, within a single RSV season, adverse events after a sixthor greater dose of Synagis are similar in character and frequency to those after the initial five doses.
OVERDOSAGE: No data from clinical studies are available on overdosage. No toxicity was observed in rabbits adminis-tered a single intramuscular or subcutaneous injection of Synagis at a dose of 50 mg/kg.
DOSAGE AND ADMINISTRATION: The recommended dose of Synagis is 15 mg/kg of body weight. Patients, including thosewho develop an RSV infection, should continue to receive monthly doses throughout the RSV season. The first dose shouldbe administered 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. Synagis serum levels are decreased after cardio-pulmonary bypass (see CLINICAL PHARMACOLOGY). Patients under-going cardio-pulmonary bypass should receive a dose of Synagis as soon as possible after the cardio-pulmonary bypassprocedure (even if sooner than a month from the previous dose). Thereafter, doses should be administered monthly.Synagis should be administered in a dose of 15 mg/kg intramuscularly using aseptic technique, preferably in the antero-lateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk ofdamage to the sciatic nerve. The dose per month = patient weight (kg) x 15 mg/kg ÷ 100 mg/mL of Synagis. Injectionvolumes over 1 mL should be given as a divided dose. Administration of Synagis • DO NOT DILUTE THE PRODUCT• DO NOT SHAKE OR VIGOROUSLY AGITATE THE VIAL• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administra-
tion. Do not use any vials exhibiting particulate matter or discoloration. • Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the Synagis vial, and
wipe the rubber stopper with a disinfectant (e.g., 70% isopropyl alcohol). Insert the needle into the vial, and with-draw into the syringe an appropriate volume of solution. Administer immediately after drawing the dose into thesyringe.
• Synagis is supplied as a single-dose vial and does not contain preservatives. Do not re-enter the vial after withdrawalof drug; discard unused portion. Only administer one dose per vial.
• To prevent the transmission of hepatitis viruses or other infectious agents from one person to another, sterile disposable syringes and needles should be used. DO NOT reuse syringes and needles.
HOW SUPPLIED: Synagis is supplied in single-dose vials as a preservative-free, sterile liquid solution at 100 mg/mL forIM injection. 50 mg vial NDC 60574-4114-1The 50 mg vial contains 50 mg Synagis in 0.5 mL. 100 mg vial NDC 60574-4113-1The 100 mg vial contains 100 mg Synagis in 1 mL.There is no latex in the rubber stopper used for sealing vials of Synagis. Upon receipt and until use, Synagis should be stored between 2°C and 8°C (35.6°F and 46.4°F) in its original container. DO NOT freeze. DO NOT use beyond theexpiration date.
REFERENCES: 1. Press E, and Hogg N. The Amino Acid Sequences of the Fd Fragments of Two Human Gamma-1 Heavy Chains.
Biochem. J. 1970; 117:641-660. 2. Takahashi N, Noma T, and Honjo T. Rearranged Immunoglobulin Heavy Chain Variable Region (VH) Pseudogene that
Deletes the Second Complementarity-Determining Region. Proc. Nat. Acad. Sci. USA 1984; 81:5194-5198. 3. Bentley D, and Rabbitts T. Human Immunoglobulin Variable Region Genes - DNA Sequences of Two Vκ Genes and a
Pseudogene. Nature 1980; 288:730-733. 4. Beeler JA, and Van Wyke Coelingh K. Neutralization Epitopes of the F Protein of Respiratory Syncytial Virus: Effect
of Mutation Upon Fusion Function. J. Virology 1989; 63:2941-2950. 5. Johnson S, Oliver C, Prince GA, et al. Development of a Humanized Monoclonal Antibody (MEDI-493) with Potent In
Vitro and In Vivo Activity Against Respiratory Syncytial Virus. J. Infect. Dis. 1997; 176:1215-1224. 6. Malley R, DeVincenzo J, Ramilo O, et al. Reduction of Respiratory Syncytial Virus (RSV) in Tracheal Aspirates in
Intubated Infants by Use of Humanized Monoclonal Antibody to RSV F Protein. J. Infect. Dis. 1998; 178:1555-1561.7. 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.
Synagis® is a registered trademark of MedImmune, Inc.
Manufactured by: MedImmune, Inc. Gaithersburg, MD 20878 U.S. Gov't. License No. 1252 (1-877-633-4411)
Date: October 2007 RAL-SYNV9SYN07-178
SYN08-106 06/08 © 2008 MedImmune, LLC
