h1n1 guidelines pharmaceutical mngt
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Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
Contents
CONTENTS ................................................................................................. ............................................................. 2SUMMARY............................................ .............................................................................................................. ..... 3
1. INTRODUCTION .......................................................................................... ...................................................... 4
2. CASE DESCRIPTION............................................................................................... .......................................... 5
3. RISK GROUPS.............................................................................. ....................................................................... 6
4. EPIDEMIOLOGY......................................................................................................................................... ....... 7
5. GENERAL CONSIDERATIONS ...................................................................................................... ................ 8
6. RECOMMENDATIONS............................................................................................................... .................... 10
6.1UseofantiviralsfortreatmentofpandemicinfluenzaA(H1N1)2009virusinfectioninadultsand
adolescents.................................................................................................................................................................. 106.2UseofantiviralsfortreatmentofuncomplicatedpandemicinfluenzaA(H1N1)2009virusinfectionin
adultsandadolescents.............................................................................................................................................. 146.3UseofantiviralsfortreatmentofpandemicinfluenzaA(H1N1)2009virusinfectioninchildren................. 156.4Useofantiviralswhereantiviralresistanceisknownorsuspected...................................................................... 176.5Antiviraltreatmentrecommendations: Otherinfluenzavirusstrains.................................................................. 186.6UseofantiviralsforchemoprophylaxisofpandemicinfluenzaA(H1N1)2009virusinfection...................... 196.7Otherconsiderations...................................................................................................................................................... 20
7. OTHER INTERVENTIONS FOR MANAGEMENT OF PATIENTS WITH INFLUENZA................. 20
8. PRODUCT SUPPLY......................................................................................................... ................................. 24
9. PRIORITIES FOR UPDATE .......................................................................................... ................................. 25
Plansforupdatingthisguideline....................................................................................................................................... 25
Updatingor
adapting
recommendations
locally ............................................................................................................ 25
10. PRIORITIES FOR RESEARCH ........................................................................................ ........................... 26
ANNEX 1: RISK FACTORS FOR SEVERE DISEASE................................................................................... 27
ANNEX 2: LIST OF PARTICIPANTS ........................................................................................... ................... 28
ANNEX 3: DECLARATIONS OF INTERESTS............................................................................................... 30
ANNEX 4: TABLE OF STANDARD DOSAGES ................................................................................ ............. 32
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Part I: Recommendations
3
Summary
Thisguidance
updates
and
replaces
the
recommendations
published
in
August
2009.
This
documentwillagainbereviewedinSeptember2010and,ifnecessary,updated.
Keychangestotheguidelinesare:
Simplification of recommendations as pandemic influenza A(H1N1) 2009 virus has
becomethepredominantinfluenzavirusworldwide.
Specificguidanceforthetreatmentofyoungchildrenfrombirth,includingguidance
ondoseandformulation(Recommendations0608).
Additional guidance for treatment or chemoprophylaxis of patients with severe
immunosuppression(Recommendations03and04).
Considerationofawiderrangeof investigational,regional1oradjunctivetreatments
(Recommendations14
and
15).
Specificcontraindicationsforsomemedicines(Recommendations1618).
Thetablebelowsummarizesthetreatmentrecommendationsthataredescribedinfullinthe
subsequentsections:
Use of antivirals for treatment of influenza
Population PandemicinfluenzaA(H1N1)2009andother
seasonalinfluenzavirusesInfluenzavirusesknownorsuspectedtobeoseltamivir
resistantUncomplicatedclinicalpresentationPatientsinhigherrisk
groups
Treatwithoseltamiviror
zanamivirassoonaspossible
(05)
Treatwithzanamivirassoonas
possible(05)
SevereorprogressiveclinicalpresentationAllpatients(including
childrenandadolescents)
Treatwithoseltamiviras
soonaspossible(01)
(zanamivirshouldbeusedif
oseltamivirunavailable)(02)
Treatwithzanamivirassoonas
possible(03)
Patientswithsevere
immunosuppression
Treatwithoseltamiviras
soonaspossible. Consider
higherdosesandlonger
durationoftreatment(03)
Treatwithzanamivirassoonas
possible(03)
1Regionalproductsarethosethathavemarketauthorisations inonlyoneorafewcountries.
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1. Introduction
Thepurposeofthisdocumentistoprovideabasisforadvicetocliniciansontheuseofthe
currently available antivirals for patients presenting with illness due to influenza virusinfection,aswelltheiruseforchemoprophylaxis.Thisdocumentaddressesthemostwidely
availableandlicensedantiviralmedicines,thetwoneuraminidaseinhibitorsoseltamivirand
zanamivir, and the two M2 inhibitors amantadine and rimantadine. It also includes
recommendationsontheuseofsomeotherpotentialpharmacologicaltreatments,including
other investigational neuraminidase inhibitors, other agents such as arbidol, ribavirin,
intranasal interferons, immunoglobulins, and corticosteroids. While the focus of the
documentisonmanagementofpatientswithpandemic(H1N1)2009virusinfection,italso
includesguidanceontheuseofantiviralsforseasonalinfluenzaAandBvirusstrains,and
forinfectionsduetonovelinfluenzaAvirusstrains.
WHO recommends that national and regional authorities periodically issue local guidance
that place these recommendations in the context of local epidemiological and antiviral
susceptibilitydataonthecirculatinginfluenzavirusstrains. Suchlocalguidancewouldalso
takeintoaccountlocalhealthprioritiesandresources.
ThisguidanceupdatesandreplacestherecommendationspublishedinAugust2009.These
recommendations are based on a review of available data obtained on treatment of
previouslycirculatinginfluenzavirusstrainsandtreatmentofhumaninfectionwithhighly
pathogenic avian influenza A (H5N1) virus,aswell as more recent observational data and
experience intheclinicalmanagementofpandemic(H1N1)2009influenza.It isanticipated
that
as
the
prevalence
and
severity
of
the
current
epidemic
changes,
further
information
will
becomeavailablethatmaywarrantrevisionoftherecommendations.
Thisrevisedguidanceispublishedintwoparts.PartIcontainstreatmentrecommendations.
Part II documents the procedures followed in developing this guidance, together with a
reviewofevidenceandothernewinformationonthepharmacologicalagentsconsidered.
TheseguidelinesshouldbereadinconjunctionwiththeWorldHealthOrganizations(WHO)
revised guidance for clinical management of human infection with pandemic influenza
A(H1N1)2009virus,publishedinNovember2009.2
The
WHO
rapid
advice
guidelines
on
pharmacological
management
of
humans
infected
with highly pathogenic avian influenza A(H5N1) virus3remain unchangedby these new
guidelines.
2Clinicalmanagementofhumaninfectionwithpandemic(H1N1)2009:revisedguidance.WorldHealth
Organization, November2009.Availableat:
http://www.who.int/csr/resources/publications/swineflu/clinical_management/en/index.html.Lastaccessedon10
February2010.3WHORapidAdviceGuidelinesonpharmacologicalmanagementofhumansinfectedwithavianinfluenzaA
(H5N1)virus.WorldHealthOrganization,May2006.Availableat:
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2. Case description
Human infection with influenza virus can vary from asymptomatic infection to
uncomplicated upper respiratory tract disease to serious complicated illness that mayincludeexacerbationofotherunderlyingconditionsandsevereviralpneumoniawithmulti
organfailure.Sinceawiderangeofpathogenscancauseinfluenzalikeillness(ILI),aclinical
diagnosis of influenza shouldbe guidedby clinical and epidemiologic data and canbe
confirmedby laboratory tests. However, on an individual patientbasis, initial treatment
decisionsshouldbebasedonclinicalpresentationandepidemiologicaldataandshouldnot
bedelayedpendinglaboratoryconfirmation.Indevelopingtheseguidelines,theGuidelines
Panel(thePanel)consideredthreebroadscenarios,setoutbelow.
Uncomplicated influenza
Influenza
like
illness
(ILI)
symptoms
include:
fever,
cough,
sore
throat,
nasal
congestionorrhinorrhea,headache,musclepain,andmalaise,butnotshortnessof
breathandnotdyspnoea.Patientsmaypresentwithsomeorallofthesesymptoms.
Gastrointestinalillnessmayalsobepresent,suchasdiarrhoeaand/orvomiting,
especiallyinchildren,butwithoutevidenceofdehydration.
Somepatientswithuncomplicatedillnessmayexperienceatypicalsymptomsand
maynothavefever(e.g.elderlyorimmunosuppressedpatients).
Complicated or severe influenza
Presentingclinical(e.g.shortnessofbreath/dyspnoea,tachypnoea,hypoxia)and/or
radiologicalsignsoflowerrespiratorytractdisease(e.g.pneumonia),centralnervoussystem(CNS)involvement(e.g.encephalopathy,encephalitis),severedehydration,or
presentingsecondarycomplications,suchasrenalfailure,multiorganfailure,and
septicshock.Othercomplicationscanincluderhabdomyolysisandmyocarditis.
Exacerbationofunderlyingchronicdisease,includingasthma,chronicobstructive
pulmonarydisease(COPD),chronichepaticorrenalinsufficiency,diabetes,orother
cardiovascularconditions(e.g.congestivecardiacfailure).
Anyotherconditionorclinicalpresentationrequiringhospitaladmissionforclinicalmanagement(includingbacterialpneumoniawithinfluenza).
Anyofthesignsandsymptomsofprogressivediseaselistedbelow.
Signs and symptoms of progressive disease
Patientswhopresentinitiallywithuncomplicatedinfluenzamayprogresstomoresevere
disease.Progressioncanberapid(i.e.within24hours).Thefollowingaresomeofthe
indicatorsofprogression,whichwouldnecessitateanurgentreviewofpatientmanagement:
http://www.who.int/csr/disease/avian_influenza/guidelines/pharmamanagement/en/index.htmlLastaccessedon
10February2010.
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Symptomsandsignssuggestingoxygenimpairmentorcardiopulmonary
insufficiency:
o Shortnessofbreath(withactivityoratrest),difficultyinbreathing,
tachypnoea,presenceofcyanosis,bloodyorcolouredsputum,chestpain,and
lowbloodpressure;
o Inchildren,
fast
or
laboured
breathing;
and
o Hypoxia,asindicatedbypulseoximetryorarterialbloodgases.
SymptomsandsignssuggestingCNScomplications:
o Alteredmentalstatus,unconsciousness,drowsiness,ordifficulttoawaken
andrecurringorpersistentconvulsions(seizures),confusion,severeweakness,
orparalysis.
Evidenceofsustainedvirusreplicationorinvasivesecondarybacterialinfectionbased
onlaboratorytestingorclinicalsigns(e.g.persistentorrecurrenthighfeverandother
symptomsbeyond3dayswithoutsignsofresolution).
Severedehydration,manifestedasdecreasedactivity,dizziness,decreasedurineoutput,andlethargy.
3. Risk groups
Certainpatientswithseasonalinfluenzavirusinfectionorpandemicinfluenza(H1N1)2009
virus infection are recognized tobe at higher risk of developing severe or complicatedillness.TheGuidelinesPaneldidnotreview theevidencefor thedefinitionofthesehigher
risk groups, but adopted, as the basis for treatment decisions in the context of these
guidelines,the
description
developed
through
the
WHO
Consultation
on
Clinical
Aspects
of
Pandemic(H1N1)2009Influenza4aslistedinPartI,Annex1.
However,animportantconsiderationinthemanagementofinfluenzavirusinfectionsisthat
influenza virus infection in any patient can result in severe or complicated illness. This is
particularlytrueforpandemic(H1N1)2009virusinfection,inwhichabout1/3ofseverelyill
patientsadmitted to intensivecareunitswerepreviously healthypersonsnotbelonging to
anyknownhigherriskgroup.
4Clinicalmanagementofhumaninfectionwithpandemic(H1N1)2009:revisedguidance.WorldHealth
Organization, November2009.Availableat:
http://www.who.int/csr/resources/publications/swineflu/clinical_management/en/index.html.Lastaccessedon10
February2010.
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4. Epidemiology
Currently, WHO publishes weekly information from global influenza surveillance 5 . As of
December 2009, the mostprevalent circulating influenza
virus was pandemic (H1N1)
2009. The following figure
shows the breakdown of
results of laboratory testing of
7380 influenza viral isolates
from 27 countries (mostly in
theNorthernHemisphere):
For the purpose of
developmentoftheserevisedguidelines, it is anticipated
that the prevalent influenza viruses in the coming year are most likely tobe pandemic
(H1N1)2009,H3N2andinfluenzaBvirusstrains,asisreflectedinthevaccinecomposition
recommendationsfortheSouthernHemisphere2010season.6
Theimpactofpandemic(H1N1)2009virusinfectionhasbeenhighestinthepaediatricand
youngeradultpopulations,whenmeasuredbyattackratesandhospitalizationrates.
InfluenzaA(H5N1)virus(avianinfluenza)continuestocausesporadichumaninfectionsin
some countries, with 72 cases (32 deaths) reported in 2009 in 5 countries.7 Thus, although
pandemic influenza A (H1N1) 2009 virus may displace other circulating influenza A virusstrains,novelinfluenzaAviruses,suchasH5N1,remainapandemicthreat.
5Situationupdates Pandemic(H1N1)2009.WorldHealthOrganization.Availableat:
http://www.who.int/csr/disease/swineflu/updates/en/index.html.Lastaccessedon10February2010.6Pandemicinfluenzaa(H1N1)2009virusvaccineconclusionsandrecommendations fromtheOctober2009
meetingoftheimmunizationStrategicAdvisoryGroupofExperts.WorldHealthOrganization,WeeklyEpidemiologicalRecord,4December2009,8449:505509.Availableat:http://www.who.int/wer/2009/wer8449.pdf .Lastaccessedon10February2010.7CumulativeNumberofConfirmedHumanCasesofAvianInfluenzaA/(H5N1)ReportedtoWHO.World
HealthOrganization,30December2009.Availableat:
http://www.who.int/csr/disease/avian_influenza/country/cases_table_2009_12_30/en/index.html.Lastaccessedon
10February2010.
Characterization of circu lating in fluenza viruses Dec 2009
Pandemic
A(H1N1)
Seasonal A(H1N1)
A(H3N2)
B
A (not typed)
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5. General Considerations
TheGuidelinesPanelidentifiedthefollowingtreatmentoutcomesascriticalfordeveloping
recommendations:
mortality;
hospitalization;
complications;
seriousadverseevents(drugrelated);and
antiviraldrugresistance.
There are no adequate data from headtohead randomized, controlled trials directly
comparingtheefficacyofoneantiviralmedicineagainstanotherfortreatmentofinfluenza.
Alltreatmentrecommendationsarebasedontrialsthatcompareactiveantiviraltreatmentto
placebo among patients with seasonal influenza and, therefore, comparisons betweentreatmentsareindirect.
All the recommendations herein are strongly influencedby patterns of antiviral resistance.
Resistance prevalence in circulating influenza strains is collated and reportedby WHO.8
Therefore, these recommendations may need tobe modified in light of current or local
knowledgeoftheantiviralsusceptibilityofcirculatingviruses.
AsofJanuary2010,theantiviralsusceptibilitiesofcirculatingvirusesare:
Oseltamivir Zanamivir M2inhibitorsbPandemic(H1N1)2009 Susceptiblea Susceptible ResistantSeasonalA(H1N1)c Mostlyresistant Susceptible MostlysusceptibleSeasonalA(H3N2) Susceptible Susceptible ResistantInfluenzaB Susceptible Susceptible Resistanta.Seetextbelow
b.Amantadineandrimantadine
c. Seasonal A (H1N1) refers to the human influenza A (H1N1) viruses that were circulating prior to the
introductionofpandemicinfluenzaA(H1N1)2009virusandwhichcontinuedtocirculateduring2009.
ThePanelrecommendsthatanantiviralshouldnotbeusedfortreatmentwherethevirusis
known or highly likely tobe resistant to that antiviral. Since the current epidemiological
data
indicate
an
exceptionally
low
level
of
prevalence
of
seasonal
H1N1
influenza
viruses,
amantadine and rimantadine are not currently recommended for use in the treatment of
illnessfromcirculatinginfluenzavirusstrains,exceptwhenseasonalH1N1virusinfectionis
proven or strongly suspected, since all other circulating human influenza virus strains are
resistanttotheseantivirals.
8InfluenzaAvirusresistancetooseltamivirandotherantiviralmedicines.WorldHealthOrganization,4June
2009.Availableat:http://www.who.int/csr/disease/influenza/20089nhemisummaryreport/en/index.html .Last
accessedon10February2010.
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Infections with oseltamivirresistant pandemic (H1N1) 2009 virus havebeen documented,
comprisingbothsporadiccasesandalimitednumberofclusters. Whilelimitedtransmission
of these viruses among contacts hasbeen observed, there is no evidence of their wider
communitylevelorongoingcirculation.WHOsassessmentandconclusionsonoseltamivir
resistant pandemic (H1N1) 2009 viruses, as set out in the WeeklyEpidemiologicalRecord9,10include:
All oseltamivirresistant isolates have the same H275Y mutation that confers
resistancetooseltamivir,butnotzanamivir.
Noevidenceofreassortmentbetweenpandemic influenzaA(H1N1)2009andother
seasonalinfluenzaAviruses.
Noassociationwithanalteredorunexpectedseverityofdisease,although fatalities
haveoccurredinsomeseverelyillpatients.
Thelargestproportionofcasesofoseltamivirresistantpandemic(H1N1)2009virusinfection
hasoccurredinseverelyimmunocompromisedpatients.Transplantpatients(andespecially
bone marrow or haemopoetic stem cell transplant recipients) on immunosuppressive
chemotherapyhaveemergedasaparticularlyvulnerablepatientgroup.Anumberofcases
havealsobeenassociatedwithfailureofpostexposureoseltamivirchemoprophylaxis.
Chemoprophylaxis is not generally recommended for the established circulating human
influenzaviruses, includingpandemic(H1N1)2009,as theopportunitycostandutilization
ofantiviraldrugsthatmaybeneededfortreatmentisnotwarranted.Withtheavailabilityof
vaccinesforbothseasonalinfluenzaandpandemicH1N12009influenza,thereshouldnow
be lessrelianceonantiviralchemoprophylaxisforpreventionof illness inclosecommunity
settings and in groups such as healthcare workers. The association of post exposure
chemoprophylaxis failures (described above) with oseltamivir resistance is an additional
consideration in reducing chemoprophylactic use of antiviral medicines. Different
considerationshoweverapplytotheavian(H5N1)andotherzoonoticinfluenzaviruses11.
9Oseltamivirresistantpandemic(H1N1)2009influenzavirus,October2009.WorldHealthOrganization,WeeklyEpidemiologicalRecord,30October2009,8444:453458.Availableat:http://www.who.int/wer/2009/wer8444/en/index.html .Lastaccessedon10February2010.10UpdateonoseltamivirresistantpandemicA(H1N1)2009influenzavirus,January2010.WorldHealth
Organization, WeeklyEpidemiologicalRecord,5February2010,8506:3739.Availableat:
http://www.who.int/wer/2010/wer8506.pdf .Lastaccessedon10February2010.11
WHORapidAdviceGuidelinesonpharmacologicalmanagementofhumansinfectedwithavianinfluenzaA
(H5N1)virus.WorldHealthOrganization,May2006.Availableat:
http://www.who.int/csr/disease/avian_influenza/guidelines/pharmamanagement/en/index.htmlLastaccessedon
10February2010.
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6. Recommendations
Formal recommendations are set outbelow as numbered, highlighted paragraphs (0120).
Most recommendations are accompanied by other treatment considerations, since therecommendationsmaynotcoverallsituations,and,inmostcases,arebasedonloworvery
lowqualityevidence.
For the purpose of these guidelines,reference to adults includes adolescents aged 13 to 18
years. Children are defined as persons up to and including the age of 12. Treatment
recommendations for children are generally the same as for adults (see Recommendations
0106),butwithspecialconsiderationsfordosinginyoungerchildren(seeRecommendation
08).
6.1 Use of antivirals for treatment of pandemic influenzaA (H1N1) 2009 virus infection in adults and adolescents
Context: Treatment of adults and adolescents with confirmed or strongly suspectedinfection with pandemic influenza A(H1N1) 2009 virus, where clinical
presentation is severeorprogressiveandantiviralmedications for influenzaare
available.Rec01: Patients who have severe or progressive clinical illness shouldbe treated with
oseltamivirassoonaspossible.(Strongrecommendation,lowqualityevidence.)
This recommendation applies to all patient groups, including pregnant and
postpartumwomenupto2weeksfollowingdelivery,andbreastfeedingwomen.
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
Timing. Treatment should be started as soon as possible. Laboratory
confirmation of influenza virus infection is not necessary for the initiation of
treatmentandanegativelaboratorytestforH1N1doesnotexcludethediagnosis
in all patients, therefore early, empiric treatment is strongly recommended. The
evidence from clinical trials in uncomplicated seasonal influenza suggests most
patientsbenefitfromantiviraltreatmentcommencingwithin48hoursofonsetofsymptoms,but experience from use in patients with H5N1 virus infection and
severe lower respiratory tract disease suggests that later initiation of treatment
mayalsobeeffective,wheneverviralreplicationispresentorstronglysuspected.
Doseandduration.Higherdosesofoseltamivirandlongerdurationoftreatmentmaybeappropriate,althoughthereisnoavailableclinicaltrialevidencetoinform
recommendations.Anadultdoseof150mgtwicedailyhasbeenadministeredto
some critically ill patients. When treating patients with renal impairment,
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consideration needs to be given to the likely higher systemic exposure to
oseltamivir(seeSection6.7below).
Wheretheclinicalcourseremainssevereorprogressive,despite5ormoredaysof
antiviral treatment, monitoring of virus replication and shedding, and antiviral
drugsusceptibilitytestingisdesirable. Antiviraltreatmentshouldbemaintained
without abreak until virus infection is resolved or there is satisfactory clinical
improvement.
Antiviralresistance. Zanamivir is the treatment of choice for all patients whereoseltamivir resistance is demonstrated or highly suspected. Intravenous
zanamivirmaybeconsideredwhereavailable.
Drugdelivery. Patientswhohavesevereorprogressiveclinical illness,butwhoareunabletotakeoralmedicationmaybetreatedwithoseltamiviradministered
bynasogastricororogastrictube(e.g.mechanicallyventilatedpatients).
R em a r k s :
Thisrecommendationtakesaccountof:
Thattheprescribing information(5daytreatmentcourse) isbasedonclinical
studies in outpatient settings, and with uncomplicated influenza virus
infection.
Evidence from case reports and case series of prolonged virus replication in
thelowerrespiratorytractofseverelyillpatients.
The concern about the increased risk of severe complications or death from
influenzainthiscontext.
The evidence from observational studies that demonstrates a reduction in
progression to severe disease and hospitalization in patients treated early
(within2daysofillnessonset)withantivirals.
The ease of use and suitability of oseltamivir compared to other currently
availableneuraminidaseinhibitors,i.e.oraladministrationversusinhaled.
Limited data from observational studies that indicate that oseltamivir
deliveredby nasogastric tube achieves adequate serum levels in critically ill
patients.
Theopportunitycostofprovidingantiviralstothesepatientsisconsideredlow.
Rec02: In situations where oseltamivir is not available, or not possible to use, patientswho have severe or progressive clinical illness shouldbe treated with inhaled
zanamivir,wherefeasible.(Strongrecommendation,verylowqualityevidence.)
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
Drugdelivery. Zanamivircontaining lactose(powderfor inhalation)shouldnotbeadministeredbynebulizer(seeRecommendation18).
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R em a r k s :
Thisrecommendationtakesaccountof:
Theneed toofferalternative treatment topatientswithsevereor progressive
illness intheabsenceofoseltamiviror if thevirus isknown toberesistantto
oseltamivir.
The practical difficulties in administering inhaled zanamivir to severely ill
patients in its current commercially available dosage form, and the need for
caution in use of inhaled zanamivir in patients with underlying respiratory
disease.
Intravenous zanamivir or peramivir may be considered if available (see
Recommendation17).
Context: Treatment of patients with confirmed or strongly suspected infection withpandemic influenza A(H1N1) 2009 virus, and who have severe
immunosuppressionexpected
to
delay
viral
clearance.
Severeorcomplicatedinfluenzavirusinfectionsattributableatleastinparttosevere
immunosuppression have been most frequently described in transplant patients
(including hematopoetic stem cell recipients,bone marrow transplant patients, and
othertransplantpatientsonimmunosuppressivechemotherapy). Otherpatientswith
severe immonosuppression include those with graft versus host disease, or with
haematologicalmalignancies.
OthercancerpatientsundergoingchemotherapyandpatientsinfectedwithHIV,who
havedevelopedsevereimmunodeficiency,mayalsoneedtobetreatedinaccordance
withthe
recommendations
below.
Rec03: Patients who have severe or progressive clinical illness shouldbe treated withoseltamivir as soon as possible. Consideration should be given to the use of
higher doses, such as 150 mg twice daily (for adults), and longer duration of
treatment depending on clinical response. (Strong recommendation, low quality
evidence.)
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
Prevention of infection in this patient group shouldbe a prime objective. This isconsidered further in the recommendations for chemoprophylaxis below(Recommendation04).
Duration. Regular monitoring of ongoing viral replication and antiviral drug
susceptibility is strongly recommended in this patient group. Antiviral treatment
shouldbe maintainedwithoutabreakuntilvirus infection isresolved (as indicated
byclinical improvement orsequentially negativeresults forvirus in the respiratory
tract).
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Antiviral resistance. Zanamivir is the treatment of choice for all patients whereoseltamivir resistance hasbeen demonstrated or is highly suspected (see pediatric
section;inhaledzanamivirisnotapprovedforuseinchildrenagedlessthan5years).
Alternative treatments. Intravenous zanamivir should be considered whereavailable and is recommended for those with serious or progressive illness. If not
available,
intravenous
peramivir
maybe
considered,
athough
oseltamivir
resistant
virusesarereportedtohavereducedsusceptibilityinvitrotoperamivir.R em a r k s :
Theserecommendationstakeaccountof:
The impaired host immune response, such that standard antiviral regimens
maynotbeaseffectiveinclearingvirus.
The higher probability of emergence of oseltamivirresistant virus in these
patients.
Rec04: Whenapersonwithinfluenzavirusinfectionispresentintheimmediatesetting,severely immunosuppressed patients may be offered chemoprophylaxis with
oseltamivirorzanamivir.(Strongrecommendation,verylowqualityevidence.)
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
Infectioncontrolproceduresshouldberigorouslyapplied inthiscontext,includingvaccinationagainstseasonalandpandemicinfluenza inallpersonswhohavedirect
contactwiththesepatients. Otherinfectioncontrolproceduresincludehandhygiene,
gloves, gowns and masks the use of which is described in full in WHO interim
guidance for infection prevention and control in health care for confirmed or
suspectedcasesofpandemic(H1N1)2009andinfluenzalikeillnesses12.
Antiviral resistance. Zanamivir maybe the preferred option for chemoprophylaxisfor those patients able to take inhalation medicine, due to the known risk of
developmentofoseltamivirresistanceinthispatientgroup.
Dose andduration. In severely immunosuppressed persons, there needs tobe ongoing weekly monitoring for evidence of prolonged viable viral replication, and
chemoprophylaxiscontinueduntil there isnoevidenceofongoingviralreplication
inanypatientinthesameroomorhealthcareunit.Whereexposuretoinfectionmay
haveoccurredandtheindividualmaybewithintheincubationperiod,consideration
shouldbegiventopresumptivetreatment(i.e.throughtheuseoftreatmentdoses).
R em a r k s :
12Infectionpreventionandcontrolinhealthcareforconfirmedorsuspectedcasesofpandemic(H1N1)2009and
influenzalikeillnesses.WorldHealthOrganization, December2009.Availableat:
http://www.who.int/csr/resources/publications/swineflu/swineinfinfcont/en/index.html. Lastaccessedon2
March2010
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Thisrecommendationtakesaccountof:
Theimportanceofpreventinginfectioninthisvulnerablepatientgroup.
6.2 Use of antivirals for treatment of uncomplicatedpandemic influenza A (H1N1) 2009 virus infection inadults and adolescents
Context: Treatmentofadultandadolescentpatientswithconfirmedorstronglysuspected,but uncomplicated illness, due to pandemic (H1N1) 2009 virus infection, and
whereantiviralmedicationsforinfluenzaareavailable.
The decision to treat patients in this context will depend on the availability of healthcare
resources (including antiviral medication), local priorities for health provision, and
assessmentof
the
risk
that
the
patient
will
develop
more
serious
disease.
While
some
groups
ofpatientsarerecognizedashavingahigherriskofdevelopingmoresevereorcomplicated
illness(seePartI,Annex1),allpatientsareatsomerisk.
The recommendation below, therefore, needs to be applied in the context of clinical
judgmentandlocalornationalguidance.
Rec05: Patientswhohaveuncomplicatedillnessduetoconfirmedorstronglysuspectedvirusinfectionandareinagroupknowntobeathigherriskofdevelopingsevere
orcomplicatedillness,shouldbetreatedwithoseltamivirorzanamivirassoonas
possible.(Strongrecommendation,lowqualityevidence.)
This recommendation applies to all patient groups, including pregnant and
postpartumwomen,upto2weeksfollowingdelivery,andbreastfeedingwomen.
Patientswhohaveuncomplicated illness,andarenotinagroupknowntobeat
higher risk of developing severe or complicated illness, may not need to be
treated with antivirals. A decision to treat will depend upon clinicaljudgment
andavailabilityofantivirals. Patientswhopresentformedicalattention,butdo
not receive antiviral treatment, shouldbe counseled on signs of progression or
deteriorationofillnessandadvisedtoseekmedicalattentionimmediately,should
theirconditiondeteriorateorpersist.
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
Antiviralresistance.Zanamivir,whereavailable,isthetreatmentofchoiceforallpatientswhereoseltamivirresistanceisdemonstratedorhighlysuspected.
R em a r k s :
Thisrecommendationtakesaccountof:
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The concern about the higher risk of severe complications or death from
influenzainthesepatientgroups.
The evidence from observational studies that demonstrates a reduction in
progression to severe disease and hospitalization in patients treated with
antivirals.
The importance of clinicaljudgment in deciding whether to initiate antiviraltreatmentforuncomplicated illness inpersonsnot inagroupknowntobeat
higherriskforinfluenzacomplications.
6.3 Use of antivirals for treatment of pandemic influenzaA (H1N1) 2009 virus infection in children
Context: Treatment of children with confirmed or strongly suspected infection withpandemic(H1N1)2009viruswhereclinicalpresentation issevereorprogressive
andantiviralmedicationsforinfluenzaareavailable.
Rec06: Children who have severe or progressive clinical illness shouldbe treated withoseltamivirassoonaspossible.(Strongrecommendation,lowqualityevidence.)
This recommendation applies to all children, including neonates and young children (in
particularthoselessthan2yearsofage).
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
There are generally fewer data available on the safety and efficacy of antiviral
medicines in very young children (especially frombirth to 1 year). In particular,
there are insufficient efficacy or safety data to support guidelines on the use of
intravenouszanamivirorperamivirinchildren.
The validity of recently recommended oseltamivir doses in children has been
independently evaluated for WHO (AbdelRahman and Kearns, Part II, Annex 7).
This evaluation wasbased on an assessment of the available literature, including
knowledge of the drugs disposition and knowledge of pathological and
physiologicalcharacteristicsofthetargetpopulation. Onthebasisofthisevaluation,
the Guidelines Panel made the following recommendations with regard to
oseltamivirdosesforyoungchildren:
Rec07: Oseltamivirtreatmentdosesforchildrenfrom14daysupto1yearofageshouldbe 3 mg/kg/dose, twice daily. For children
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Timingof treatment. Evidence indicates that the greatestbenefit is derived fromearly oseltamivir treatment. Therefore, suitable preparationsofoseltamivir need to
beavailableatthepointofcare.
Drug delivery. Where capsules containing the appropriate oseltamivir dose areavailablebutcannotbeswallowed,thecontentscanbeaddedtoasweetliquidorsoft
food immediately before administration to disguise bitter taste. Where different
dosesarerequired,thefollowingmethodsmaybeused:
Powder for oseltamivir oral suspension, where available, is the preferredformulation for children unable to take the capsules, when capsules of appropriate
strengtharenotavailableorwhere thesmallercapsuleof 30mg isgreater than the
calculated dose. Where this is not available, an oseltamivir suspension or solution
canbeproducedbyextemporaneouspreparationfromthecontentsofcapsules,orby
preparationfrombulkpowder(alsoreferredtoasActivePharmaceuticalIngredient,
orAPI).WHOrecommendsthatlocalguidancebedevelopedthattakesintoaccount
local availability of oseltamivir capsules or API, local facilities, and availability of
suitablesuspendingagentsordiluents.
The following points need to be considered in the development of such local
guidance(seealsoPartII,Annex8,reportbyANunn):
Extemporaneouspreparationofoseltamivirtreatmentcourse. Preparationofafulloseltamivir treatmentcourse isbestdonewherecommercially availablesuspending
agents,containingantimicrobialpreservatives,areavailable. Furtherinformationon
availablesuspendingagents,andproposedshelflifeforsuspensions, isprovided in
PartIIAnnex8(reportbyANunn).
Consideration also needs to be given to availability or provision of suitable
measuring devices for individual dose measurement and administration, as well as
provisionofclearinformationforthecaregiver.
Manipulation of oseltamivir capsules to prepare a solution for immediate use.Where suitable suspending agents or diluents containing preservative are not
available and stability and sterility cannot, therefore,be assured, capsules canbe
opened and mixed with a measured volume of water immediately before
administration. Any smaller dosevolume required canbecalculated andmeasured
foradministration.
Localguidanceshouldtake intoaccounttheavailabilityofmaterialsandmeasuring
devices. User instructions for choice of substrate, dilution, calculation, and
measurementofdoseshouldbeprovided.
Somewastageofdrugmaterialisinevitableunderthesecircumstances.
Magistralpreparations fromAPI. Preparation ofastable solution from oseltamivirphosphatepowder(theAPI)hasbeenusedduringthe2009/10outbreakintheUnited
Kingdom.FurtherinformationisprovidedinPartII,Annex8(reportbyANunn).
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R em a r k s :
Thisrecommendationtakesaccountof:
Theneedforaclearandsimpledoseschedule.
The lack of clinical evidence for dosing in this age group and the lack of
suitable,commerciallyavailablepaediatricformulationsofoseltamivir.
Context: Treatmentofchildrenwithconfirmedorstronglysuspected,butuncomplicated,illness due to pandemic (H1N1) 2009 virus infection and where antiviral
medicationsforinfluenzaareavailable.Rec08: Childrenwhohaveuncomplicatedillnessduetoconfirmedorstronglysuspected
influenza virus infection and are in a group known to be at higher risk ofdeveloping severe or complicated illness shouldbe treated with oseltamivir or
zanamivir
as
soon
as
possible.
(Strong
recommendation,
low
quality
evidence).
Recommendation08appliestoallinfantsandyoungchildren(inparticularthose
lessthan2yearsofage),sincetheyareknowntobeathigherriskofdeveloping
severeorcomplicatedillness.
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
Zanamivir (as inhaled powder) isonly indicated for use in personsaged5years or
above.
OseltamivirdosingshouldbeasdescribedinRecommendation07above.
Otherremarks
and
notes
are
as
given
for
Recommendation
05
above.
In
particular,
carers
of
childrenwhodonotreceiveantiviraltreatmentshould becounseledonsignsofprogression
or deterioration of illness and advised to seek medical attention immediately, should the
conditiondeteriorateorpersist.
6.4 Use of antivirals where antiviral resistance is knownor suspected
The Guidelines Panel recommends that, in general, an antiviral medication should notbe
usedwherethevirusisknownorhighlylikelytoberesistanttothatantiviral.Thisisbased
onthe
principle
that
the
drug
is
expected
to
be
ineffective
and,
therefore,
the
potential
cost
or
adverseeventswouldnotbejustified.However,theevidencefor lackofclinicalefficacy in
thesesettingsisoflowquality.
Continueduse ofan antiviraldrug (towhich resistance isknownorsuspected), theuseof
combination treatments, or alternative doses may be appropriate in the context of
prospectiveclinicalandvirologicaldatacollectionaspartofanapprovedresearchprotocol.
Ofcurrentconcern is themutation(H275Y) in theneuraminidase thatconfersresistance to
oseltamivir,but not to zanamivir, since this hadbecome prevalent in the seasonal H1N1
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influenzavirus,andsporadiccaseshavebeenreportedinpandemic(H1N1)2009virus. The
followingrecommendationaddressesthisparticularcontext:
Rec09: Patients who have severe or progressive clinical illness with virus resistant tooseltamivirbutknownorlikelytobesusceptibletozanamivir,shouldbetreated
withzanamivir. (Strongrecommendation,verylowqualityevidence.)
O t h e r T r e a t m e n t Co n s i d e r a t i o n s :
Intravenous zanamivir is likely tobe the preferred formulation in this setting,
(whereavailableandsubjecttotheprovisionsofRecommendation15).
Where intravenous zanamivir is not available, intravenous peramivir maybe
considered (subject to Recommendation 15), although oseltamivirresistant
virusesarereportedtohavereducedsusceptibilityinvitrotoperamivir.The panel noted an urgent need for alternative dosage form and products with
datato
support
their
use
in
this
population.
R em a r k s :
Thisrecommendationtakesaccountof:
Theneed toofferalternative treatment topatientswithsevereor progressive
illness intheabsenceofoseltamiviror if thevirus isknown toberesistantto
oseltamivir.
The practical difficulties in administering inhaled zanamivir to severely ill
patientsinitscurrentdosageform.
The uncertain activity and clinical efficacy of intravenous peramivir againstinfection with oseltamivirresistant pandemic (H1N1) 2009 virus that has the
H275Ymutation.
6.5 Antiviral treatment recommendations: Otherinfluenza virus strains
Antiviraltreatmentrecommendationsforinfectionwithinfluenzavirusstrainsother
than pandemic (H1N1) 2009 virus, including when the virus type or influenza A
virus subtype is not known, are generally the same as for pandemic (H1N1) 2009
virusinfection.
The
following
additional
points
should
be
considered:
Forthetreatmentofthosepresentingwithuncomplicatedillness,thedecisiontotreat
shouldallowfortheriskofdevelopmentofsevereorprogressivedisease,whichmay
notbe the same as observed with the pandemic (H1N1) 2009 virus, and shouldbe
baseduponclinicaljudgment.
Ifillnessisknownorsuspectedtobeduetoazoonotic(animalderived)influenzaA
virus, such as swine influenzaviruses (H1,H2, H3) or avian influenza viruses (H7,
H9), oseltamivir or zanamivir are treatment options. For known or suspected
infection with avian influenza H5N1 virus, antiviral treatment should follow the
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WHOrapid adviceguidelineson pharmacologicalmanagementofhumans infected
withhighlypathogenicavianinfluenzaA(H5N1)virus.13
WheretheinfectionisknownorsuspectedtobeduetoseasonalinfluenzaA(H1N1)
virus, oseltamivir is unlikely tobe effective,but either amantadine or rimantadine
maybe used when the virus is likely susceptible (subject to Recommendation 10
below).Zanamivir
is
also
atreatment
option
if
available.
Rec10: Pregnant women and children aged less than 1 year with uncomplicated illnessdue to seasonal influenza A (H1N1) virus infection should notbe treated with
amantadineorrimantadine.(Strongrecommendation,verylowqualityevidence).
R em a r k s :
Thisrecommendationtakesaccountof:
Theconcernabout the increasedriskofadverseeventsdue toamantadineor
rimantadineinpregnantwomenandlackofevidencesupportinguseinyoung
childrenaged
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Thisrecommendationtakesaccountof:
Reportsofoseltamivirresistancefollowingpostexposureprophylaxisfailure.
Severely immunosuppressed persons who may not manifest fever with
influenza
virus
infection
or
who
might
have
atypical
symptoms
that
do
not
meetadefinitionofILI.
6.7 Other considerations
Additional treatment considerations concerning the use of antiviral medicines and which
maymodifyrecommendations0111areasfollows:
RenalImpairmentWhentreatingpatientswithrenalimpairment,considerationneedstobegiventothelikely
higher systemic exposure to oseltamivir. This is particularly important for those patient
groups(pregnancy,pediatricpopulations)wherethereis lessexperienceordataontheuse
ofhigheroseltamivirdoses. Cautionshouldbeexercisedinthesepatients,particularlyover
theuseofhigherdosesofoseltamivir(informationondoseadjustmentbasedoncreatinine
clearanceisgivenintheSummaryofProductCharacteristics14).
ObesityThepanelnotedreportsofsevereillnessinobesepatientsandarecentreportindicatingthat
oseltamivirvolumeofdistributioninobesepatientswassimilartothatinnonobesepatients.
However, there are currently insufficient data to determine whether dose adjustment (e.g.
higherdosing)isneededinobesepatients.
PregnancyandbreastfeedingTreatment recommendations for pregnancy and breastfeeding are covered by
recommendations 0105 and 0918 and there are no exclusions, except as covered by
Recommendations10and13.Thefollowingaresomeadditionalconsiderationsfortreatment
ofinfluenzavirusinfectioninpregnancy:
Therearefewerdataonsafetyandefficacy inthispatientgroupforallantiviral
medicines,thoughthereismorereportedexperiencewiththeuseofoseltamivir.
The dosing recommendations are as for other adult patient groups for each
antiviraldiscussed.
7. Other interventions for managementof patients with influenza
Anumberofotherproductsarenotlicensedforthetreatmentofinfluenzainmostcountries
but havebeen used for treatment of individual patients or are approved in a very limited
14Avaiablefromhttp://www.ema.europa.eu/humandocs/PDFs/EPAR/tamiflu/emeacombinedh402en.pdf. Last
accessedon2March2010.
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numberofcountries.ThePanelconsidered theevidence for theuseof the followingdrugs
(seebelow)forthetreatmentofinfluenza,butconcludedthattherewereinsufficientdataon
either efficacy or safety orboth and, therefore, there is inadequate evidence for treatment
recommendationsatthistimefor:
Immunoglobulins(includingmonoclonalantibodies,immuneandconvalescentsera/plasma
andrelatedproducts)
Intranasalinterferons
Arbidol
Ribavirin
Favipiravir
ThePanel made tworecommendationswith regardto the lackof efficacydataandknown
toxicityofribavirin:
Rec12: In patients with confirmed or strongly suspected influenza virus infection,ribavirinshouldnotbeadministeredasmonotherapy. Ifribavirinistobeusedin
combination with other therapies, this shouldbe done only in the context of
prospectiveclinicalandvirologicaldatacollectionaspartofanapprovedresearch
protocol.
Rec13: In pregnant women with confirmed or strongly suspected influenza virusinfection,ribavirinshouldnotbeadministeredastreatmentorchemoprophylaxis.
(Strongrecommendation,regulatorycontraindication.)
Withregardtoall investigational,regional,15andotherunapprovedtherapies, includingall
antiviral medicines and their formulations as listed above, the Guidelines Panel had the
followingrecommendation:
Rec14: In patients with confirmed or strongly suspected influenza virus infection,investigational, regional, or other unapproved therapies should not be
administered unless in the context of prospective clinical and virological data
collectionaspartofanapprovedresearchprotocol.
Recommendation 16 should alsobe applied to the use of combinations of antiviral drugs
(includingapprovedmedicines),sincetherearefewpublishedclinicaltrialdataonthesafety
orefficacyofsuchcombinations.
Withregardtothe investigationalandregionalproductslistedbelow,theGuidelinesPanel
acknowledged
the
status
of
these
products
in
clinical
development
and
that
they
were
of
the
sameclassorchemicalentityastheexisting,approvedneuraminidaseinhibitors.However,
inlightofthepaucityofpublisheddataonefficacyandsafety,thepanelmadethefollowing
recommendation:
15Regionalproductsarethosethathavemarketauthorisations inonlyoneorafewcountries.
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Rec15: In patients with confirmed or strongly suspected influenza virus infection,investigationalneuraminidase inhibitorsshouldonlybeused inthecontextofa
clinicaltrialorinaccordancewithrelevantemergencyuseprovisions.R em a r k s
Thisrecommendation
applies
to
the
following
investigational
or
regional
products:
Peramivir(parenteralformulation)
Laninamivir
Zanamivir(parenteralformulation)
Oseltamivir(parenteralformulation)
PeramivirhasreceivedmarketauthorizationinJapan,butisinvestigationalorunregistered
elsewhere.Therearefewpublishedclinicaltrialdataforperamivir.
Thisrecommendationtakesaccountof:
Thelimited
availability
of
these
products
in
most
countries.
Legal and ethical complexities, including import/export restrictions and consent
requirements,oncompassionateoremergencyuseofinvestigationalorunregistered
products.
Individual countries should develop local recommendations in the context of local market
authorizations.
Rec16: Zanamivircontaininglactose(powderforinhalation)shouldnotbeadministeredbynebulizer.(Strongrecommendation,regulatorywarning.)
Exacerbatedcomorbidities(underlyingconditions)andcoinfectionsshouldbemanagedinaccordancewithstandardofcareforsuchconditions,exceptasqualifiedbelow:
Rec17: Patients who have severe or progressive clinical illness, including viralpneumonitis, respiratory failure, and ARDS due to influenza virus infection,
shouldnotbegivensystemiccorticosteroidsunlessindicatedforotherreasonsor
as part of an approved research protocol. (Strong recommendation, low quality
evidence).R em a r k s :
Thisrecommendationtakesaccountof:
Alack
of
evidence
of
benefit
in
these
patients.
Riskofharm,includingopportunisticinfectionandprolongationofvirus
replication.
Theneedforcorticosteroidtreatmentforotherconditionssuchasasthma,
COPD,ongoingantiinflammatorytreatment,andadrenalinsufficiency.
Rec18: In children and adolescent (
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R em a r k s :
Theserecommendationstakeaccountof:
The increased risk of Reyes syndrome with influenza and salicylate
administrationinyoungerpatientpopulations.
Patientswhomayalreadybetakingsuchmedicinesforotherindications.
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8. Product supply
The list of influenza antiviral medicines that have been approved through the WHO
prequalification programme is set out below. For an uptodate list, consult the WHOwebsiteatwww.who.int/prequal.Theavailabilityandpriceoftheseproductswillvaryona
countrybycountrybasis.
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9. Priorities for update
Plans for updating this guideline
Anupdatetothisguidelinewillbeneeded,ifanyofthefollowingeventsoccur:
majornewresearchispublished(particularlyrandomizedcontrolledtrialsofanyof
theantiviralsorobservationalstudies);
newantiviraldrugsordosageformsbecomeavailable;and/or
thereisachangeintheseverityofillnessassociatedwiththecurrentpandemic(H1N1)
2009orothercirculatinginfluenzaviruses,orintheirsusceptibilitytoantiviraldrugs,
ortheemergenceofanovelinfluenzaAvirusofglobalpublichealthimportance.
WHOwillreviewthevalidityoftheseguidelinesevery6months,withregardtotheabove
criteria,unlesstheseguidelinesaresupersededbynew,consolidatedorstandardguidelines.
ThenextsuchreviewwillbeSeptember2010.
Updating or adapting recommendations locally
Themethodsusedtodeveloptheseguidelinesaretransparent.Thereforeitwillbepossible
to update the informationcontained in thembyrerunning thesearch described in Part II.
Therecommendationshavebeendevelopedtobeasspecificanddetailedaspossiblewithout
losingsightof theuserfriendlinessofthisdocumentandthe individualrecommendations.
The Panel encourages feedback on all aspects of these guidelines, including theirapplicability in individual countries. It may then be possible to decide whether the
recommendations shouldbe amended to accommodate the changes in information. The
Guidelineshavealsobeendesignedinsuchawaytofacilitatethisprocess,incaseusersneed
toupdateoradapttherecommendationsbeforetheWHOhasitselfupdatedthemglobally.
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10. Priorities for research
In developing these recommendations, the Panel highlighted the following topics wherefurtherresearchisneeded:
Studiestoassesstheefficacyofexistingandinvestigationalantiviralandadjunctive
treatments,includingregionalproducts,forsevereorcomplicatedinfluenzaillness.
Studiestoassessefficacyofimmunotherapyusingeitherpostinfectionsera/plasmaor
monoclonalantibodiesincomplicatedillnessduetoinfluenzavirusinfection.
Comparativeclinicalstudiesofneuraminidaseinhibitors,usedfortreatmentof
influenzainallpopulationsbutespeciallyforparenteralneuraminidaseinhibitorsfor
criticallyillpatients,assessingcomparativeefficacyandsafety.
Standardizationofclinicalandlaboratoryvirologicalendpointsusedtoassessoutcomesforthesestudies.
Comparativestudiesofcombinationtreatmentsinallpopulations,butespeciallyfor
severelyorcriticallyillpatientswithinfluenzavirusinfection.
Studiesinchildrenunderoneyeartodefinedose,safety,andefficacyofallantivirals,
particularlyinneonateswithinfluenzavirusinfection.
Developmentofalternativeformulations,includingdifferentroutesofadministration,
ofzanamivirandoseltamivir,particularlyforuseinseverelyillpatientsandfor
infantswithinfluenzavirusinfection.
Studiesof
higher
doses,
loading
doses,
longer
durations,
and
combinations.
Definitionofprognosticfactorsfordevelopingsevereinfluenzadisease.
Betterpharmacokineticandpharmacodynamicstudies,withparticularregardto
correlationsbetweendose,routesofadministrationandviralloadinthe(lower)
respiratorytractwithinfluenzavirusinfection.
Dataontreatmentofinfluenzainparticularhigherriskgroups,includingpregnant
women,obesepatients,andimmunosuppressed(includingHIV)infectedpersons.
Developmentofbetterdefinitionsofpatientswithhigherriskforsevereor
progressiveinfluenzaillnesssuchasHIVinfectedpopulation(adultsandchildren),
obesity,pregnancy.
Prospectivestudiesonmechanismsandclinicalconditionsbywhichresistanceto
antiviralmedicationsislikelytodevelopwhileinfluenzapatientsareundertreatment.
Developmentofarobustsurveillancesystemforinfluenzaantiviralresistance
monitoring.
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Annex 1: Risk factors for severe disease
Riskfactorsforseverediseasefrompandemic(H1N1)2009virusinfectionreportedtodateare considered similar to those risk factors identified for complications from seasonal
influenza.Theseincludethefollowinggroups:
Infantsandyoungchildren,inparticular
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ProfessorGregoryL.KEARNSPediatricsandPharmacology
UniversityofMissouriatKansasCity
2401GillhamRoad
KansasCity,MO64108
USA
Tel.:
+1816
234
3961
Fax: +18168551703
ProfessorAnthonyNUNNClinicalDirector,DepartmentofPharmacy
AlderHeyChildrensNHSFoundationTrust
UniversityofLiverpool
EatonRoad
LiverpoolL122APUK
Tel:+441512525314
Fax:+441512525675
DrLisaBEROProfessorofClinicalPharmacyand
HealthPolicy
UniversityofCalifornia,SanFrancisco
3333CaliforniaStreet,Suite420
SanFrancisco,CA 94118
USA
Tel:+14154761067
AssociateProfessor
Norio
SUGAYA
KeioUniversitySchoolofMedicine
KeiyuHospital
DepartmentofPediatrics
373 Minatomirai, Nishiku, Yokohama, 2200012Kanagawa,JAPANTel. +81452218181
Fax:+81456819665
DrTimothyM.UYEKIDeputyChief,EpidemiologyandPrevention
Branch,Influenza
Division
NationalCenterforImmunizationandRespiratory
Diseases
CentersforDiseaseControlandPrevention
1600CliftonRoad,N.E.
Atlanta,Georgia30333USA
Tel.:+14046390277
Mobile:+14043849040
[email protected];[email protected]
ProfessorSylvieVANDERWERFHeadofUnitofMolecularGeneticsofRNA
Viruses
UnitdeGntiqueMolculairedesvirus
ARN
InstitutPasteur
25rue
du
Docteur
Roux
75724 ParisCedex15
France
Tel.:+33(1)45688722
Fax:+33(1)40613241
Mobile:+33(6)87761442
1. ProfessorAnitaZAIDITheA.SultanJamalProfessor
DepartmentofPaediatricsandChildHealth
AgaKhanUniversityStadiumRoad
P.O.Box
3500
Karachi74800Pakistan
Tel.:+9221349300514734
Fax:+922134934294
WHOStaff:DrSylvieBriand,HSE/GIP
DrSuzanneHill,HSS/PSM/PAR
DrNahokoShindo,HSE/EPR/GIP
DrMatthewLim,HSE/EPR/BDP
DrCathy
Roth,
HSE/EPR/BDP
DrCharlesRPenn,HSE/GIP
DrFaithMcLellan,HSE/GIP
RebeccaHarris,HSE/GIP
IndependentEvidenceReviewsby:MsPattiWhyte,Consultant,Brisbane,
Australia(Antiviralevidence)
ProfessorGregoryKearnsandProfessorSusan
AbdelRahman(Pediatricdosing)
ProfessorAnthony
Nunn
(Extemporaneous
preparations)
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Annex 3:
Declarations of Interests
The Guidelines Panel participants completed the WHO standard form for declaration of
interests prior to the meeting. At the start of the meeting, all participants were asked to
confirm their interests, and to provide any additional information relevant to the subject
matterofthemeeting.
The followingparticipantsdeclaredcurrentorrecent (
-
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Part I: Recommendations
31
took no part in the final session of the meeting during which the guidelines
recommendationswereconfirmed,andtooknopartinfinalizationoftherecommendations
(PartI)subsequenttothepanelmeeting:
DelMar,Hay,Hayden, Sugaya,VanderWerf.
Twoexperts,initiallyidentifiedaspotentialparticipants,wereaskednottoparticipateinthe
meetingonthebasisofdeclaredpersonalandcommercialinterests.
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Part I: Recommendations
Annex 4:Table of standard dosages
Thestandarddosesforoseltamivirandzanamivirarebasedonclinicalstudiesinoutpatient
settings,andwithuncomplicatedinfluenzavirusinfection. Dosesformanagementofsevere
or complicated illness are discussed within these recommendations. Specific
recommendationshavealsobeenmadefordosesforyoungchildren, infantsandneonates.
FurtherinformationisalsoprovidedinthePrescribingInformationandSummaryofProduct
Characteristicsforeachproduct.
Asareference, the standardadultsdoses,asgiven inSummaryofProductCharacteristics,
foreachproductareprovidedbelow:
Oseltamivir
Oseltamivir is indicated for treatment of patients one year of age and older.
For adolescents (13 to 17 years of age) and adults the recommended oral dose (based ondata from studies in typical uncomplicated influenza) is 75 mg oseltamivir twice daily for 5days.
Zanamivir
Zanamivir is indicated for treatment of influenza in adults and children (>5 years).
The recommended dose for treatment of adults and children from the age of 5 years (basedon data from studies in typical uncomplicated influenza) is two inhalations ( i.e. 2 x 5mg)twice daily for 5 days.