WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses potx

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WHO Guidelines for
Pharmacological Management of
Pandemic Influenza A(H1N1) 2009
and other Influenza Viruses


Revised February 2010


Part I
Recommendations




Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
Contents

CONTENTS 2
SUMMARY 3
1. INTRODUCTION 4
2. CASE DESCRIPTION 5
3. RISK GROUPS 6
4. EPIDEMIOLOGY 7
5. GENERAL CONSIDERATIONS 8
6. RECOMMENDATIONS 10
6.1UseofantiviralsfortreatmentofpandemicinfluenzaA(H1N1)2009virusinfectioninadultsand

adolescents 10

6.2UseofantiviralsfortreatmentofuncomplicatedpandemicinfluenzaA(H1N1)2009virusinfectionin
adultsandadolescents 14

6.3UseofantiviralsfortreatmentofpandemicinfluenzaA(H1N1)2009virusinfectioninchildren 15
6.4Useofantiviralswhereantiviralresistanceisknownorsuspected 17
6.5Antiviraltreatmentrecommendations:Otherinfluenzavirusstrains 18
6.6UseofantiviralsforchemoprophylaxisofpandemicinfluenzaA(H1N1)2009virusinfection 19
6.7Otherconsiderations 20
7. OTHER INTERVENTIONS FOR MANAGEMENT OF PATIENTS WITH INFLUENZA 20
8. PRODUCT SUPPLY 24
9. PRIORITIES FOR UPDATE 25
Plansforupdatingthisguideline 25
Updatingor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
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
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3

Summary
This guidance updates and replaces the recommendations published in August 2009. This
documentwillagainbereviewedinSeptember2010and,ifnecessary,updated.

Keychangestotheguidelinesare:

• Simplification of recommendations as pandemic influenza A(H1N1) 2009 virus has
becomethepredominantinfluenzavirusworldwide.
• Specificguidancefor
thetreatmentofyoungchildrenfrombirth,includingguidance
ondoseandformulation(Recommendations06‐08).
• Additional guidance for treatment or chemoprophylaxis of patients with severe
immunosuppression(Recommendations03and04).
• Consideration ofa wider rangeof investigational, regional
1
oradjunctivetreatments
(Recommendations14and15).
• Specificcontraindicationsforsomemedicines(Recommendations16‐18).
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Thetablebelowsummarizesthetreatmentrecommendationsthataredescribedinfullinthe
subsequentsections:
Use of antivirals for treatment of influenza
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Population PandemicinfluenzaA
(H1N1)2009andother
seasonalinfluenzaviruses
Influenzavirusesknownor
suspectedtobeoseltamivir
resistant
Uncomplicatedclinicalpresentation
Patientsinhigherrisk
groups
Treatwithoseltamiviror
zanamivirassoonaspossible
(05)

Treatwithzanamivirassoonas
possible(05)
Severeorprogressiveclinicalpresentation
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Allpatients(including
childrenandadolescents)
Treatwithoseltamiviras
soonaspossible(01)
(zanamivirshouldbeusedif
oseltamivirunavailable)(02)
Treatwithzanamivirassoonas
possible(03)
Patientswithsevere
immunosuppression
Treatwithoseltamiviras
soonaspossible.Consider
higherdosesandlonger
durationoftreatment(03)
Treatwithzanamivirassoonas
possible(03)


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1
Regionalproductsarethosethathavemarketauthorisationsinonlyoneorafewcountries.
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
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4
1. Introduction

Thepurpose ofthisdocumentistoprovideabasisforadvicetocliniciansontheuseofthe
currently available antivirals for patients presenting with illness due to influenza virus
infection,aswelltheiruseforchemoprophylaxis.Thisdocumentaddressesthemostwidely
availableandlicensedantiviralmedicines,thetwo
neuraminidaseinhibitorsoseltamivirand
zanamivir, and the two M2 inhibitors amantadine and rimantadine. It also includes
recommendationsontheuseofsomeotherpotentialpharmacologicaltreatments,including
other investigational neuraminidase inhibitors, other agents such as arbidol, ribavirin,
intranasal interferons, immunoglobulins, and corticosteroids. While the focus of the
documentis on
managementof patientswithpandemic(H1N1)2009virusinfection,it also
includesguidanceon theuseof antivirals forseasonal influenzaA andB virusstrains,and
forinfectionsduetonovelinfluenzaAvirusstrains.

WHO recommends that national and regional authorities periodically issue local guidance
that place these recommendations
 in the context of local epidemiological and antiviral
susceptibilitydataonthecirculatinginfluenzavirusstrains.Suchlocalguidancewouldalso
takeintoaccountlocalhealthprioritiesandresources.

Thisguidance updatesandreplacestherecommendations publishedin August2009.These
recommendations are based on a review of available data
obtained on treatment of
previouslycirculatinginfluenzavirusstrainsandtreatment ofhumaninfection withhighly
pathogenic avian influenza A (H5N1) virus, as well as more recent observational data and
experience intheclinical management ofpandemic (H1N1)2009 influenza.Itis anticipated
thatastheprevalenceandseverityofthe
currentepidemicchanges,furtherinformationwill
becomeavailablethatmaywarrantrevisionoftherecommendations.


Thisrevisedguidanceispublishedintwoparts.PartIcontainstreatmentrecommendations.
Part II documents the procedures followed in developing this guidance, together with a
reviewofevidenceandothernewinformationonthe
pharmacologicalagentsconsidered.
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TheseguidelinesshouldbereadinconjunctionwiththeWorldHealthOrganizationʹs(WHO)
revised guidance for clinical management of human infection with pandemic influenza
A(H1N1)2009virus,publishedinNovember2009.
2


The WHO rapid advice guidelines on pharm acological management of humans infected
with highly pathogenic avian influenza A(H5N1) virus
3
remain unchanged by these new
guidelines.


2
Clinicalmanagementofhumaninfectionwithpandemic(H1N1)2009:revisedguidance.WorldHealth
Organization,November2009.Availableat:
/>.Lastaccessedon10
February2010.
3
WHORapidAdviceGuidelinesonpharmacologicalmanagementofhumansinfectedwithavianinfluenzaA
(H5N1)virus.WorldHealthOrganization,May2006.Availableat:
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
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5

2. Case description
Human infection with influenza virus can vary from asymptomatic infection to
uncomplicated upper respiratory tract disease to serious complicated illness  that may
includeexacerbationofotherunderlyingconditionsandsevereviralpneumoniawithmulti‐
organfailure.Sinceawiderangeofpathogenscancauseinfluenza‐likeillness(ILI),aclinical
diagnosis
 of influenza should be guided by clinical and epidemiologic data and can be
confirmed by laboratory tests. However, on an individual patient basis, initial treatment
decisionsshouldbebasedonclinicalpresentationandepidemiological dataandshouldnot
bedelayedpendinglaboratoryconfirmation.Indevelopingtheseguidelines,theGuidelines
Panel
(thePanel)consideredthreebroadscenarios,setoutbelow.
Uncomplicated influenza
– Influenza‐likeillness(ILI)symptomsinclude:fever,cough,sorethroat,nasal
congestionorrhinorrhea,headache,musclepain,andmalaise,butnotshortnessof
breathandnotdyspnoea.Patientsmaypresentwithsomeorallofthesesymptoms.
– Gastrointestinalillnessmayalsobepresent,suchasdiarrhoeaand/orvomiting,

especiallyinchildren,butwithoutevidenceofdehydration.
– Somepatientswithuncomplicatedillnessmayexperienceatypicalsymptomsand
maynothavefever(e.g.elderlyorimmunosuppressedpatients).
Complicated or severe influenza
– Presentingclinical(e.g.shortnessofbreath/dyspnoea,tachypnoea,hypoxia)and/or
radiologicalsignsof lowerrespiratorytractdisease(e.g.pneumonia),centralnervous
system(CNS)involvement(e.g.encephalopathy,encephalitis),severedehydration,or
presentingsecondarycomplications,suchasrenalfailure,multiorganfailure,and
septicshock.Othercomplications canincluderhabdomyolysisandmyocarditis.
– Exacerbation
ofunderlyingchronicdisease,includingasthma,chronicobstructive
pulmonarydisease(COPD),chronichepaticorrenalinsufficiency,diabetes,orother

cardiovascularconditions(e.g.congestivecardiacfailure).
– Anyotherconditionorclinicalpresentationrequiringhospitaladmissionforclinical
management(includingbacterialpneumoniawithinfluenza).

– Anyofthesignsandsymptomsofprogressivediseaselistedbelow.
Signs and symptoms of progressive disease
Patientswhopresentinitiallywithuncomplicatedinfluenzamayprogresstomoresevere
disease.Progressioncanberapid(i.e.within24hours).Thefollowingaresomeofthe
indicatorsofprogression,whichwouldnecessitateanurgentreviewofpatientmanagement:



/>10February2010.
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
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6
– Symptomsandsignssuggestingoxygenimpairmentorcardiopulmonary
insufficiency:
o Shortnessofbreath(withactivityoratrest),difficultyinbreathing,
tachypnoea,presenceofcyanosis,bloodyorcolouredsputum,chestpain,and
lowbloodpressure;
o Inchildren,fastorlabouredbreathing;and
o Hypoxia,asindicatedby
pulseoximetryorarterialbloodgases.

– SymptomsandsignssuggestingCNScomplications:
o Alteredmentalstatus,unconsciousness,drowsiness,ordifficulttoawaken
andrecurringorpersistentconvulsions(seizures),confusion,severeweakness,
orparalysis.

– Evidenceofsustainedvirusreplicationorinvasivesecondarybacterialinfectionbased
onlaboratorytestingor
clinicalsigns(e.g.persistentorrecurrenthighfeverandother
symptomsbeyond3dayswithoutsignsofresolution).
– Severedehydration,manifestedasdecreasedactivity,dizziness,decreasedurine
output,andlethargy.
3. Risk groups
Certainpatientswithseasonalinfluenzavirusinfectionorpandemic influenza(H1N1)2009
virus infection are recognized to be at higher risk of developing severe or complicated
illness. The Guidelines Paneldid not review theevidence forthe definition of thesehigher
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)2009Influenza
4
aslistedinPartI,Annex1.

However,animportantconsiderationinthemanagementofinfluenzavirusinfectionsisthat
influenza virus infection in any patient can result in severe or complicated illness.This is
particularlytrueforpandemic(H1N1)2009virusinfection,inwhichabout1/3ofseverelyill

patients admitted to intensive care units were previously healthy persons notbelongingto
anyknownhigherriskgroup.


4
Clinicalmanagementofhumaninfectionwithpandemic(H1N1)2009:revisedguidance.WorldHealth
Organization,November2009.Availableat:
/>.Lastaccessedon10
February2010.

Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

7
4. Epidemiology
Currently, WHO  publishes wee kly information from glo bal influenza sur veillance
5
.As of
December 2009, th e most
prevalent cir culating infl uenza
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
theNorthernHemisphere):

For the purpose of
developmentoftheserevised
guidelines, it is anticipated

that the prevalent influenza viruses in the coming year are most likely to be pandemic
(H1N1)2009,H3N2andinfluenza Bvirusstrains,as isreflectedin thevaccinecomposition
recommendationsfortheSouthernHemisphere2010season.
6


Theimpactof pandemic(H1N1)2009 virusinfectionhasbeen highestinthepaediatricand
youngeradultpopulations,whenmeasuredbyattackratesandhospitalizationrates.


InfluenzaA(H5N1)virus(avianinfluenza)continuestocausesporadichumaninfectionsin
some countries, with 72 cas es (32 deaths) reported in 2009 in
 5 countries.
7
 Thus, although
pandemic influenza A (H1N1) 2009 virus may displace other circulating influenza A virus
strains,novelinfluenzaAviruses,suchasH5N1,remainapandemicthreat.


5
Situationupdates‐Pandemic(H1N1)2009.WorldHealthOrganization.Availableat:
 />.Lastaccessedon10February2010.
6
Pandemicinfluenzaa(H1N1)2009virusvaccine–conclusionsandrecommendationsfromtheOctober2009
meetingoftheimmunizationStrategicAdvisoryGroupofExperts.WorldHealthOrganization,Weekly
EpidemiologicalRecord,4December2009,8449:505‐509.Availableat: />.
Lastaccessedon10February2010.
7
CumulativeNumberofConfirmedHumanCasesofAvianInfluenzaA/(H5N1)ReportedtoWHO.World
HealthOrganization,30December2009.Availableat:
/>.Lastaccessedon
10February2010.

Characterization of circulating influenza viruses Dec 2009
Pandemic 
A
(H1N1)
Seasonal A(H1N1)
A

(H3N2)
B
A
(not typed)
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

8
5. General Considerations
TheGuidelines Panelidentifiedthefollowing treatmentoutcomes ascritical fordeveloping
recommendations:

– mortality;
– hospitalization;
– complications;
– seriousadverseevents(drug‐related);and
– antiviraldrugresistance.

There are no adequate data from head‐to‐head randomized, controlled trials directly
comparing theefficacy ofoneantiviral  medicine
against anotherfortreatmentof influenza.
Alltreatmentrecommendationsarebasedontrialsthatcompareactiveantiviraltreatmentto
placebo among patients with seasonal influenza and, therefore, comparisons between
treatmentsareindirect.

All the recommendations herein are strongly influenced by patterns of antiviral resistance.
Resistance prevalence in circulating influenza strains
is collated and reported by WHO.
8


Therefore, these recommendations may need to be modified in light of current or local
knowledgeoftheantiviralsusceptibilityofcirculatingviruses.

AsofJanuary2010,theantiviralsusceptibilitiesofcirculatingvirusesare:

 Oseltamivir Zanamivir M2inhibitors
b
Pandemic(H1N1)2009
Susceptible
a
Susceptible Resistant
SeasonalA(H1N1)
c
Mostlyresistant Susceptible Mostlysusceptible
SeasonalA(H3N2)
Susceptible Susceptible Resistant
InfluenzaB
Susceptible Susceptible Resistant
a.Seetextbelow
b.Amantadineandrimantadine
c. Seasonal A (H1N1) refers to the human influenza A (H1N1) viruses that were circulating prior to the
introductionofpandemicinfluenzaA(H1N1)2009vir usandwhichcontinuedtocirculateduring2009.

ThePanelrecommendsthatanantiviralshouldnotbeusedfortreatmentwherethevirusis
known or highly likely to be 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
illnessfromcirculatinginfluenzavirusstrains,exceptwhenseasonalH1N1virusinfectionis
proven or strongly suspected, since all other circulating human influenza virus strains are

resistanttotheseantivirals.



8
InfluenzaAvirusresistancetooseltamivirandotherantiviralmedicines.WorldHealthOrganization,4June
2009.Availableat: />.Last
accessedon10February2010.
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

9
Infections with oseltamivir‐resistant pandemic (H1N1) 2009 virus have been documented,
comprisingbothsporadiccasesandalimitednumberof clusters.Whilelimitedtransmission
of these viruses among contacts has been observed, there is no evidence of their wider
communityleveloron‐goingcirculation.WHOʹsassessmentand
conclusionsonoseltamivir‐
resistant pandemic (H1N1) 2009 viruses, as set out in the Weekly Epidemiological Record
9,10

include:

• All oseltamivir‐resistant isolates have the same H275Y mutation that confers
resistancetooseltamivir,butnotzanamivir.
• Noevidenceof reassortmentbetween pandemic influenza A(H1N1) 2009and other
seasonalinfluenzaAviruses.
• No associationwith an altered or unexpected severityof disease,although fatalities
have
occurredinsomeseverelyillpatients.


Thelargestproportionofcasesofoseltamivirresistantpandemic(H1N1)2009virusinfection
hasoccurredinseverelyimmunocompromisedpatients.Transplant patients(andespecially
bone marrow or haemopoetic stem cell transplant recipients) on immunosuppressive
chemotherapy haveemerged asaparticularly vulnerablepatientgrou p. Anumber
 ofcases
havealsobeenassociatedwithfailureofpost‐exposureoseltamivirchemoprophylaxis.

Chemoprophylaxis is not generally recommended for the established circulating human
influenza viruses, including pandemic (H1N1) 2009, asthe opportunity costand utilization
ofantiviraldrugsthatmaybeneededfortreatmentisnotwarranted.Withtheavailability
of
vaccines forbothseasonalinfluenza andpandemicH1N12009influenza,thereshouldnow
be lessrelianceon antiviralchemoprophylaxisfor preventionof illnessin close community
settings and in groups such as health‐care 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
considerationshoweverapplytotheavian(H5N1)andotherzoonoticinfluenzaviruses
11
.


9
Oseltamivir‐resistantpandemic(H1N1)2009influenzavirus,October2009.WorldHealthOrganization,Weekly
EpidemiologicalRecord,30October2009,8444:453‐458.Availableat:
/>.Lastaccessedon10February2010.
10
UpdateonoseltamivirresistantpandemicA(H1N1)2009influenzavirus,January2010.WorldHealth
Organization,WeeklyEpidemiologicalRecord,5February2010,8506:37‐39.Availableat:
/>.Lastaccessedon10February2010.

11
WHORapidAdviceGuidelinesonpharmacologicalmanagementofhumansinfectedwithavianinfluenzaA
(H5N1)virus.WorldHealthOrganization,May2006.Availableat:
/>Lastaccessedon
10February2010.

Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

10
6. Recommendations
Formal recommendations are set out below as numbered, highlighted paragraphs (01‐20).
Most recommendations are accompanied by other treatment considerations, since the
recommendationsmaynotcoverallsituations,and, inmostcases,arebasedonloworvery
lowqualityevidence.

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
01‐06),butwithspecialconsiderationsfordosinginyoungerchildren(seeRecommendation
08).

6.1 Use of antivirals for treatment of pandemic influenza
A (H1N1) 2009 virus infection in adults and adolescents
Context: Treatment of adults and adolescents with confirmed or strongly suspected
infection with pandemic influenza A(H1N1) 2009 virus, where clinical
presentation is severe or progressive and antiviral medicationsfor influenza are
available.
Rec01: Patients who have severe or progressive clinical illness should be treated with

oseltamivirassoonaspossible.(Strongrecommendation,lowqualityevidence.)
This recommendation applies to all patient groups, including pregnant and
postpartumwomenupto2weeksfollowingdelivery,andbreastfeedingwomen.

Other Treatment Considerations:
Timing. Treatment should be started as soon as possible. Laboratory
confirmation of influenza virus infection is not necessary for the initiation of
treatmentandanegativelaboratorytestforH1N1doesnotexcludethediagnosis
in all patients, therefore early, empiric treatment is strongly recommended. The
evidence from clinical trials in uncomplicated seasonal influenza suggests most
patientsbenefitfromantiviraltreatmentcommencingwithin48hoursofonsetof
symptoms, but experience from use in patients with H5N1 vi rus infection and
severe lower respiratory tract disease suggests that later initiation of treatment
mayalsobeeffective,wheneverviralreplicationispresentor
stronglysuspected.

Doseandduration.Higherdosesofoseltamivirandlongerdurationoftreatment
maybeappropriate,althoughthereisnoavailableclinicaltrialevidencetoinform
recommendations.Anadultdoseof150mgtwicedailyhasbeenadministeredto 
some critically ill patients. When treating patients with renal impairment,
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

11
consideration needs to be given to the likely higher systemic exposure to
oseltamivir(seeSection6.7below).

Wheretheclinicalcourseremainssevereorprogressive,despite5ormoredaysof
antiviral treatment, monitoring of virus replication and shedding, and antiviral
drugsusceptibilitytestingisdesirable.Antiviraltreatmentshould

bemaintained
without a break until virus infection is resolved or there is satisfactory clinical
improvement.
Antiviral resistance. Zanamivir is the treatment of choice for all patients where
oseltamivir resistance is demonstrated or highly suspected.Intravenous
zanamivirmaybeconsideredwhereavailable.

Drug delivery.Patientswho have severe or progressive
clinical illness, butwho
are unabletotakeoralmedicationmaybetreatedwithoseltamiviradministered
bynasogastricororogastrictube(e.g.mechanicallyventilatedpatients).
Remarks:
Thisrecommendationtakesaccountof:

– That the prescribing information(5 day treatmentcourse) isbased onclinical
studies in outpatient settings, and with uncomplicated influenza virus
infection.
– Evidence from case reports and case series of prolonged virus replication in
thelowerrespiratorytractofseverelyillpatients.
–
The concern about the increased risk of severe complications or death from
influenzainthiscontext.
– The evidence from observational studies that demonstrates a reduction in
progression to severe disease and hospitalization in patients treated early
(within2daysofillnessonset)withantivirals.
– The ease of use and
 s uitability of oseltamivir compared to other currently
availableneuraminidaseinhibitors,i.e.oraladministrationversusinhaled.
– Limited data from observational studies that indicate that oseltamivir
delivered by nasogastric tube achieves adequate serum levels in crit ically ill

patients.
– Theopportunitycostofprovidingantiviralstothesepatientsisconsideredlow.

Rec02: In situations where oseltamivir is not available, or not possible to use, patients
who have severe or progressive clinical illness should be treated with inhaled
zanamivir,wherefeasible.(Strongrecommendation,verylowqualityevidence.)
Other Treatment Considerations:
Drug delivery. Zanamivir containing lactose(powder for inhalation) should not
beadministeredbynebulizer(seeRecommendation18).
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

12
Remarks:
Thisrecommendationtakesaccountof:

– The need to offer alternative treatment to patients with severe or progressive
illness inthe absence ofoseltamivir orif thevirus isknown to be resistant to
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 
Recommendation17).
Context: Treatment of patients with confirmed or strongly suspected infection with
pandemic influenza A(H1N1) 2009 virus, and who have severe
immunosuppressionexpectedtodelayviralclearance.
Severeorcomplicatedinfluenzavirusinfectionsattributableatleastinparttosevere

immunosuppression have been most frequently described in transplant patients
(including hematopoetic stem cell recipients, bone marrow transplant patients, and
othertransplantpatientsonimmunosuppressivechemotherapy).Otherpatientswith
severe immonosuppression include those with graft versus host disease, or
 with
haematologicalmalignancies.

OthercancerpatientsundergoingchemotherapyandpatientsinfectedwithHIV,who
havedevelopedsevereimmunodeficiency,mayalsoneedtobetreatedinaccordance
withtherecommendationsbelow.

Rec03: Patients who have severe or progressive clinical illness should be treated with
oseltamivir 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.)
Other Treatment Considerations:
Prevention of infection in this patient group should be a prime objective. This is
considered further in the recommendations for chemoprophylaxis below
(Recommendation04).
Duration. Regular monitoring of on‐going viral replication and antiviral drug
susceptibility is strongly recommended in this patient group.Antiviral treatment
should bemaintain ed without abreak
 untilvirus infection is resolved(as indicated
by clinical improvement or sequentially negative results for virus in therespiratory
tract).
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

13

Antiviral resistance. Zanamivir is the treatment of choice for all patients where
oseltamivir resistance has been demonstrated or is highly suspected(see pediatric
section;inhaledzanamivirisnotapprovedforuseinchildrenagedlessthan5years).
Alternative treatments.Intravenous zanamivir should be considered where
available and is
recommended for those with serious or progressive illness. If not
available, intravenous peramivir may be considered, athough oseltamivir‐resistant
virusesarereportedtohavereducedsusceptibilityinvitrotoperamivir.
Remarks:
Theserecommendationstakeaccountof:

– The impaired host immune response, such that standard antiviral regimens
maynotbeaseffectiveinclearingvirus.
– The higher probability of emergence of oseltamivir‐resistant virus in these
patients.

Rec04: Whenapersonwithinfluenzavirusinfectionispresentintheimmediatesetting,
severely immunosuppressed patients may be offered chemoprophylaxis with
oseltamivirorzanamivir.(Strongrecommendation,verylowqualityevidence.)
Other Treatment Considerations:
Infection controlprocedures shouldberigorously appliedinthiscontext,including
vaccination againstseasonal and pandemic influenzain allpersonswho havedirect
contactwiththesepatients.Otherinfectioncontrolproceduresincludehandhygiene,
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
suspectedcasesofpandemic(H1N1)2009andinfluenza‐likeillnesses
12
.
Antiviral resistance. Zanamivir may be the preferred option for chemoprophylaxis

for those patients able to take inhalation medicine, due to the known risk of
developmentofoseltamivirresistanceinthispatientgroup.
Dose and duration. In severely immunosuppressed persons, there needs to be on‐
going weekly monitoring for evidence of
 prolonged viable viral replication, and
chemoprophylaxis continueduntil there is noevidence of on‐going viral replication
inanypatientinthesameroomorhealthcareunit.Whereexposuretoinfectionmay
haveoccurredandtheindividualmaybewithintheincubationperiod,consideration
shouldbegiventopresumptivetreatment
(i.e.throughtheuseoftreatmentdoses).

Remarks:



12
Infectionpreventionandcontrolinhealthcareforconfirmedorsuspectedcasesofpandemic(H1N1)2009and
influenza‐likeillnesses.WorldHealthOrganization,December2009.Availableat:
/>Lastaccessedon2
March2010

Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

14
Thisrecommendationtakesaccountof:

– Theimporta nceofpreventinginfecti oninthisvulnerablepatientgroup.

6.2 Use of antivirals for treatment of uncomplicated

pandemic influenza A (H1N1) 2009 virus infection in
adults and adolescents
Context: Treatmentofadultandadolescentpatientswithconfirmedorstronglysuspected,
but uncomplicated illness, due to pandemic (H1N1) 2009 virus infection, and
whereantiviralmedicationsforinfluenzaareavailable.
The decision to treat patients in this context will depend on the availability of health‐care
resources (including antiviral medication), local priorities for health provision, and
assessmentoftheriskthatthepatientwilldevelopmoreseriousdisease.Whilesomegroups
ofpatientsarerecognizedashavingahigherriskof
developingmoresevereorcomplicated
illness(seePartI,Annex1),allpatientsareatsomerisk.

The recommendation below, therefore, needs to be applied in the context of clinical
judgmentandlocalornationalguidance.
Rec05: Patientswhohave uncomplicatedillnessduetoconfirmedorstronglysuspected
virusinfectionandareinagroupknowntobeathigherriskofdevelopingsevere
orcomplicatedillness,shouldbetr eatedwithoseltamivirorzanamivirassoonas
possible.(Strongrecommendation,lowqualityevidence.)
This recommendation applies to all patient groups, including pregnant and
postpartumwomen,upto2weeksfollowingdelivery,andbreastfeedingwomen.

Patientswho haveuncomplicatedillness, andare notin agroupknownto beat
higher risk of developing severe or complicated illness, may
 not need to be
treated with antivirals.A decision to treat will depend upon clinical judgment
and availabilityof antivirals.Patients whopresent formedicalattention,but do
not receive antiviral treatment, should be counseled on signs of progression or
deteriorationofillnessandadvisedtoseekmedicalattentionimmediately,
should
theirconditiondeteriorateorpersist.

Other Treatment Considerations:
Antiviralresistance.Zanamivir,whereavailable,isthetreatmentofchoiceforall
patientswhereoseltamivirresistanceisdemonstratedorhighlysuspected.
Remarks:
Thisrecommendationtakesaccountof:

Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

15
– The concern about the higher risk of severe complications or death from
influenzainthesepatientgroups.
– The evidence from observational studies that demonstrates a reduction in
progression to severe disease and hospitalization in patients treated with
antivirals.
– The importance of clinical judgment in deciding whether
to initiate antiviral
treatment foruncomplicatedillness inpersons notina groupknownto beat
higherriskforinfluenzacomplications.
6.3 Use of antivirals for treatment of pandemic influenza
A (H1N1) 2009 virus infection in children
Context: Treatment of children with confirmed or strongly suspected infection with
pandemic (H1N1)2009viruswhereclinicalpresentationissevere orprogressive
andantiviralmedicationsforinfluenzaareavailable.
Rec06: Children who have severe or progressive clinical illness should be treated with
oseltamivirassoonaspossible.(Strongrecommendation,lowqualityevidence.)
This recommendation applies to all children, including neonates and young children (in
particularthoselessthan2yearsofage).
Other Treatment Considerations:

There are generally fewer data available on the safety and efficacy of antiviral
medicines in very young children (especially from birth to 1 year).In particular,
there are insufficient efficacy or safety data to support guidelines on the use of
intravenouszanamivirorperamivirinchildren.

The validity of recently
recommended oseltamivir doses in children has been
independently evaluated for WHO (Abdel‐Rahman and Kearns, Part II, Annex 7).
This evaluation was based on an assessment of the available literature, including
knowledge of the drugʹs disposition and knowledge of pathological and
physiologicalcharacteristicsofthetargetpopulation.Onthebasis
ofthisevaluation,
the Guidelines Panel made the following recommendations with regard to
oseltamivirdosesforyoungchildren:
Rec07: Oseltamivirtreatmentdosesforchildrenfrom14daysupto1yearofageshould
be 3 mg/kg/dose, twice daily.For children <14 days of age, the recommended
oseltamivir dose is 3 mg/kg/dose once daily. Lower doses should be considered
for infantswho are not receiving regular oral feedingsand/or those whohave a
concomitant medical condition which is expected to reduce significantly renal
function.
Other Treatment Considerations:
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

16
Timing of treatment.Evidence indicates that the greatest benefit is derived from
early oseltamivir treatment.Therefore, suitable preparations of oseltamivir need to
beavailableatthepointofcare.

Drug delivery. Where capsules containing the appropriate oseltamivir dose are

availablebutcannotbeswallowed,thecontentscanbeadded
toasweetliquidorsoft
food immediately before administration to disguise bitter taste.Where different
dosesarerequired,thefollowingmethodsmaybeused:

Powder for oseltamivir oral suspension, where available, is the preferred
formulation for children unable to take the capsules, when capsules of appropriate
strength arenot
available orwhere the smaller capsule of 30 mgis greaterthan the
calculated dose.Where this is  not available, an oseltamivir suspension or solution
canbeproducedbyextemporaneouspreparationfromthecontentsofcapsules,orby
preparationfrombulkpowder(alsoreferredtoasActivePharmaceuticalIngredient,
orAPI ).
WHOrecommendsthatlocalguidancebedevelopedthattakesintoaccount
local availability of oseltamivir capsules or API, local facilities, and availability of
suitablesuspendingagentsordiluents.

The following points need to be considered in the development of such local
guidance(seealsoPartII,Annex8,reportby
ANunn):

Extemporaneouspreparationofoseltamivirtreatmentcourse.Preparationofafull
oseltamivir treatment courseis best done where commercially available suspending
agents,containingantimicrobialpreservatives,areavailable.Furtherinformationon
available suspendingagents, and proposed shelflifefor suspensions, isprovidedin
PartIIAnnex8(reportbyA
Nunn).

Consideration also needs to be given to availability or provision of suitable
measuring devices for individual dose measurement and administration, as well as

provisionofclearinformationforthecaregiver.

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 can be
opened and mixed with a measured volume of water immediately before
administration. Any smaller dose volume required can be calculated and measured
foradministration.

Localguidance shouldtake intoaccount the availabilityof materialsand measuring

devices. User instructions for choice of substrate, dilution, calculation, and
measurementofdoseshouldbeprovided.

Somewastageofdrugmaterialisinevitableunderthesecircumstances.

Magistral preparations from API. Preparation of a stable solution from oseltamivir
phosphatepowder(theAPI)hasbeenusedduringthe2009/10outbreakinthe
United
Kingdom.FurtherinformationisprovidedinPartII,Annex8(reportbyANunn).
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

17
Remarks:
Thisrecommendationtakesaccountof:

– Theneedforaclearandsimpledoseschedule.
– The lack of clinical evidence for dosing in this age group and the lack of

suitable,commerciallyavailabl epaediatricformulationsofoseltamivir.

Context: Treatment ofchildren withconfirmed orstronglysuspected, butuncomplicated,
illness due to pandemic (H1N1) 2009 virus infection and where antiviral
medicationsforinfluenzaareavailable.
Rec08: Childrenwhohaveuncomplicatedillnessduetoconfirmedorstronglysuspected
influenza virus infection and are in a group known to be at higher risk  of
developing severe or complicated illness should be treated with oseltamivir or
zanamivirassoonaspossible.(Strongrecommendation,lowqualityevidence).
Recommendation08appliestoallinfantsandyoungchildren(inparticularthose
lessthan2 yearsof age),sincetheyareknowntobeathigherriskofdeveloping
severeorcomplicatedillness.
Other Treatment Considerations:
Zanamivir (as inhaled powder) is only indicated for use in persons aged 5 years or
above.
OseltamivirdosingshouldbeasdescribedinRecommendation07above.

OtherremarksandnotesareasgivenforRecommendation05above.Inparticular,carersof
childrenwhodonotreceiveantiviraltreatmentshouldbe
counseledonsignsofprogression
or deterioration of illness and advised to seek medical attention immediately, should the
conditiondeteriorateorpersist.
6.4 Use of antivirals where antiviral resistance is known
or suspected
The Guidelines Panel recommends that, in general, an antiviral medication should not be
usedwherethevirusisknownorhighlylikelytoberesistanttothatantiviral.Thisisbased
ontheprinciplethatthedrugisexpectedtobeineffectiveand,therefore,thepotentialcostor
adverse eventswould
 notbe justified. However,the evidence forlack ofclinical efficacyin
thesesettingsisoflowquality.

Continued use of an antiviral drug (to which resistance is known orsuspected), the use of
combination treatments, or alternative doses may be appropriate in the context of
prospectiveclinicalandvirological
datacollectionaspartofanapprovedresearchprotocol.
Of current concernis the mutation(H275Y) in the neuraminidase thatconfers resistance to
oseltamivir, but not to zanamivir, since this had become prevalent in the seasonal H1N1
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

18
influenzavirus,andsporadiccaseshavebeenreportedinpandemic(H1N1)2009virus.The
followingrecommendationaddressesthisparticularcontext:
Rec09: Patients who have severe or progressive clinical illness with virus resistant to
oseltamivirbutknownorlikelytobesusceptibletozanamivir,shouldbetreated
withzanamivir.(Strongrecommendation,verylowqualityevidence.)
Other Treatment Considerations:
Intravenous zanamivir is likely to be the preferred formulation in this setting,
(whereavailableandsubjecttotheprovisionsofRecommendation15).

Where intravenous zanamivir is not available, intravenous peramivir may be
considered (subject to Recommendation 15), although oseltamivir‐resistant
virusesarereportedtohavereducedsusceptibilityinvitroto
peramivir.

The panel noted an urgent need for alternative dosage form and products with
datatosupporttheiruseinthispopulation.
Remarks:
Thisrecommendationtakesaccountof:

– The need to offer alternative treatment to patients with severe or progressive

illness inthe absence ofoseltamivir orif thevirus isknown to be resistant to
oseltamivir.
– The practical difficulties in administering inhaled zanamivir to severely ill
patientsinitscurrent
dosageform.
– The uncertain activity and clinical efficacy of intravenous peramivir against
infection with oseltamivir‐resistant pandemic (H1N1) 2009 virus that has the
H275Ymutation.
6.5 Antiviral treatment recommendations: Other
influenza virus strains
Antiviraltreatmentrecommendationsforinfectionwithinfluenzavirusstrainsother
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
virusinfection.Thefollowingadditionalpointsshouldbeconsidered:
Forthetreatmentofthose
presentingwithuncomplicatedillness,thedecisiontotreat
shouldallowfortheriskofdevelopmentofsevereorprogressivedisease,whichmay
not be the same as observed with the pandemic (H1N1) 2009 virus, and should be
baseduponclinicaljudgment.
Ifillnessisknownorsuspectedtobedue
toazoonotic(animal‐derived)influenzaA
virus, such as swine influenza viruses (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
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

19
WHO rapid advice guidelines on pharmacological management of humans infected
withhighlypathogenicavianinfluenzaA(H5N1)virus.

13

WheretheinfectionisknownorsuspectedtobeduetoseasonalinfluenzaA(H1N1 )
virus, oseltamivir is unlikely to be effective, but either amantadine or rimantadine
may be used when the virus is likely susceptible (subject to Recommendation 10 
below).Zanamivirisalsoatreatmentoptionifavailable.
Rec10: Pregnant women and children aged less than 1 year with uncomplicated illness
due to seasonal influenza A (H1N1) virus infection should not be treated with
amantadineorrimantadine.(Strongrecommendation,verylowqualityevidence).
Remarks:
Thisrecommendationtakesaccountof:

– The concern about the increased risk of adverse events dueto amantadine or
rimantadineinpregnantwomenandlackofevidencesupportinguseinyoung
childrenaged<1year.
6.6 Use of antivirals for chemoprophylaxis of pandemic
influenza A (H1N1) 2009 virus infection
Antiviralchemoprophylaxisisgenerallynotrecommended,

Presumptive(post‐exposure)antiviraltreatmentmayhaveparticularbenefitsinsomehigher
risk situations. That is, the initiation of an antiviral treatment course (twice daily) on the
presumption that influenza virus infection has happened, even if symptoms have not yet
appeared. This is likely
to be limited to health‐care settings such as groups of patients at
higher risk for complications from influenza virus infection (including, but not limited to, 
transplant units, other patients with severe immunosuppression, neonatal units) and other
highly vulnerable patients in other settings.In these situations, when influenza virus
infection is
 present in the institution or immediate community, the following
recommendationapplies:

Rec11: Ifhigherriskindividualshavebeenexposedtoapatientwithinfluenza,consider
presumptive treatment with oseltamivir or zanamivir. (Strong recommendation,
verylowqualityevidence).
In other situations where risk of infection is a cause for concern, caregivers are advised to
monitor exposed, high‐risk patients closely for early signs and symptoms of acute
respiratory infection and ILI (see Section 2: Case Description) and to initiate antiviral
treatmentpromptlyasdescribedin
Recommendations05and08.

Remarks:

13
WHORapidAdviceGuidelinesonpharmacologicalmanagementofhumansinfectedwithavianinfluenzaA
(H5N1)virus.WorldHealthOrganization,May2006.Availableat:
/>.Lastaccessedon
10February2010.
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

20

Thisrecommendationtakesaccountof:

– Reportsofoseltamivirresistancefollowingpost‐exposureprophylaxisfailure.
– Severely immunosuppressed persons who may not manifest fever with
influenza virus infection or who might have atypical symptoms that do not
meetadefinitionofILI.
6.7 Other considerations
Additional treatment considerations concerning the use of antiviral medicines and which
maymodifyrecommendations01‐11areasfollows:


RenalImpairment
Whentreatingpatientswithrenalimpairment,considerationneedsto begiventothe likely
higher systemic exposure to oseltamivir.This is particularly important for those patient
groups(pregnancy, pediatric
populations) wherethereislessexperience ordataonthe use
ofhigheroseltamivirdoses.Cautionshouldbeexercisedinthesepatients,particularlyover
theuseof higherdoses ofoseltamivir(information ondose adjustmentbased oncreatinine
clearanceisgivenintheSummaryofProductCharacteristics
14
).

Obesity
Thepanelnotedreportsofsevereillnessinobesepatientsandarecentreportindicatingthat
oseltamivirvolumeofdistributioninobesepatientswassimilartothatinnon‐obesepatients.
However, there are currently insufficient data to determine whether dose adjustment (e.g.
higherdosing)isneededin
obesepatients.

Pregnancyandbreastfeeding
Treatment recommendations for pregnancy and breastfeeding are covered by
recommendations 01‐05 and 09‐18 and there are no exclusions, except as covered by
Recommendations10and13.Thefollowingaresomeadditionalconsiderationsfortreatment
ofinfluenzavirusinfectioninpregnancy:
• There are
fewerdataon safetyand efficacyin thispatient groupfor allantiviral
medicines,thoughthereismorereportedexperiencewiththeuseofoseltamivir.
• The dosing recommendations are as for other adult patient groups for each
antiviraldiscussed.
7. Other interventions for management

of patients with influenza
Anumberofotherproductsarenotlicensedforthetreatmentofinfluenzainmostcountries
but have been used for treatment of individual patients or ar e approved in a very limited


14
Avaiablefrom />accessedon2March2010.

Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
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21
number of countries. The Panel considered theevidence for theuse of the following drugs
(seebelow)forthetreatmentofinfluenza,butconcludedthattherewereinsufficientdataon
either efficacy or safety or both and, therefore, there is inadequate evidence for treatment
recommendationsatthistimefor:

Immunoglobulins(includingmonoclonalantibodies,immuneandconvalescentsera/plasma
andrelatedproducts)
Intranasalinterferons
Arbidol
Ribavirin
Favipiravir

The Panelmade two recommendations with regard to the lack of efficacy dataand known
toxicityofribavirin:
Rec12: In patients with confirmed or strongly  suspected influenza virus infection,
ribavirinshouldnotbeadministeredasmonotherapy.Ifribavirinistobeusedin
combination with other therapies, this should be done only in the context of
prospectiveclinicalandvirologicaldatacollectionaspartofanapprovedresearch

protocol.
Rec13: In pregnant women with confirmed or strongly suspected influenza virus
infection,ribavirinshouldnotbeadministeredastreatmentorchemoprophylaxis.
(Strongrecommendation,regulatorycontraindication.)
With regard toall investigational, regional,
15
and otherunapproved therapies,inclu ding all
antiviral medicines and their formulations as listed above, the Guidelines Panel had the
followingrecommendation:
Rec14: 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
collectionaspartofanapprovedresearchprotocol.
Recommendation 16 should also be applied to the use of combinations of antiviral drugs
(includingapprovedmedicines),sincetherearefewpublishedclinicaltrialdataonthesafety
orefficacyofsuchcombinations.

Withregard totheinvestigational andregionalproductslisted below,
the Guidelines Panel
acknowledgedthestatusoftheseproductsinclinicaldevelopmentandthattheywereofthe
sameclass orchemicalentityastheexisting, approvedneuraminidaseinhibitors.However,
inlightofthepaucityofpublisheddataonefficacyandsafety,thepanelmadethefollowing
recommendation:



15
Regionalproductsarethosethathavemarketauthorisationsinonlyoneorafewcountries.
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

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22
Rec15: In patients with confirmed or strongly su spected influenza virus infection,
investigational neuraminidase inhibitors shouldonly be usedin the context of a
clinicaltrialorinaccordancewithrelevantemergencyuseprovisions.
Remarks
Thisrecommendationappliestothefollowinginvestigationalorregionalproducts:

• Peramivir(parenteralformulation)
• Laninamivir
• Zanamivir(parenteralformulation)
• Oseltamivir(parenteralformulation)

Peramivirhasreceivedmarket authorization inJapan,butisinvestigationalorunregistered
elsewhere.Therearefewpublishedclinicaltrialdataforperamivir.

Thisrecommendationtakesaccountof:
• Thelimitedavailabilityoftheseproductsinmostcountries.
• Legal and ethical complexities, including import/export restrictions and consent
requirements,
oncompassionateoremergency useofinvestigationalorunregistered
products.

Individual countries should develop local recommendations in the context of local market
authorizations.

Rec16: Zanamivircontaininglactose(powderforinhalation)shouldnotbeadministered
bynebulizer.(Strongrecommendation,regulatorywarning.)

Exacerbatedco‐morbidities(underlyingconditions)andco‐infectionsshouldbemanagedin

accordancewithstandardofcareforsuchconditions,exceptasqualifiedbelow:

Rec17: Patients who have severe or progressive clinical illness, including viral
pneumonitis, respiratory failure, and ARDS due to influenza virus infection,
shouldnotbegivensystemiccorticosteroidsunlessindicatedforotherreasonsor
as part of an approved research protocol. (Strong recommendation, low quality 
evidence).
Remarks:
 Thisrecommendationtakesaccountof:

• Alackofevidenceofbenefitinthesepatients.
• Riskof harm,includingopportunisticinfection andprolongation ofvirus
replication.
• Theneedforcorticosteroidtreatmentforotherconditionssuchasasthma,
COPD,ongoinganti‐inflammatorytreatment,andadrenalinsufficiency.
Rec18: In children and adolescent (<18 year old) patients with confirmed or strongly
suspected influenza virus infection, treatment with drugs containing salicylates
(e.g. aspirin) should not be initiated. (Strong recommendation, regulatory
warning.)
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations

23
Remarks:

 Theserecommendationstakeaccountof:
• The increased risk of Reyeʹs syndrome with influenza and salicylate
administrationinyoungerpatientpopulations.
• Patientswhomayalreadybetakingsuchmedicinesforotherindications.
Pharmacological Management of Pandemic Influenza A (H1N1) 2009

Part I: Recommendations

24
8. Product supply
The list of influenza antiviral medicines that have been approved through the WHO
prequalification programme is set out below. For an up‐to‐date list, consult the WHO
websiteatwww.who.int/pr equal
.Theavailabilityandpriceoftheseproductswillvaryona
country‐by‐countrybasis.
Pharmacological Management of Pandemic Influenza A (H1N1) 2009
Part I: Recommendations
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25

9. Priorities for update
Plans for updating this guideline
Anupdatetothisguidelinewillbeneeded,ifanyofthefollowingeventsoccur:

– majornewresearchispublished(particularlyrandomizedcontrolledtrialsofanyof
theantiviralsorobservationalstudies);
– newantiviraldrugsordosageformsbecomeavailable;and/or
– thereisachangeinthe
severityofillnessassociatedwiththecurrentpandemic(H1N1)
2009orothercirculatinginfluenzaviruses,orintheirsusceptibilitytoantiviraldrugs,
ortheemergenceofanovelinfluenzaAvirusofglobalpublichealthimportance.
WHOwillreviewthevalidityoftheseguidelinesevery6months,withregardtothe
above
criteria,unlesstheseguidelinesaresupersededbynew,consolidatedorstandardguidelines.
ThenextsuchreviewwillbeSeptember2010.
Updating or adapting recommendations locally

Themethodsused todeveloptheseguidelinesaretransparent.Thereforeitwill bepossible
to update the information contained in them by re‐running the search described in Part II.
Therecommendationshavebeendevelopedtobeasspecificanddetailedaspossiblewithout
losing sightof theuser‐friendliness of
 thisdocument and the individualrecomm endations.
The Panel encourages feedback on all aspects of these guidelines, including their
applicability in individual countries. It may then be possible to decide whether the
recommendations should be am ended to accommodate the changes in information. The
Guidelineshavealsobeendesignedinsucha
waytofacilit atethisprocess,incaseusersneed
toupdateoradapttherecommendationsbeforetheWHOhasitselfupdatedthemglobally.