h1n1 Guidelines Pharmaceutical Mngt

8/13/2019 h1n1 Guidelines Pharmaceutical Mngt

1/32


2/32

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


3/32



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)


possible(03)

Patientswithsevere

immunosuppression

Treatwithoseltamiviras

soonaspossible. Consider

higherdosesandlonger

durationoftreatment(03)


possible(03)

1Regionalproductsarethosethathavemarketauthorisations inonlyoneorafewcountries.


4/32



4

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:


5/32



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 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.


6/32



6

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.


7/32



7

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)


8/32



8

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.


9/32



9

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.


10/32



10

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,


11/32



11

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.)


Drugdelivery. Zanamivircontaining lactose(powderfor inhalation)shouldnotbeadministeredbynebulizer(seeRecommendation18).


12/32



12

R em a r k s :


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.)


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).


13/32



13

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.)


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


14/32



14


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.


Antiviralresistance.Zanamivir,whereavailable,isthetreatmentofchoiceforallpatientswhereoseltamivirresistanceisdemonstratedorhighlysuspected.

R em a r k s :



15/32



15

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).


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


16/32



16

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).


17/32



17

R em a r k s :


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.


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


18/32



18

influenzavirus,andsporadiccaseshavebeenreportedinpandemic(H1N1)2009virus. The

followingrecommendationaddressesthisparticularcontext:

Rec09: Patients who have severe or progressive clinical illness with virus resistant tooseltamivirbutknownorlikelytobesusceptibletozanamivir,shouldbetreated

withzanamivir. (Strongrecommendation,verylowqualityevidence.)


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 :


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


19/32



19

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 :


Theconcernabout the increasedriskofadverseeventsdue toamantadineor

rimantadineinpregnantwomenandlackofevidencesupportinguseinyoung

childrenaged


20/32



20


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.


21/32



21

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.


22/32



22

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.


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 :


Alack

of

evidence

of

benefit

in

these

patients.

Riskofharm,includingopportunisticinfectionandprolongationofvirus

replication.

Theneedforcorticosteroidtreatmentforotherconditionssuchasasthma,

COPD,ongoingantiinflammatorytreatment,andadrenalinsufficiency.

Rec18: In children and adolescent (


23/32



23

R em a r k s :

Theserecommendationstakeaccountof:

The increased risk of Reyes syndrome with influenza and salicylate

administrationinyoungerpatientpopulations.

Patientswhomayalreadybetakingsuchmedicinesforotherindications.


24/32



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 uptodate list, consult the WHOwebsiteatwww.who.int/prequal.Theavailabilityandpriceoftheseproductswillvaryona

countrybycountrybasis.


25/32



25

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.


26/32



26

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.


27/32



27

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


28/32


29/32



29

ProfessorGregoryL.KEARNSPediatricsandPharmacology

UniversityofMissouriatKansasCity

2401GillhamRoad

KansasCity,MO64108

USA

Tel.:

+1816

234

3961

Fax: +18168551703

[email protected]

ProfessorAnthonyNUNNClinicalDirector,DepartmentofPharmacy

AlderHeyChildrensNHSFoundationTrust

UniversityofLiverpool

EatonRoad

LiverpoolL122APUK

Tel:+441512525314

Fax:+441512525675

[email protected]

DrLisaBEROProfessorofClinicalPharmacyand

HealthPolicy

UniversityofCalifornia,SanFrancisco

3333CaliforniaStreet,Suite420

SanFrancisco,CA 94118

USA

Tel:+14154761067

[email protected]

AssociateProfessor

Norio

SUGAYA

KeioUniversitySchoolofMedicine

KeiyuHospital

DepartmentofPediatrics

373 Minatomirai, Nishiku, Yokohama, 2200012Kanagawa,JAPANTel. +81452218181

Fax:+81456819665

[email protected]

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

[email protected]

1. ProfessorAnitaZAIDITheA.SultanJamalProfessor

DepartmentofPaediatricsandChildHealth

AgaKhanUniversityStadiumRoad

P.O.Box

3500

Karachi74800Pakistan

Tel.:+9221349300514734

Fax:+922134934294

[email protected]

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)


30/32



30

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 (


31/32



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.


32/32



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.

h1n1 Guidelines Pharmaceutical Mngt

Documents

Transcript of h1n1 Guidelines Pharmaceutical Mngt