Clinical and Programmatic Guide for Patient Management ... guide for New … · 1 Introduction Two new anti-TB drugs have been granted conditional medical approval by stringent regulatory

endTB

Clinical and Programmatic Guide for Patient Management with

New TB Drugs

Version 4.0

Version4.0,January2018 Page2of70

NoticeThis guide is designed to give guidance to the endTB sites on the use of new TB drugsbedaquilineanddelamanid.Itisintendedtobearesourceforphysiciansandotherhealthcareprofessionals involved in the endTB. Every effort possible has beenmade to ensure that thematerialpresentedhereisaccurate,reliable,andinaccordwithcurrentstandards.It is the responsibility of the individual physician or other health care professional to usehis/herbestmedicaljudgmentindeterminingappropriatepatientcareortreatment.Youruseof this guide is provided on an "as-is" basis without warranty of any kind, and none of theentitieslistedaboverepresentorwarrantthattheinformationcontainedhereiniscompleteoraccurateor free fromerror.Bychoosing touse thisguide,youacknowledgeandagree to thetermsofthisdisclaimer.Updated versions of this guide are posted at www.endTB.org. Future versions will also beavailableinSpanish,FrenchandRussian.Ifreproducingpartorallofthisguide,pleasereferencewiththeappropriateversionanddate:

endTB Consortium. endTB Clinical and Programmatic Guide for Patient ManagementwithNewTBDrugs.Version4.0;January2018.


Table of Contents Tableoftables..............................................................................................................................................................................5 Acknowledgements..................................................................................................................................................................6 Listofabbreviations.................................................................................................................................................................7 1 Introduction.......................................................................................................................................................................9 2 Groupingofanti-TBdrugsusedforthetreatmentofRRandMDR-TB............................................10 3 Eligibility...........................................................................................................................................................................11 3.1 Eligibilitycriteriaforbedaquilineordelamanid................................................................................11 3.2 NewandrepurposeddrugstobeusedinendTB...............................................................................11 3.3 Cautionsandwarnings....................................................................................................................................12 3.3.1 Contraindicationsfornewandrepurposeddrugs..................................................................12 3.3.2 Drug-druginteractions..........................................................................................................................13 3.3.3 Overlappingtoxicities............................................................................................................................14

4 Regimendesign.............................................................................................................................................................16 4.1 Step-by-stepdirectionsforregimendesign.........................................................................................16 4.2 OperationalresearchonshorterstandardizedregimensusingthenewandrepurposedTBdrugs.................................................................................................................................................................................19 4.3 InterpretationofphenotypicandgenotypicDSTresults..............................................................20 4.4 Howtochoosebetweenbedaquilineanddelamanid......................................................................21 4.5 Dosingofnewandrepurposeddrugs......................................................................................................21 4.6 Durationofbedaquilineanddelamanid.................................................................................................22 4.7 Off-labeluseofnewandrepurposedTBdrugs..................................................................................23 4.7.1 Children.........................................................................................................................................................24 4.7.2 Pregnancyorlactation...........................................................................................................................25 4.7.3 ExtrapulmonaryTB.................................................................................................................................26

4.8 Specialpopulations...........................................................................................................................................26 5 Patientconsent..............................................................................................................................................................28 5.1 Patientconsent....................................................................................................................................................28 5.2 Example ofmedication guide andpatient consent for the clinical use of bedaquilineanddelamanid.....................................................................................................................................................................28

6 Monitoringschedule...................................................................................................................................................37 6.1 Monitoringscheduleforpatientfollow-up...........................................................................................37

7 Drugsafety.......................................................................................................................................................................40 7.1 Scopeofsafetydatacollectionanddefinitions...................................................................................40 7.2 Recording,medicalassessmentandnotificationofadverseevents........................................41 7.3 Clinicalmanagementofadverseeventsofinterest..........................................................................43 7.3.1 Peripheralneuropathy..........................................................................................................................43


7.3.2 Myelosuppression(anemia,thrombocytopenia,orneutropenia)..................................46 7.3.3 ProlongedQTinterval............................................................................................................................47 7.3.4 Opticnervedisorder(opticneuritis).............................................................................................52 7.3.5 Elevatedliverenzymes(hepatotoxicity).....................................................................................53 7.3.6 Hearingimpaired.....................................................................................................................................54 7.3.7 Acutekidneyinjury.................................................................................................................................58 7.3.8 Hypokalemia...............................................................................................................................................59 7.3.9 Hypothyroidism........................................................................................................................................62

7.4 Frequentadverseevents................................................................................................................................64 8 References........................................................................................................................................................................69


Table of tables

Table1Medicinesrecommendedforthetreatmentofrifampicin-resistantandmultidrug-resistantTB(adaptedfromWHO2016treatmentguidelinesforDR-TB)...............................................10Table2Contraindicationsfornewandrepurposeddrugs*..............................................................................12Table3Possibledrug-druginteractionswiththenewTBdrugs§................................................................13Table4Possibledrug-druginteractionsbetweenantiretroviralsandthenewTBdrugs...............14Table5Non-TBdrugsthathavepotentialoverlappingtoxicitieswiththenewTBdrugs..............15Table6ThebuildingstepsforM/XDR-TBregimens...........................................................................................16Table7Examplesofpossibleregimens......................................................................................................................18Table8Dosingofnewandrepurposeddrugsinadults.....................................................................................21Table9Treatmentofchildrenwithnewandrepurposeddrugs...................................................................24Table10Treatmentofpregnantorlactatingwomenwithnewandrepurposeddrugs...................25Table11TreatmentofextrapulmonaryTBwithnewandrepurposeddrugs.......................................26Table12Specialpopulations............................................................................................................................................26Table13Monitoringschedule.........................................................................................................................................37Table14Generaldefinitionofseverity.......................................................................................................................42Table15Causalitycategoriesdefinition....................................................................................................................42Table16Clinicalmanagementofperipheralneuropathyaccordingtoseveritygrading................43Table17Clinicalmanagementofmyelosuppressionaccordingtoseveritygrading..........................46Table18ClinicalmanagementofprolongedQTintervalaccordingtoseveritygrading..................51Table19Clinicalmanagementofopticnervedisorderaccordingtoseveritygrading.....................53Table20Clinicalmanagementofelevatedliverenzymesaccordingtoseveritygrading................54Table21Clinicalmanagementofhearingimpairmentaccordingtoseveritygrading......................56Table22Clinicalmanagementofacutekidneyinjuryaccordingtoseveritygrading........................58Table23Clinicalmanagementofhypokalemiaaccordingtoseveritygrading......................................60Table24Clinicalmanagementofhypomagnesemiaaccordingtoseveritygrading...........................60Table25Potassiumreplacementtherapy.................................................................................................................61Table26Magnesiumreplacementtherapy...............................................................................................................62Table27Clinicalmanagementofhypothyroidismaccordingtoseveritygrading...............................62


Acknowledgements

This guide and endTB are generously supported by Unitaid. Unitaid is a unique fundingmechanismengagedinfindingnewwaystoprevent,treatanddiagnoseHIV/AIDS,tuberculosisandmalariamorequickly,morecheaplyandmoreeffectively.Ittakesgame-changingideasandturns them into practical solutions that can help accelerate the end of the three diseases.Website:www.unitaid.euCoreWritingTeam:

KJSeungMichaelRichFrancisVaraineContributorsandReviewers:

CathyHewisonAlexTelnovCharlesSsonkoUzmaKhanNathalieLachenalLorenzoGuglielmetti


List of abbreviations

aDSM activeTBDrug-SafetyMonitoringandManagementACTG AIDSClinicalTrialGroupAE AdverseEventADL ActivitiesofdailylivingALT AlanineaminotransferaseAm AmikacinAmx AmoxicillinART Anti-retroviraltherapyARV Anti-retroviralAST AspartateaminotransferaseAZT ZidovudineBdq BedaquilineBMI BodyMassIndexBPNS BriefPeripheralNeuropathyScreenBSA BodySurfaceAreaCfx ClofazimineClv ClavulanateCm CapreomycinCln CilastatinCNS CentralNervousSystemCs CycloserineCTCAE CommonTerminologyCriteriaforAdverseEventsCYP CytochromeP450d4T StavudineDAA Direct-actingAntiviralsddI DidanosineDIP DistalinterphalangealDlm DelamanidDMID DivisionofMicrobiologyandInfectiousDiseasesDR-TB Drug-resistantTuberculosisDST DrugSusceptibilityTestingE EthambutolECG ElectrocardiogramECOG EasternCooperativeOncologyGroupEFV EfavirenzEMA EuropeanMedicinesAgencyEMR ElectronicmedicalrecordendTB ExpandNewDrugsforTBEPO ErythropoietinEto EthionamideFDA UnitedStatesFoodandDrugAdministrationFQ FluoroquinoloneGI GastrointestinalH IsoniazidHh High-doseisoniazidHIV HumanImmunodeficiencyVirusIpm ImipenemIRD InteractiveResearchandDevelopmentKm KanamycinLfx LevofloxacinLLN LowerLimitofNormal


Lzd LinezolidMCV MeanCorpuscularVolumeMDR Multidrug-resistanceMDR-TB Multidrug-resistantTuberculosisMfx MoxifloxacinMfxh High-dosemoxifloxacinMSF MédecinsSansFrontièresMTB/RIF MycobacteriumTuberculosis/RifampicinMWF Monday-Wednesday-FridayNCI NationalCancerInstituteNIAID NationalInstituteofAllergyandinfectiousDiseasesNTP NationalTuberculosisProgramNVP NevirapineOfx OfloxacinPAS Para-AminosalicylicAcidPIH PartnersInHealthPto ProthionamidePO PerosPV PharmacovigilanceQTcF QTintervalFridericia’scorrectionS StreptomycinSAE SeriousAdverseEventSL SecondLineSLD SecondLineDrugSSRI SelectiveSerotoninRe-uptakeInhibitorTB TuberculosisTrd TerizidoneTDF TenofovirTSH ThyroidStimulatingHormoneULN UpperLimitofNormalWHO WorldHealthOrganizationXDR ExtensiveDrugResistanceXDR-TB ExtensivelyDrug-resistantTuberculosisZ Pyrazinamide


1 Introduction

Twonewanti-TBdrugshavebeengrantedconditionalmedicalapprovalbystringentregulatoryauthorities,bedaquilinebytheFDA(2012)1andEMA(2013)2anddelamanidbyEMA(2013).Togainfullapproval,thedrugmanufacturershavebeenrequiredtoperformPhaseIIItrialsinthenextfewyearstodemonstrateefficacyandsafety.Otsukahasrecentlyreportedinterimresultsof the Phase III study of Delamanid trial 213. Janssen hasnot registered a phase III trial forbedaquiline although it forms part of several regimens under investigation in other studies(endTB,TBPRACTECAL,NiX-TB,Next,STREAM2).InadditiontothetwonewTBdrugs,in2016,tworepurposeddrugs,linezolidandclofaziminewereelevatedbytheWorldHealthOrganization(WHO)tocoresecond-linemedicinesforMDR-TBtreatment.Thereisalsoevidencefromclinicalstudiesthatsupportstheuseofcarbapenems(imipenem/cilastatinandmeropenem)forthetreatmentofMDR-TBincertaincircumstances.UnderthefundingmechanismofUnitaid,endTBaimstoincreaseuptakeofthenewTBdrugsandrepurposedTBdrugsthroughanumberofinitiatives.AmainactivityoftheprojectisgiveaccesstonewTBdrugsandregimenstoalargecohortofpatientsacrossmultiplecountrieswhoarereceivingclosemonitoringandpharmacovigilance.Theobjectiveof thisguideistoprovideguidance tophysicianswhoaremanaging thecareofMDR-TBpatientsenrolledinendTB.ThisguideisnotmeanttoreplaceWHOguidelinesorNTPguidelines;itaimsatcomplementingthenationalguidelinesiftheyhavenotyetincorporatednewTB drugs or updating them if already incorporated. The guide ismeant to be used as atemplateandtobeadaptedbyNTPsandprojects,aslongastheadaptationsremainconsistentwithWHOrecommendations.Thisguideprovidesthefollowinginstructionstoaidtheclinician:• IdentifyingwhoneedsnewTBdrugs.• HowtobuildaMDRregimenwiththenewTBdrugs.• Implementing close monitoring of patients for response to treatment and for potential

adverseevents.The endTB project employs active pharmacovigilance for adverse events, including potentialreactions to anewTBdrugwhich are yet tobedescribed, through immediatenotificationofseriousadverseeventstocentralpharmacovigilanceunit.Thisguideincludesprotocolsonthegradingandmanagementofadverseevents.

1FDAwebsite[online].Availableat:http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm293600.htm2EMAwebsite[Online].Availablefrom:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002552/human_med_001699.jsp&mid=WC0b01ac058001d124.


2 Grouping of anti-TB drugs used for the treatment of RR and MDR-TB

In2016,theWHOregroupedtheTBmedicinesbeingusedforrifampicin-resistantTB(RR-TB)andMDR-TB.Bedaquilineanddelamanidwereplacedintheanti-TBdrugGroupDbytheWHO:"Add-onagents(notpartof the coreMDR-TBregimen)".Because thenewTBdrugshave themostevidenceofefficacy,GroupD2isprioritizedoverD1andD3.RepurposeddrugssuchastheGroup C drugs linezolid and clofazimine and Group D3 drugs (imipenem/cilastatin andmeropenem)alsoplayanimportantroleinbuildinganeffectiveregimen.ThisguideaddresseshowtousebothnewandrepurposeddrugsinthetreatmentofMDR-TB.SeeSection4.1forastep-by-stepguideforbuildinganMDR-TBregimen.

Table1Medicinesrecommendedforthetreatmentofrifampicin-resistantandmultidrug-resistantTB(adaptedfromWHO2016treatmentguidelinesforDR-TB)

GroupA:Fluoroquinolones

LevofloxacinMoxifloxacin

LfxMfx

GroupB:Second-lineinjectableagents

AmikacinCapreomycinKanamycin

AmCmKm

GroupC:*Othercoresecond-lineagents

Ethionamide/ProthionamideCycloserine/Terizidone

Linezolid�Clofazimine

Eto/PtoCs/TrdLzd�Cfz

GroupD:†Add-onagents

(notpartofthecoreMDR-TBregimen)

D1 PyrazinamideEthambutol

High-doseisoniazid

ZEHh

D2 BedaquilineDelamanid

BdqDlm

D3 p-aminosalicylicacidImipenem-cilastatin

MeropenemErtapenem

Amoxicillin-clavulanate

PAS�Ipm/ClnMpmEpm

Amx/Clv†Carbapenemsandclavulanatearemeanttobeusedtogether;clavulanateisonlyavailableinformulationscombinedwithamoxicillin.


3 Eligibility

3.1 Eligibility criteria for bedaquiline or delamanid

Therearetwogroupsofpatientseligiblefortheuseofbedaquilineordelamanid: ThefirsteligibilitygroupisforanypatientthatdoesnothavefivelikelyeffectivedrugsfromGroups A, B or C with at least one from group A and one from group B at the start oftreatment.Commonsituationsforthefirsteligibilitycriteriainclude:a. XDR-TB(resistancetoafluoroquinoloneandatleastoneinjectable).b. Pre-XDR-TB (resistance to a fluoroquinolone or to at least one second-line injectable,

butnotboth).c. PatientswithtwoormoreoftheGroupCdrugs(Eto/Pto,Cs,Lzd,Cfz)compromised.d. Contactwithapatientwithastrainwithresistancepatternofa,b,c.e. PatientsunabletotolerateMDR-TBdrugsnecessaryforconstructionoftheregimen(for

example, ototoxicity due to an injectable agent, psychosis due to cycloserine, or non-retractablenauseaandvomitingduetoethionamide).

f. Patientswhomeet theoutcomedefinitionof "failure"ofanMDR-TBregimenbyWHO2013definitions.

The second eligibility group includes any patient who has a high risk of unfavorableoutcomeforwhomastrongerregimenisrecommended:a. Patients with extensive or advanced disease (X-ray demonstrating cavitary disease,

bilaterallesions,orextensiveparenchymaldamageormultiplesysteminvolvement).b. Patients with increased likelihood of acquisition of additional resistance, treatment

failure, or death due to co-morbidities or other conditions (drug contraindication,patientswithlowbodymassindex(BMI),HIV,diabetes).

c. Patients coming from catchment areas that have poor MDR-TB treatment outcomesdespite good programmatic conditions (e.g. sites with extensive second-line drugresistancebackground).

Patients should have a sputum sample collected for second-line DST at the time of startingtreatmentwithnewTBdrugs.Second-lineDSTisimportantbecausethesecond-lineresistancepatterncanaffectthedesignofthetreatmentregimen.Ofnote,basedon theabovecriteria, second-lineDST isnotarequirement for theuseofnewdrugs. Some patients may be treated with new drugs without second-line DST, based on aclinicalhistorythataregimenwithfivelikelyeffectivedrugsincludingafluoroquinoloneandaninjectableisnotpossible; intolerancetoakeysecond-lineanti-TBdrug;orhaveahighriskofunfavorableoutcome.MDR-TB programs with success rates below 80% should consider redesigning theirstandardizedandindividualizedregimenstoincludethenewandrepurposedTBdrugs.Thisisespecially true for programs with poor treatment outcomes despite strong programmanagementandpatientsupport.SeeSection4.1onconstructinganMDR-TBregimenformoreinformation.

3.2 New and repurposed drugs to be used in endTB

Newdrugs(GroupD2):

o Bedaquiline(Bdq)


o Delamanid(Dlm)Repurposeddrugs:

o Linezolid(Lzd)(GroupC).o Clofazimine(Cfz)(GroupC).o Carbapenems(GroupD3).Imipenem/cilastatin(Ipm/Cln)ormeropenem(Mpm)arethe

twomostcommonlyused.Itisrecommendedtocombinethecarbapenem,anantibioticinthebeta-lactamclass,withclavulanicacid,abeta-lactamaseinhibitor.Clavulanicaciddoesnotexistinpillbyitselffromaquality-assuredsupplier,soamoxicillin/clavulanate(Amx/Clv)isrecommended.Meropenemhasthemostdatapublishedintheformofcaseseries.Itisusuallydosedthreetimesdaily.Ertapenem(Epm)isalsoacarbapenemwithanti-TBactivityandcanbedosedoncedaily.Thereislittleexperiencewithertapenemto date3,4and should only be considered when the use of Ipm/Cln or Mpm is notpossible.

o Evidence suggests Amoxicillin/Clavulanate (Amx/Clv) (Group D3) is at best weaklyeffective,andshouldnotbeusedalonewithoutthecarbapenem.

3.3 Cautions and warnings

3.3.1 Contraindications for new and repurposed drugs TherearenoabsolutecontraindicationsfortheuseofanydruginthetreatmentofMDR-andXDR-TB, a disease that poses serious risk of death or debilitation to the patient if treatedinadequately. However, there are relative contraindications for the use of the new andrepurposeddrugs.Iftheclinicianjudgesthatthepotentialbenefitsoutweighthepotentialrisk,treatmentmayproceedwithcaution.TheendTBCentralMedicalCommitteeisalwaysavailableforcase-by-caseadvice.

Table2Contraindicationsfornewandrepurposeddrugs*

Drug Relativecontraindications Remarks/Precautions

Alldrugs Knownhypersensitivitytothedrug AhistoryofanaphylaxisorseveredrugreactionlikeStevens-Johnsonsyndromeisanabsolutecontraindication.

Bdq,Dlm • BaselineECGdemonstratingaQTcF>500ms(repeated);or

• Historyofsyncopalepisodes,ventriculararrhythmiasorseverecoronaryarterydisease

UsewithcautionifQTcF>450/470msinmale/femalepatients.WeeklyECGmonitoringandserumelectrolytescreeningshouldbeperformedifBdqorDlmisbeinguseddespiteacardiaccontraindication.DlmmayprolongtheQTintervallessthanBdq.

Bdq Severehepaticfailure Cautioninpatientswithseverehepaticimpairment.

3TiberiS,D’AmbrosioL,DeLorenzoS,etal.ErtapenemmaybeusefulforMDR/XDR-TBtosimplifyadministrationofcarbapenemwhenthepatientisathome.EurRespirJ2016;47:333–336.4vanRijnSP,vanAltenaR,AkkermanOW,vanSoolingenD,vanderLaanT,deLangeWC,etal.Pharmacokineticsofertapeneminpatientswithmultidrug-resistanttuberculosis.EurRespirJ2016;47(4):1229-34.


Bdq,Dlm,Lzd

Severerenalfailure Cautioninpatientswithsevererenalimpairment.

Ipm/Cln,Mpm,Epm

Patientswithcentralnervoussystemdisorders

Usewithcautionascarbapenemshavebeenassociatedwithseizures.

*SeeTable10forsafetyduringpregnancy.

3.3.2 Drug-drug interactions

Table3Possibledrug-druginteractionswiththenewTBdrugs§

Drugs Examples/notes

AvoidusewithBdq

Strong/moderateinducersofcytochromeP450maydecreasebloodlevelsofBdq

• Efavirenz*• Rifamycins:

o Rifampicino Rifapentineo Rifabutin

• Phenytoin• Carbamazepine• Phenobarbital• St.John’sWort

Strong/moderateinhibitorsofcytochromeP450mayincreasebloodlevelsofBdq

• Ritonavir-boostedPIs*• Oral azole antifungals (can be used up to two

weeks):o Itraconazoleo Fluconazole†

• Macrolideantibioticsotherthanazithromycin‡:o Clarithromycino Erythromycin

AvoidusewithDlm

First-linestandardanti-TBtherapy(isoniazid,rifampicin,ethambutol,pyrazinamide)

• First line anti-TB therapy with fixed dosecombination ofHREZ appears to decrease levelsof Dlm in early studies. The mechanism is notclear.

*SeeTable4foracompletelistofARTinteractions.†AllfouroralazolesinhibitCYP3A4;itraconazoleandposaconazolearemorepotentinhibitorsthanfluconazoleorvoriconazole.5‡AzithromycindoesnotinhibitCYPisoenzymesbutdoesprolongtheQTintervalsomaywanttobeavoidedforthisreason.§ ForamorecomprehensivelistofdrugsthataffectandareaffectedbythecytochromeP450system,seetheDrugInteractionswebpageoftheDepartmentofMedicineofIndianaUniversity(http://medicine.iupui.edu/clinpharm/ddis/).

5BrüggemannRJ,AlffenaarJC,BlijlevensNM,etal.Clinicalrelevanceofthepharmacokineticinteractionsofazoleantifungaldrugswithothercoadministeredagents.ClinInfDis2009;48(10):1441–58.


Table4Possibledrug-druginteractionsbetweenantiretroviralsandthenewTBdrugs

Drugs Instructions

ARVstoavoidwithBdq

Efavirenz(EFV)(UsingEFVwithBdqwillresultinlowlevelsofBdq)

• Substitute nevirapine (NVP) or integrase inhibitorinsteadofEFV.Allowa5daywashoutofEFVifpossible(substituteNVPonday1andthenstartMDRregimen5days later). If patient is critically ill with MDR-TB, nowashoutperiodisnecessary.

• WhenswitchingbacktoEFVafterendingtreatmentwithBdq,thiscanbedoneimmediatelyafterBdqisstopped.

Ritonavircontainingproteaseinhibitors(PIs)(UsingritonavirwithBdqwillresultinhighlevelsofBdq)

• Ifpossible,useanARVregimenwithnoPI.Onepossiblesolution is to substitute the PI with an integraseinhibitors(INSTIs),e.g.dolutegravir(DTG)orraltegravir(RAL).

• If a ritonavir-containing PI must be used, check ECGeverytwoweeks.

ARVstoavoidwithDlm None

• Dlmhasverylittledrug-druginteractionswithARVsandno extra drug monitoring or regimen adjustment isneeded.6

3.3.3 Overlapping toxicities Every effort should bemade to avoid the use of drugswith overlapping toxicities. However,there may be circumstances where no other option is available and the potential benefitsoutweightherisks.Forexample,afragilementalhealthpatientwithahighriskofsuicidethatmust have linezolid in the regimen (no other anti-TB drug options) could require aserotoninergicmedication.Psychiatric drugs are commonly used in MDR-TB patients for the treatment of cycloserine-inducedpsychosisorreactivedepression.Theanti-psychotics inparticulararewell-knowntoprolongtheQTinterval.ItistheresponsibilityoftheTBphysiciantounderstandtheeffectsandsideeffectsofpsychiatricdrugs,andtomonitorMDR-TBpatientstakingthesedrugscarefully,evenifthepatientisreferredtoapsychiatrist.Finally, anumberof cardiacdrugsare listed in this table. Cardiacdrugsareused inMDR-TBpatients for a number of incorrect reasons, such as to "prevent" arrhythmia, to treat cardiacsymptoms,ortodecreasetheQTinterval.Infact,thereisnocardiacdrugthatcancounteractor"protect" fromQTprolongation.Cardiacrhythm-controllingandrate-controllingdrugsshouldthereforeonlybeusedforclearindications.Sinustachycardiaisoftenaphysiologicresponsetootherpathologies. It shouldbe viewedasasymptom,not as a cardiacdisorder. For example,beta-blockersshouldnotbeusedtotreatsinustachycardiainTBpatients.7

6MallikaarjunS,WellsC,PetersenC,PaccalyA,ShoafSE,etal.Delamanidcoadministeredwithantiretroviraldrugsorantituberculosisdrugsshowsnoclinicallyrelevantdrug-druginteractionsinhealthysubjects.AntimicrobAgentsChemother,2016;60(10):5976-85.7endTBMedicalReviewBoard.Beta-blockeruseinMDR-TBpatients,ver2.0.17January2017.


Table5Non-TBdrugsthathavepotentialoverlappingtoxicitieswiththenewTBdrugs

Drugs Examples/notes

AvoidwithBdq,Dlm

DrugsthatcauseQTprolongationoraffecttheheartrhythm*

• Oralazoleantifungals(canbeuseduptotwoweeks):o Ketoconazoleo Itraconazoleo Fluconazole

• Macrolideantibiotics:o Azithromycino Clarithromycino Erythromycin

• Antipsychotics(allhavesomerisk),including:o Haloperidolo Risperidone

• Manyanti-nauseadrugs,forexample:o Ondansetrono Granisetrono Domperidoneo Chlorpromazine

• Methadone• Cardiacdrugsthatmayaffecttheheartrhythm,forexample:

o Amiodaroneo Beta-blockerso Digoxino Quinidine

AvoidwithLzd

Medicinesthatincreaseserotoninlevels

• Serotoninre-uptakeinhibitors(SSRIs):fluoxetine,paroxetine• Tricyclicantidepressants:amitriptyline,nortriptyline• Serotonin5-HT1receptoragonists• MAOinhibitors:phenelzine,isocarboxazid• Other serotoninergic agents: meperidine, bupropion, or

buspirone,quetiapine

*Thisisnotacomprehensivelist.DoctorsshouldinformthemselvesaboutpotentiallyQT-prolongingdrugsthattheirMDR-TBpatientsmaybetaking(seeCredibleMeds.org).8

8WoosleyRL,BlackK,HeiseCW,RomeroK.CredibleMeds.org:Whatdoesitoffer?TrendsCardiovascMed,2017.pii:S1050-1738(17)30114-7.


4 Regimen design

4.1 Step-by-step directions for regimen design

ThedesignorconstructionofaregimenwithnewTBdrugsisdoneaccordingtoWHOinterimguidelines for bedaquiline (2013) and delamanid (2014), and is consistent with new WHOrecommendations produced in 2016 for drug-resistant TB and updated guidelines forbedaquiline (2017). The WHO 2016 guidelines for DR-TB revised the hierarchy of druggroupingusedtotreatrifampicin-resistantTB(GroupsAtoD).

"TheconventionalregimenisdesignedwithatleastfiveeffectiveTBmedicinesduringtheintensivephase,includingpyrazinamideandfourcoresecond-lineTBmedicines - one chosen from group A, one from group B, and at least two fromgroupC(conditionalrecommendation,very lowcertainty in theevidence). If theminimumofeffectiveTBmedicinescannotbecomposedasabove,anagent fromgroupD2andotheragentsfromD3maybeaddedtobringthetotaltofive."9

The definition of an "effective TB medicine" includes both laboratory DST results and thepatient'sTBtreatmenthistory, includingtheTBcontacthistory.Inshort,clinical judgementisoftennecessarytodecidewhetheraspecificdrugcountsasaneffectiveTBmedicine.Ananti-TBdrugisconsideredlikelytobeeffectiveif:1. Thedrughasnotbeenusedinaregimenthatfailedtocuretheindividualpatient.2. DSTperformedonthepatient’sstrainindicatesthatitissusceptibletothedrug.3. No known resistance to drugs with high cross-resistance. For example, resistance to

kanamycinishighlyassociatedwithamikacinresistance.4. Noknownclosecontactswithresistancetothedrug.5. Drug resistance surveys demonstrate that resistance to the drug is rare in patients with

similarTBhistory.10ThisisparticularlyimportantfordrugsforwhichDSTisnotroutinelyperformed.

ThehierarchyofthebuildingstepsisbasedonevidenceofeffectivenessofthedrugagainstTB,potentialadverseeffects,andthelikelybackgroundresistanceinMDR-TBstrains.

Table6ThebuildingstepsforM/XDR-TBregimens

Steps Group Drugs

Step1:Assesstheneedforbedaquilineordelamanid:

• UseBdqorDlmintheregimenforanypatientwithriskofapooroutcomeasdetailed insection3.1.2, includingpatientscoming fromcatchmentareas thathave poor MDR-TB treatment outcomes (success < 80%) despite goodprogrammaticconditions.

• Insomepatients,BdqorDlmmaybeaddedasa sixthdrug in theregimen in

D2 BdqDlm

9WHO.TreatmentguidelinesforDR-TB:2016update(WHO/HTM/TB/2016.04).2016.Table1,p.10.http://apps.who.int/iris/bitstream/10665/250125/1/9789241549639-eng.pdf10WHO.CompanionhandbooktotheWHOguidelinesfortheprogrammaticmanagementofDR-TB(WHO/HTM/TB/2014.11).2014.Section5.7.1.http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf


ordertomaximizetheprobabilityofhavingfiveeffectivedrugs(alternatively,BdqorDlmcanbecountedasoneofthefiveeffectivedrugsintheregimen).

• BdqorDlmarethefirstchoiceincaseofconfirmedorsuspectedresistancetosecond-linedrugs(e.g.XDRorpre-XDR)orintoleranceorcontraindicationstoothersecond-lineTBdrugs.

• BdqandDlmcanbeused in thesameregimen.ConsiderusingbothBdqandDlminallcasesofFQ-resistantstrains.AddbothD2drugsifneededtoreachfiveeffectivedrugsintheregimen.

• Bdq or Dlm are the first choice when substituting another drug for theinjectable.

Step2.Usealatergenerationfluoroquinolone(FQ).

• AvoidMfxifpossiblewhenusingmultipleQT-prolongingdrugs.• Ifthereisonlylow-levelresistancetotheFQ,theuseofhigh-doseMfx(Mfxh)

canbeconsidered;inthiscase,thisdrugshouldnotbecountedaseffective.• BecauseoftheirexcellentactivityagainstMDRTBandtheirrelativelygoodside

effectprofile,FQmaystillbeusedinpatientswheneffectivenessisuncertain,butnotcountedasaneffectivedrug.

A LfxMfx

Step3.Addasecond-lineinjectable.

• Duetohighratesofadverseevents,injectableareoftennotusedunlesstheyarelikelytobeeffectiveandcanbeproperlymonitored.Whentheeffectivenessisuncertain (forexamplesusceptibleDSTbutpreviouslyused ina regimen thatdid not cure the patient) the risks and benefits of inclusion in the regimenshouldbediscussedwiththepatient."

• Ifasecond-lineinjectableisadded,closemonitoringofhearing,renalfunctionandelectrolytesisindicated(stoptheinjectableforGrade1hearinglossorGrade1renaltoxicity).Ifclosemonitoringcannotbedone,usealternativedrugs.

• Avoidtheinjectableinchildren,theelderly,andHIVpatients.

B AmCmKm

Step4.Addtwoormorecoresecond-linedrugs.

• Lzdisconsideredveryeffective,buthasahighincidenceofAEs.• IfEto/PtoorCs/Trdhavebeenusedinthepatient'sregimenpreviouslywithout

success,theyarerarelyusedduetohighratesofadverseevents.Iftheyareusedinsuchpatients,theyshouldnotbecountedaseffectivedrugs.

C LzdCfzEto/PtoCs/Trd

Step5.Considerfirst-linedrugs.

• First-lineTBdrugsaregenerallyoflimitedutilitybecausetheyhavebeenusedbefore,buttheycanbeconsideredinsomecases.

• Inmanycountries,theprevalenceofZresistanceamongMDR-TBstrainsissignificant.Insuchsituations,Zcanbeaddedtotheregimenbutnotcountedasoneofthe5effectivedrugs.

• IfDSTdemonstratesresistancetoZfromareliablelaboratory,considernotaddingittotheregimen.Insuchcases,itshouldnotbecountedasaneffectivedrug.

• High-doseHshouldneverbecountedasalikelyeffectivedrug.

D1 ZHhE


• Avoidhigh-doseHwithLzdbecauseofpotentialadditivetoxicityofneuropathy.

Step6.AddGroupD3drugs.

• AddGroupD3drugsuntilthereare5likelyeffectivedrugsintheregimen.• Whenthecarbapenemsareused,itisadvisedtoalsouseclavulanate(clavulanic

acid).

D3 PASIpm/ClnMpmEpm

Theabovestepsdonotmakeuseofthedrugsstreptomycinorthioacetazone.GiventheunclearroleofstreptomycinorthioacetazoneinimprovingefficacyofMDRregimensandtheadverseevents associated with these drugs, many clinicians leave these drugs out completely whendesigningMDRregimens.Ifnootheroptionsareavailable,thesedrugsmightbeconsideredforuseinanMDR-TBregimen: • StreptomycinisoftenresistantinMDR-TBstrainsandthereisalmostalwaysanalternative

injectables.Usestreptomycinonlywithdocumentedsusceptibility,meetscriteriaforlikelyeffective,unabletousesecond-lineinjectableagents,thepatienthasnohistoryofinjectableototoxicity,andtherearenootheroptionstoreachfiveeffectivedrugsintheregimen.

• Thioacetazone is aweak bacteriostatic drug and likely hasminimal effect onMDR-TB. ItshouldbeusedonlyinHIV-negativepatients.Itisnotcounteditasalikelyeffectivedrug.

Table7Examplesofpossibleregimens

Patienttype TypicalMDRRegimen*plusnewandrepurposeddrugs Examples†

PatientisverysickinsevereconditionorwithextensivelungdamagebuthasneverbeentreatedforMDR-TBbefore("SimpleMDR";SLDresistanceisunlikely).

TypicalMDRRegimenplusDlmorBdq Bdq-Lfx-Km-Pto-Cs-ZDlm-Lfx-Km-Pto-Cs-Z

PatientscomingfromcatchmentareasthathavepoorMDR-TBtreatmentoutcomesdespitegoodprogrammaticconditions(e.g.siteswithextensivesecond-linedrugresistancebackground).

TypicalMDRRegimenplusDlmorBdq Bdq-Lfx-Km-Pto-Cs-ZDlm-Lfx-Km-Pto-Cs-Z

PatienthasresistancetoinjectablesonDSTorexperiencing(orathighriskforexperiencing)ototoxicity,ornephrotoxicity.

TypicalMDRRegimenwithBdqorDlmsubstitutedfortheinjectable.LzdcanbeaddedifEto/Pto,Cs/TrdorZisunlikelytobeeffectiveoreffectivenessisunknown.

Bdq-Lfx-Pto-Cs-ZDlm-Lfx-Pto-Cs-ZDlm-Lfx-Lzd-Pto-Cs-Z

PatienthasFQresistanceonDST. TypicalMDRRegimenwithnoFQplustwoofthefollowing:Bdq/Dlm/Lzd.AllthreecanbeaddedifthereisotherresistanceinadditiontotheFQ

Bdq-Lzd-Km-Pto-Cs-ZBdq-Lzd-Km-Pto-Cs-Z-MfxH


High-doseMfxcanbeusedincaseoflow-levelFQresistancebutshouldnotbecountedasaneffectivedrug.

Bdq-Dlm-Km-Pto-Cs-ZBdq-Dlm-Lzd-Km-Z

DocumentedXDR-TBOrPatientfailedtreatmentwithtypicalMDRregimenandlikelyhasresistancetoinjectablesandthefluoroquinolones("probableXDR").

AnyGroupA-CdrugsthoughttostillbeeffectiveplusthreetofourGroupDdrugs.InthecaseoffailureofanMDRregimen,Eto/Pto,CsandZusuallycannotbeconsideredlikelyeffective.High-doseMfxcanbeusedincaseoflow-levelFQresistance.

Bdq-Dlm-Lzd-Cfz-Cs-PASBdq-Dlm-Lzd-Cfz-Eto-CsBdq-Dlm-Lzd-Cfz-Cs-PAS-MfxH

Bdq-Dlm-Lzd-Cfz-Eto-Cs-Ipm/Cln-Amx/Clv

*"TypicalMDRRegimen"meansthe2016WHO-recommendedMDRregimenwhichistypicallycomposeddesignedwithatleastfiveeffectiveTBmedicinesduringtheintensivephase,includingpyrazinamideandfourcoresecond-lineTBmedicines—onechosenfromgroupA,onefromgroupB,andatleasttwofromgroupC.†Examplesarenotcomprehensive.Alwaysreferto"howtobuildaregimen"principles.

4.2 Operational research on shorter standardized regimens using the new and repurposed TB drugs

Some programs may choose to conduct operational research using shorter standardizedregimens with new and repurposed TB drugs. Standardized regimens should only beimplemented under operational research conditions,with a research protocol andadditionalethical approval, enhanced monitoring and analysis and dissemination of results. A studyprotocoltemplateformodifiedshorterMDR-TBregimensusingnewandrepurposedTBdrugsis available from the Global Drug-resistant TB Initiative (GDI) website(http://www.stoptb.org/wg/mdrtb/)andassistance inadaptingtheprotocoltolocalcontextscanberequested.ExamplesofshorterstandardizedMDR-TBregimenswithnewandrepurposedTBdrugswhichcouldbeusedunderoperationalresearchconditionsinclude:

• 9Bdq-Lzd-Mfx-Z• 9Bdq-Cfz-Lzd-Lfx-Z• 9Bdq-Dlm-Lzd-Lfx-Z• 9Dlm-Cfz-Lzd-Lfx-Z• 9Dlm-Cfz-Mfx-Z

ExamplesofshorterstandardizedXDR-TBregimenswithnewandrepurposedTBdrugswhichcouldbeusedunderoperationalresearchconditionsinclude:

• 9Bdq-Dlm-Lzd-CfzThe above regimens have the advantage of being part of planned endTB clinical trials.Treatment outcomes and adverse events must be reported. Positive (or negative) results ofoperationalresearchon theaboveregimenscaneventuallybevalidatedby theendTBclinicaltrials.


4.3 Interpretation of phenotypic and genotypic DST results

Drug Notes

H • ResistancetoHisclassifiedaseitherhigh-level(MIC>2µg/mL)orlow-level(MIC0.2–1µg/mL)resistance.

• AkatGmutationconfershigh-levelresistancetoH;inhAconferslow-levelresistancetoH.

• Someclinicianswillusehigh-doseHwhenifDSTshowslow-levelresistance,butthereisverylimitedclinicalevidencetosupportthispractice.

Z • SequencingofthepncAgenemaybehelpfulindeterminingpyrazinamideresistance.

• PhenotypictestingZcanbedoneinqualifiedlaboratories.

FQ • AgyrAmutationconfershigh-levelresistanceacrosstheclassofFQ.FQ(includingMfxH)isshouldnotbeusedinsuchcases.

• Thedefinitionsoflow-andhigh-levelresistancearebasedonthelatestexpertconsultationandaresubjecttochange:o Low-levelresistancetotheFQisdefinedasresistanceinMGITtoOfxat2.0

mg/LorLfxat1.0mg/LorMfxat0.25mg/L)butsusceptibletohigh-levelMfxat1.0mg/L(cut-offvaluesdifferinLowensteinJensen(LJ),Middlebrook7H10and7H11medium).MfxHmaybeusedinsuchcases,butshouldnotbecountedasaneffectivedrug.

o High-levelresistancetotheFQisdefinedasresistancetoMfxinMGITat1.0mg/L.MfxHisunlikelytobeeffectiveinsuchcases.

Injectable • Anrrsmutationisthoughttoconfercross-resistancetoallinjectables,includingmoderateresistancetoCm.

• Aneispromotormutationisthoughttoconferlow-levelresistancetoKm,Am,andCm.SomeclinicianswilluseAmorCminthepresenceoftheeispromotormutationwhileothersareoftheopinionthatthesideeffectprofileandthelowlevelresistanceassociatedwiththeeismutationdoesnotjustifytheuseofAmorCmifotherdrugsareavailable.Insuchcases,AmorCmshouldnotbecountedasaneffectivedrug.

Eto/Pto • TheinhAmutationconferscross-resistancetoHandEto/Pto;katGmutationconfersresistancetoHbutnottoEto/Pto.IfinhAmutationispresent,thenEto/Ptoshouldnotbeused.IntheabsenceofinhAmutation,theclinicalhistoryshouldbetakenintoconsideration,sincethereareothermutationsthatconferresistancetoEto/Pto(e.g.ethA)thatarenottestedincommerciallyavailableLPA.

• PhenotypictestingtoEto/Ptocanbedoneinqualifiedlaboratories.

Cs,PAS • PhenotypictestingofPASandCs/Trdcanbedoneinqualifiedlaboratories.However,laboratoriesoutsideofthesupranationallaboratorynetworkareincreasinglyoptingnottodothesetestsbecauseofdifficultyinobtainingreliableresults.

Lzd,Cfz,Bdq,Dlm • Phenotypictestingofthesedrugsislimitedtosupranationallaboratoriesand


generallyconsideredreliable.Theclinicalsignificanceoftheseresults,however,isstillunclear.

4.4 How to choose between bedaquiline and delamanid

Factorstobetakeninconsiderationwhendecidingbetweenbedaquilineanddelamanid:

• Thereiscurrentlymoreexperiencewiththeuseofbedaquiline11,12,13,14inthetreatmentofXDR-TBthanthereisfordelamanid15.

• Delamanid'sexcellentsafetyprofilewasconfirmedinthephaseIIIclinicaltrial.Therewasalso quicker culture conversion in some of the analyses, butno significant effect on finaltreatmentoutcome.BedaquilinehasnotcompleteditsphaseIIIclinicaltrial.

• Delamanid has less drug-drug interactionwith ART and other drugsmetabolized by thecytochromeP450enzymeslikeCYP3A4.

• Thereistheoreticalcross-resistancebetweenclofazimineandbedaquiline.

4.5 Dosing of new and repurposed drugs

Table8Dosingofnewandrepurposeddrugsinadults

Drug Suggesteddosing* Remarks

Bdq(100mgtablets)

400mgoncedailyfor2weeks,then200mg3timesperweekafterwards.

• Minimum48hoursbetweendosesafterthefirst2weeks.

Dlm(50mgtablets)

100mgtwicedaily(200mgtotaldailydose).

• 7daysperweek.

Lzd(600mgtablets)

600mgoncedailyfordurationoftreatment

• 7daysperweekispreferred,althoughmanyprogramsuse6daysaweekdosing.

• Alternativedosingregimensforpatientswithadverseeffects:600mgthriceweekly(MWF),or300mgdaily.

Cfz(50,100mggel

200mgoncedailyfor2months,followedby100mgdailyfor

• 7daysperweekispreferred,althoughmany

11GuglielmettiL,JaspardM,LeDuD,LachatreM,Marigot-OuttandyD,etal.Long-termoutcomeandsafetyofprolongedbedaquilinetreatmentformultidrug-resistanttuberculosis.EurRespirJ2017;49(3):1601799.12NdjekaN,ConradieF,SchnippelK,HughesJ,BantubaniN,etal.Treatmentofdrug-resistanttuberculosiswithbedaquilineinahighHIVprevalencesetting:aninterimcohortanalysis.IntJTubercLungDis2015;19(8):979-985.13PymAS,DiaconAH,TangSJ,ConradieF,DanilovitsM,etal.Bedaquilineinthetreatmentofmultidrug-andextensivelydrug-resistanttuberculosis.EurRespirJ2016;47(2):564-574.14UdwadiaZF,GanatraS,MullerpattanJB.Compassionateuseofbedaquilineinhighlydrug-resistanttuberculosispatientsinMumbai,India.EurRespirJ2017;49(3).15HewisonC,FerlazzoG,AvalianiZ,HayrapetyanA,JonckheereS,etal.Six-monthresponsetodelamanidtreatmentinMDRTBpatients.EmergInfectDis2017;23(10).doi:10.3201/eid2310.170468.


capsules) durationoftreatment programsuse6daysaweekdosingforconvenience.

Ipm/Cln**(onevialhasIpm500mgandCln500mg)andothercarbapenems

Ipm/Cln:1gIVtwicedaily(basedontheIpmcomponent);twovialsadministeredasa40-60minuteinfusiontwicedaily(totaloffourvialsdaily).Minimumof10hoursbetweeninfusions.Mpm:2gIVthreetimesaday.Epm:2gIVoncedaily.

• 7daysperweekduringhospitalizationoratthestartoftreatment:6daysperweekduringtheambulatoryphaseisallowed.

• Thefirstdosealwaysinhealthcaresettingsuppliedwithanti-shockkit.

• Durationdependsonthenumberofeffectivedrugsintheregimen.Atleast4effectivedrugsaftercultureconversionuntiltheendoftreatmentisstronglyadvised.SomepatientswithhighlyresistantstrainsmayrequireIpm/Clnfortheentiredurationoftreatment.

Amx/Clv875/125tabletsor1000/200powderforinjection

Ifdosingasadjunctivetherapywithacarbapenem:• Dosebasedontheclavulanic

acidcomponent,125mg60minutesorallybeforetheIVinfusionofthecarbapenem.

• Or200mgIV30minutesbeforetheIVinfusionofthecarbapenem.

IfdosingasaGroup5drugintheregimenwithoutacarbapenem,dosebasedontheamoxicillincomponent(maxdailydoseis3000mgofamoxicillin):• Adultsandchildren:80

mg/kg/dayofamoxicillincomponentin2divideddoses.

• Amx/Clvshouldbeaddedwhenacarbapenemisbeingused.

• Acarbapenemisthepreferredbeta-lactamantibioticwhenoneisindicated;however,ifacarbapenemisnotavailable,someprogramsmaychoosetouseAmx/Clvinstead.

*AlldurationsarethefulllengthoftheMDR-TBtreatmentunlessotherwisenoted.**PatientsonIpm/Clnrequirelong-termaccesstocentralveinsbecauseoftwicedailyIVinjections.Implantableaccesssystemssuchas"Port-a-cath"arethepreferredoption:Whilenotrequiredtoreceiveimipenem,theplacementofaPort-a-cathmakeslong-terminjectionofimipenemmoreconvenient,morehygienic,andlessdamagingtoperipheralveinsthanrelyingonrepeatedtwice-dailyinjectionsofimipenem.Port-a-cathinsertionisaminorsurgicalprocedurethatneeds30minto1hour.Stitchesareremovedonpost-operativeday7-10.Typicallythedeliveryoffluidsandmedicationsisdonethroughaspecialnon-coringneedleinsertedthroughtheskinandchangedonceperweek,ideallytakenoutonSaturdayeveningandreplacedonMondaymorningsothatthepatientcanhaveadaywithouttheneedle(tohaveashowerandwashhairasthesiteisnotsupposedtogetwetwhentheneedleisinserted).

4.6 Duration of bedaquiline and delamanid

One of the most common misunderstandings among clinicians is that bedaquiline anddelamanidcanonlybeprescribedfor24weeks.Infact,thesedrugsshouldbeprescribedforaminimumof24weeks,andmaybeextendeduntiltheentirelengthoftreatment.


The endTB patients are often heavily previously treated and DST shows extensive drugresistance.There isnoneed tostopbedaquilineanddelamanidif these theonlylastsafeandeffectivedrugs.Doingsorisksreversionevenaftercultureconversion.16Other studies have shown good safety of prolonged use of bedaquiline 17 and endTBpharmacovigilance through2017 have not demonstrated any unexpected safety concerns foreither bedaquiline or delamanid. Treatment should therefore be extended at the clinicaldiscretionoftheprescribingdoctorunderappropriatemonitoring.Commonreasonsforextendingbedaquilineordelamanidlongerthan24weeksinclude:• LessthanfiveeffectivedrugsintheregimenifBdqorDlmisstopped.• Lateorslowresponsetotreatment.Forexample,thepatientisslowtosputumconvert(still

stronglysmearorculturepositiveaftermonth2),hasslowresolutionofTBsymptoms,orhasextensivelungdamage.

Theconsentformsforbedaquilineordelamanidhavebeenmodifiedtoconsentto24weeksormore of treatment. There is no need to seek a second signed consent for extended use ofbedaquilineordelamanid.Theextendeduseofbedaquilineanddelamanidshouldbediscussedwith the patient in all cases; it is always recommended todocument such discussions in themedicalchart.

4.7 Off-label use of new and repurposed TB drugs

Off-labeluseisdefinedasuseforindication,dosageform,doseregimen,populationorotheruseparameternotmentionedintheapprovedlabeling.Itmayalsoincludeusingofthemedicineinan age group, in a dosage or in a form of administration different from the one of originalapproval.A number ofMDR-TB drugs, such as fluoroquinolones, some second-line injectableagents,clofazimineandlinezolid,havebeen"repurposed"foruseinTBandareusedroutinelyasoff-label.As isthecase formanyTBdrugs,off-labeluse isoftenrecommended inWHOguidelines.Forexample,delamanidisrecommendedbyWHOforchildrenolderthansixyears.However,suchpractice is currently off-label until the EuropeanMedical Agency updates the registration ofdelamanid.Furthermore, the lack of aWHO recommendation is not synonymouswith off-label use. Theconcomitantuseofbedaquilineanddelamanidtogetherisnotregardedasoff-label,sincebothdrugsarebeingusedaccordingtotheirindications.18Cliniciansshouldconsultexpertswhentreatingdifficultcases.CountriesoftenhavesetupMDR-TBcommitteesor"consilia"forthispurpose.TheendTBMedicalCommitteeisavailabletogiveadvicetoanyclinician,whetherornottheyworkatanendTBsite.

16SinhaA,TassewY,KhusainovaZ,etal.EffectivenessofTBtreatmentregimenscontainingbedaquilinewithrepurposeddrugsfordrug-resistanttuberculosisintheChechenRepublic,RussianFederation.AbstractOA-3036.[Online].2016[Cited2017May16].Availablefrom:http://www.theunion.org/what-we-do/journals/ijtld/body/UNION_Abstract_Book_2016-Web.pdf.17GuglielmettiL,JaspardM,LeDuD,LachatreM,Marigot-OuttandyD,etal.Long-termoutcomeandsafetyofprolongedbedaquilinetreatmentformultidrug-resistanttuberculosis.EurRespirJ2017;49(3):pii:1601799.18WHO.WHObest-practicestatementontheoff-labeluseofbedaquilineanddelamanidforthetreatmentofmultidrug-resistanttuberculosis(WHO/HTM/TB/2017.20).WHO:Geneva,2017.


4.7.1 Children

Table9Treatmentofchildrenwithnewandrepurposeddrugs19

Drugs Experiencetodate Dosing

Bdq

Enrollmentinclinicaltrialsisongoing.Thereisalsoexperienceincompassionateandprogrammaticuseinchildren.20

StudiesofthepharmacokineticsofBdqinchildrenarenotyetcompleted.NorecommendationbytheWHO.

>12yearsand>33kg:400mgdailyfor14daysfollowedby200mgthreetimesaweek(sameasadultdose)<12yearsor<33kg:correctdoseisunknown,but6mg/kgfor2weeks,then3mg/kgafterwardsmaybetried.

Dlm

Enrollmentinclinicaltrialsisongoing.Thereisalsoexperienceincompassionateandprogrammaticuseinchildren.Dlmpharmacokineticsinolderchildren(6-17years)hasbeenstudiedbythemanufacturer.DlmisrecommendedbyWHOforuseinthisagegroupbasedonthisdata.21StudyofpharmacokineticsofDlminyoungerchildrenisongoing.

>35kg:100mgtwicedaily(sameasadultdose)20-34kg:50mgtwicedaily<20kg:correctdoseisunknown,but3-4mg/kgmaybetried.

Lzd

Thereisexperiencewithprogrammaticuseinchildren.ThepharmacokineticsofLzdhasbeenstudiedinchildreninmultipleclinicaltrials,butnotinchildrenwithTB.

>=12years:10mg/kgoncedaily<12years:10mg/kgtwicedaily

Cfz

ThereisexperiencewithprogrammaticuseinchildrenbothinTBandleprosy.Pharmacokineticsofclofazimineinchildrenhasnotbeenstudied.

2-3mg/kgdailyoreveryotherdayforamaximumdailydoseof100mg(gelcapscannotbesplit)

Ipm/ClnPharmacokineticsofimipenemandhavebeenstudiedinchildren(includingprematureinfants).

3monthsto<3years:25mg/kg/dose3-12years:15mg/kg/dose

19HarauszEP,Garcia-PratsAJ,SeddonJA,etal.SentinelProjectonPediatricDrug-ResistantTuberculosis.Newandrepurposeddrugsforpediatricmultidrug-resistanttuberculosis.practice-basedrecommendations.AmJRespirCritCareMed2017;195(10):1300-1310.20AcharJ,HewisonC,CavalheiroAP,etal.Off-labeluseofbedaquilineinchildrenandadolescentswithmultidrug-resistanttuberculosis.EmergInfectDis2017;23(10).21WHO.Theuseofdelamanidinthetreatmentofmultidrug-resistanttuberculosisinchildrenandadolescents:interimpolicyguidelines(WHO/HTM/TB/2016.14).WHO:Geneva,2016.


4.7.2 Pregnancy or lactation

InMDR-TBpatientswhoarepregnant,themainobjectiveistodesignaregimenthatiseffectiveandlikelytocurethemother.ThehighestrisktobothmotherandfetusisfrominadequatelytreatedMDR-TB.Whiledrugswithidentifiedteratogenicrisksmaybenotprimarychoices,thepotentialteratogenicimpactofthesedrugsshouldbeconsideredinperspectiveoftheriskstothemother/baby/family/communityofnottreatingthemotherwithanappropriateregimen.

ThefollowingtablesummarizesthelimitedevidenceaboutthesafetyofnewandrepurposedTBdrugsinpregnantandlactatingwomen.LittleisknownaboutthesafetyofotherMDR-TBdrugsaswell,butdrugslikeinjectablesandethionamidearegenerallyavoidedduringpregnancy.

Table10Treatmentofpregnantorlactatingwomenwithnewandrepurposeddrugs

DrugsUSFDAsafetyclass

Summary

Bdq B

Animalstudieshavenotrevealedanyevidenceofharmtothefetusoranyeffectsonfertilityinfemales;somemalestreatedwithhighdosesfailedtoproduceoffspring.Therearenocontrolleddatainhumanpregnancy.22Pharmacokineticdatainratstreatedwithdoses1-2timesthehumanclinicaldosehaveshown6-to12-foldhigherbedaquilineconcentrationsinmilkthanthemaximumconcentrationsobservedinmaternalplasma.

Dlm

NotyetassignedanFDAsafetyclass.

Inrabbitsreproductivestudies,embryo-fetaltoxicitywasobservedatmaternallytoxicdosages.Avoidinpregnancy;howeverthebenefitsinpatientswithnootheroptionsmayoutweightherisks.Pharmacokineticdatainanimalshaveshownexcretionofdelamanid/metabolitesintobreastmilk.Inlactatingrats,theCmaxfordelamanidinbreastmilkwas4-foldhigherthanthatoftheblood.

Lzd CAnimalstudieshavefailedtorevealevidenceofteratogenicity,butembryofetaltoxicitywasobservedatmaternotoxicdoses.Placentaltransferofthisdrugand/oritsmetaboliteswasobservedinrats.Therearenocontrolleddatainhumanpregnancy.

Cfz C

Therearenostudiesofclofazimineuseinpregnantwomen.Fewcasesofclofazimineuseduringpregnancyhavebeenreportedintheliterature.Embryofetaltoxicitystudieswereconductedinrats,rabbitsandmice.Inmice,clofazimine-inducedembryotoxicityandfetotoxicitywasevident.

Ipm/Cln CDevelopmentaltoxicitystudieswithimipenemandcilastatinsodium(aloneorincombination)administeredtomonkeys,rabbits,rats,andmicerevealednoevidenceofteratogenicity.However,animipenem-cilastatindoseof40mg/kggiventopregnantmonkeysbybolusintravenousinjectioncausedsignificant

22JaspardM,Elefant-AmouraE,MelonioI,DeMontgolfierI,VezirisN,etal.Bedaquilineandlinezolidforextensivelydrug-resistanttuberculosisinpregnantwoman.EmergInfectDis2017;23(10).doi:10.3201/eid2310.161398.


maternaltoxicityincludingdeathandembryofetalloss.Itisnotknownwhetherimipenem-cilastatinsodiumisexcretedinhumanmilk.

*A=Safetyestablishedusinghumanstudies;B=Presumedsafetybasedonanimalstudies;C=Uncertainsafety,nohumanstudiesandanimalstudiesshowanadverseeffect;D=Unsafe,evidenceofriskthatmaybejustifiableundercertainclinicalcircumstances.

4.7.3 Extrapulmonary TB

Table11TreatmentofextrapulmonaryTBwithnewandrepurposeddrugs

Drugs Recommendations

BdqVerylimitedexperiencewithBdqinTBmeningitisorTBosteomyelitis.OnepatientwithmeningitishadundetectablelevelsofBdqinCSF.23DrugisproteinboundandlikelyhaslowpenetrationintotheCSF.

Dlm VerylimitedexperiencewithDlminTBmeningitisorTBosteomyelitis.DrugisproteinboundandlikelyhaslowpenetrationintotheCSF.

Lzd Excellentboneandsoft-tissuepenetration;commonlyusedforosteomyelitisduetogram-positivebacteria.

Cfz Cfzhasbeenusedextensivelytotreatleprosylesionsinsofttissue,thoughitisunclearifthismeansthatboneandsofttissuepenetrationisadequate.

Ipm/ClnMpm

BothIpm/ClnandMpmreachmeasurableconcentrationsinCSF,butMpmisthoughttobelessneurotoxic(seizures).Bothdrugshavebeenusedtotreatosteomyelitiscausedbyotherbacteria.

4.8 Special populations

Table12Specialpopulations

Situation Recommendations

HIV

• Antiretroviraltherapy(ART)shouldbegiventoanyHIVco-infectedMDR-TBpatientwithoutdelay.

• ARTcanbestartedassoonasMDR-TBtreatmentistolerated—usuallywithinafewdays.TheriskofimmunereconstitutionsyndromecanbemitigatedbydesigninganappropriateMDR-TBregimen.

• BedaquilinehasimportantinteractionswithARTthatwillaffectthechoiceofART(seesection3.3.2).

Chronicrenal • Bedaquilineanddelamanidarenotrenallyexcretedandnodoseadjustmentis

23AkkermanOW,OdishOF,BolhuisMS,etal.Pharmacokineticsofbedaquilineincerebrospinalfluidandseruminmultidrug-resistanttuberculousmeningitis.ClinInfDis2016;62(4):523-4.


insufficiency requiredinmild/moderaterenalinsufficiency.Thereisnodataontheuseofeitherofthesedrugsinpatientswithsevererenalimpairment.

• Nodoseadjustmentoflinezolidisrequiredinpatientswithrenalimpairment;however,thetwoprimarymetabolitesoflinezolidaccumulateinpatientswithrenalimpairmentandtheclinicalsignificanceofthisisunknown.

• Nodoseadjustmentofclofazimineisrequiredinpatientswithrenalimpairment.

HepatitisC

• MDR-TBisstronglycorrelatedwithhepatitisCinfectioninmanycountries.• ActivehepatitisCisariskfactorforMDR-TBtreatmentfailure.• Direct-actingantivirals(DAA)arewell-toleratedwhengivenwithMDR-TB

treatment.


5 Patient consent

5.1 Patient consent

Afterproviding thepatienteducationmaterial tothepatient, consentinpatientsstartingnewTBdrugsmustbeobtained.Theconsentprocesswillensurethepatientis:• AwareofthenovelnatureofthenewTBdrug;• Appreciates the reasonwhy thedrug is beingproposed tobe included in their treatment

regimen;• Recognizes the possible benefits and potential harms, including the uncertainty that

surroundsoutcomes.In the case of bedaquiline, the informed consentwill be documentedwith a signature of thepatient. In the caseof delamanid, the informed consentwill bedocumentedwith a signaturefromthepatient(orifallowedbylocalstandardspatientconsentcanbeverbal).For patients considered minor or incapacitated by national law, consent from the legalrepresentativeisadditionallyrequired.

5.2 Example of medication guide and patient consent for the clinical use of bedaquiline and delamanid.

Belowareexamplesamedicationguideandconsentforbedaquilineanddelamanid.Allpatientsshouldbe informedof the risks andbenefits of thenewTBdrugsbefore treatment. Patientsshouldnotbe coerced into taking thenewTBdrugs.The information in the examplesbelowshouldbeprovidedtothepatientinaone-on-onesetting.Ifthepatientisilliterateallpartsofthemedicationguideshouldbereadandexplainedtothepatient.ThepatientshouldbegiventheopportunitytoaskquestionsandtakeadequatetimebeforemakingadecisiononwhetherornottoconsenttotreatmentwithnewTBdrugs.


MEDICATIONGUIDEANDCONSENTFORBEDAQUILINE

WhatisthemostimportantinformationIshouldknowaboutbedaquiline?

Bedaquilineisadrugusedtotreatmultidrug-resistanttuberculosis(MDR-TB)lungsinpeoplewith limited treatmentoptions.MDR-TB is aseriousdisease that can result indeath, and forwhichtherearefewtreatmentchoices.It is important to complete the full course of treatment of bedaquiline and your other TBmedicinesandnotskipdoses.Skippingdosesmaydecreasetheeffectivenessofthetreatmentand increase thelikelihoodthatyourTBdiseasewillnotbetreatablebybedaquilineorothermedicines.

Itisnotknownifbedaquilineissafein:

• Childrenunder18years.• Inpregnancy.• InformsofTBthatisnotdrug-resistantornotinthelungs.• Inpatientswithheart,kidney,liverorotherhealthproblems.

Beforeyoutakebedaquiline,tellyourhealthcareproviderif:

• Youhavehadanabnormalheartrhythmorotherheartproblems.• AnyoneinyourfamilyhasorhashadaheartproblemcalledcongenitallongQTsyndrome.• Youhaveliverorkidneyproblemsoranyothermedicalconditions,includingHIVinfection.• Youarepregnantorplantobecomepregnant.Itisnotknownifbedaquilinewillharmyour

unbornbaby.• Youarebreastfeedingorplantobreastfeed.Itisnotknownifbedaquilinepassesintobreast

milk. You and your healthcare provider should decide if you will take bedaquiline orbreastfeed.

• You are taking any prescription and nonprescription medicines, vitamins and herbalsupplements.

HowshouldItakebedaquiline?

• Bedaquiline must always be taken with other medicines to treat TB. Your healthcareproviderwilldecidewhichothermedicinesyoushouldtakewithbedaquiline.

• Alwaystakebedaquilinewithalightmeal(notheavyinfat).• Swallowthetabletswholewithwater.• Takebedaquiline for aminimumof24weeks (6months). Youmaybeprescribed longer

than6monthsbyyourclinicianwhowilldiscussthiswithyouunlessotherwiseprescribedbyyourclinician.o Week1andWeek2:Take400mg(4tablets)onceaday,7daysaweek.o Week3toWeek24(orendofprescribedduration):Take200mg(2tablets)thricea

week. For example, you may take bedaquiline onMonday,Wednesday and Friday ofeveryweek.

• YouwillneedtotakeyourotherTBmedicinesforlongerthan24weeks,andatleastfor20


monthsintotal(theinjectabledrugisusuallygivenforupto8months).• Yourtreatmentwillbeprovidedunderdirectlyobservedtreatment(DOT),withapatient-

centredapproach,whichmeansthatahealthcareproviderwillaccompanyyouduringthetreatment.

• Donot skipbedaquilinedoses. If you skipdoses,ordonot complete the totalprescribedtreatmentofbedaquilineyourtreatmentmaynotworkaswellandyourTBmaybehardertotreat.

• Ifforsomereasonyoumissadose,informthepersonresponsibleforyourtreatmentrightaway,theywilltellyouwhattodo.

WhatshouldIavoidwhiletakingbedaquiline?

• Youshouldnotdrinkalcoholwhiletakingbedaquiline.

Whatarethepossiblesideeffectsofbedaquiline?

• Serious heart rhythm changes. Tell your health-care provider right away if you have achange inyourheartbeat (a fastor irregularheartbeat),or ifyou faint.Yourheartwillbemonitoredperiodicallywithamachinethatchecksthattheheartrhythmisnormal.

• Liverproblems(hepatotoxicity).Livertoxicitycanpresentinmanyways.Tellyourdoctorofsymptoms such as nausea or vomiting, stomach pain, fever, weakness, itching, unusualtiredness,lossofappetite,lightcolouredbowels,darkcoloredurine,yellowingofyourskinoryellowingofthewhiteofyoureyes.

• Other side effects of bedaquiline include nausea, joint pain, headache, an abnormallaboratorytestassociatedwithdamagetothepancreas,coughingupblood,chestpain,lossofappetite,and/orrash.

Itispossiblethatitmayalsocausesomeproblemsthatwearenotawareof.However,youwillbefollowedcloselyforanyunwantedeffectsoranyproblems.Othermedicinestodecreasethesymptomsofthesideeffectsorreactionsmayalsobegiven.Alwaystellyourhealth-careproviderofanysideeffectsorproblemsyouarehaving.Sometimesbecauseofsideeffectsbedaquilineorotherdrugsmayneedtobestopped.

WhatmonitoringtestsdoIneedwhileonbedaquiline?

• Youwill need the samemonitoring test that all patients onMDR-TB treatment need. Inaddition, you will need heart monitoring, extra blood tests for the liver and yourelectrolytes.Talktoyourhealth-careprovideronthescheduleofallyourmonitoringtestsandregulardoctorvisits.

Generalinformationabouttherisksversusthebenefitsoftakingbedaquiline

• RISK:Itispossiblethatyouwillbeatgreaterriskthanyouwouldotherwisebeofcertainsideeffectsduetothedrug.Itispossiblethatasideeffectcouldbeseriousandevenresultindeath.

• BENEFIT:Thereisagreaterchancethatyouwillbecuredoftuberculosisthanifyoudidnottakethemedicine.Youwillpossiblyalsobecomebetterverymuchsoonerthanifyouonlytook the standardmedicines for treatment of resistant TB. Also, it is less likely that thedrugsyouaretakingwilldevelopresistanceifyouaretakingbedaquiline.


Confidentialityandsharinginformation

• Becausebedaquilineisanewdrugforwhichwehavelimitedexperiencewearecollectinginformationonpatientstakingthem.

• The information that we collect from you will be kept confidential and no one but theclinicalstaffwillbeabletoseeyourmedicalinformation.

• Anyinformationcollectedtohelpusbetterusethedruginpatientswillbeunlinkedtoyourname(madeanonymous)beforeweshareoranalyseit.

Righttorefuseorwithdraw

• Youdonothave toagree to takebedaquiline ifyoudonotwish todoso,andrefusing toaccept the drug aspart of your treatment schedulewill not affect your treatment at thisclinicinanyway.Youwillstillhaveallthebenefitsthatyouwouldotherwisehaveatthisclinic.

• If you agree to take bedaquiline, youmay also at any point after you startwish to stopwithoutlosinganyofyourrightsasapatienthere.Yourtreatmentatthisclinicwillnotbeaffectedinanyway.

Contactperson

Ifyouhaveanyquestions,youmaycontactanyofthefollowingpersons:Name_______________________.Title______________.Phone_______________.Name_______________________.Title______________.Phone_______________.Name_______________________.Title______________.Phone_______________.Nameofresponsiblephysician:_____________________________________________Nameofclinic/hospital/institution:_____________________________________________


TREATMENTCONSENTStatementfromthepatient:

IhavereadtheprovidedMedicationGuide,orithasbeenreadtome.Ihavehadtheopportunityto ask questions about it and any questions that I have asked have been answered to mysatisfaction.Iconsenttoreceivebedaquilinefortreatingthedrug-resistanttuberculosisdiseasethatIamsufferingfrom.PrintNameofPatient:_____________________________________________________SignatureofPatient:_______________________________________________________Date:_________________________________(Day/month/year)If illiterate, a literate witness must sign. (If possible, this person should be selected by theparticipant and should haveno connection to the care providers). Patientswho are illiterateshouldincludetheirthumbprint.Statementfromthewitness:

I have witnessed the accurate reading of the consent form to the potential recipient ofbedaquiline, and the individual has had the opportunity to ask questions. I confirm that theindividualhasgivenconsentfreely.Printnameofwitness:_________________________ANDThumbprintofpatientSignatureofwitness:__________________________Date:_________________________________(Day/month/year) Statementfromthepersontakingconsent:I confirmthattheparticipantwasgivenanopportunity toaskquestionsaboutthe treatment,andallthequestionsaskedbytheparticipanthavebeenansweredcorrectlyandtothebestofmy ability. I confirm that the individual has not been coerced into giving consent, and theconsenthasbeengivenfreelyandvoluntarily.Acopyofthisinformedconsentformhasbeenprovidedtotheparticipant.Printnameofpersontakingtheconsent:_____________________________________Signatureofpersontakingtheconsent:______________________________________ Date:_________________________________(Day/month/year)


MEDICATIONGUIDEANDCONSENTFORDELAMANID

WhatisthemostimportantinformationIshouldknowaboutdelamanid?

Delamanid isadrugused to treatmultidrug-resistant tuberculosis (MDR-TB) lungs inpeoplewith limited treatmentoptions.MDR-TB is aseriousdisease that can result indeath, and forwhichtherearefewtreatmentchoices.It is important to complete the full course of treatment of delamanid and your other TBmedicinesandnotskipdoses.Skippingdosesmaydecreasetheeffectivenessofthetreatmentand increase the likelihood that yourTBdiseasewill notbe treatablebydelamanidorothermedicines.

Itisnotknownifdelamanidissafein:

• Childrenunder6years.• Inpregnancy.• InformsofTBthatisnotdrug-resistantornotinthelungs.• Inpatientswithheart,kidney,liverorotherhealthproblems.

Beforeyoutakedelamanid,tellyourhealthcareproviderif:

• Youhavehadanabnormalheartrhythmorotherheartproblems.• AnyoneinyourfamilyhasorhashadaheartproblemcalledcongenitallongQTsyndrome.• Youhaveliverorkidneyproblemsoranyothermedicalconditions,includingHIVinfection.• Youarepregnantorplantobecomepregnant.Itisnotknownifdelamanidwillharmyour

unbornbaby.• Youarebreastfeedingorplantobreastfeed.Itisnotknownifdelamanidpassesintobreast

milk. You and your healthcare provider should decide if you will take delamanid orbreastfeed.

• You are taking any prescription and nonprescription medicines, vitamins and herbalsupplements.

HowshouldItakedelamanid?

• DelamanidmustalwaysbetakenwithothermedicinestotreatTB.Yourhealthcareproviderwilldecidewhichothermedicinesyoushouldtakewithdelamanid.

• Alwaystakedelamanidwithalightmeal(notheavyinfat).• Swallowthetabletswholewithwater.• Take delamanid for aminimum of 24 weeks (6months) unless otherwise prescribed by

yourclinician.o Take100mg(2tablets)earlyinthemorningandagain100mg(2tablets)inthe

evening,everydayoftheweek(includingtheweekends).

• YouwillneedtotakeyourotherTBmedicinesforlongerthan24weeks,andatleastfor20monthsintotal(theinjectabledrugisusuallygivenforupto8months).

• Yourtreatmentwillbeprovidedunderdirectlyobservedtreatment(DOT),withapatient-centredapproach,whichmeansthatahealthcareproviderwillaccompanyyouduringthe


treatment.• Do not skip delamanid doses. If you skip doses, or do not complete the total prescribed

treatmentofdelamanidyourtreatmentmaynotworkaswellandyourTBmaybehardertotreat.

• Ifforsomereasonyoumissadose,informthepersonresponsibleforyourtreatmentrightaway,theywilltellyouwhattodo.

WhatshouldIavoidwhiletakingdelamanid?

• Youshouldnotdrinkalcoholwhiletakingdelamanid.

Whatarethepossiblesideeffectsofdelamanid?

• Serious heart rhythm changes. Tell your health-care provider right away if you have achange inyourheartbeat (a fastor irregularheartbeat),or ifyou faint.Yourheartwillbemonitoredperiodicallywithamachinethatchecksthattheheartrhythmisnormal.

• Other side effects of delamanid include nausea, vomiting, and dizziness. Other importantadversedrugreactionsareanxiety,paraesthesia,andtremor.Tellyourdoctorofsymptomssuchasnauseaorvomiting,dizziness,anxiety,itching,ortremor.

Itispossiblethatitmayalsocausesomeproblemsthatwearenotawareof.However,youwillbefollowedcloselyforanyunwantedeffectsoranyproblems.Othermedicinestodecreasethesymptomsofthesideeffectsorreactionsmayalsobegiven.Alwaystellyourhealth-careproviderofanysideeffectsorproblemsyouarehaving.Sometimesbecauseofsideeffectsdelamanidorotherdrugsmayneedtobestopped.

WhatmonitoringtestsdoIneedwhileondelamanid?

• Youwill need the samemonitoring test that all patients onMDR-TB treatment need. Inaddition, you will need heart monitoring, extra blood tests for the liver and yourelectrolytes.Talktoyourhealth-careprovideronthescheduleofallyourmonitoringtestsandregulardoctorvisits.

Generalinformationabouttherisksversusthebenefitsoftakingdelamanid

• RISK:Itispossiblethatyouwillbeatgreaterriskthanyouwouldotherwisebeofcertainsideeffectsduetothedrug.Itispossiblethatasideeffectcouldbeseriousandevenresultindeath.

• BENEFIT:Thereisagreaterchancethatyouwillbecuredoftuberculosisthanifyoudidnottakethemedicine.Youwillpossiblyalsobecomebetterverymuchsoonerthanifyouonlytook the standardmedicines for treatment of resistant TB. Also, it is less likely that thedrugsyouaretakingwilldevelopresistanceifyouaretakingdelamanid.

Confidentialityandsharinginformation

• Becausedelamanid isanewdrug forwhichwehave limitedexperiencewearecollectinginformationonpatientstakingthem.

• The information that we collect from you will be kept confidential and no one but theclinicalstaffwillbeabletoseeyourmedicalinformation.

• Anyinformationcollectedtohelpusbetterusethedruginpatientswillbeunlinkedtoyour


name(madeanonymous)beforeweshareoranalyseit.

Righttorefuseorwithdraw

• You do not have to agree to takedelamanid if you do notwish todo so, and refusing toaccept the drug aspart of your treatment schedulewill not affect your treatment at thisclinicinanyway.Youwillstillhaveallthebenefitsthatyouwouldotherwisehaveatthisclinic.

• If you agree to take delamanid, you may also at any point after you start wish to stopwithoutlosinganyofyourrightsasapatienthere.Yourtreatmentatthisclinicwillnotbeaffectedinanyway.

Contactperson

Ifyouhaveanyquestions,youmaycontactanyofthefollowingpersons:Name_______________________.Title______________.Phone_______________.Name_______________________.Title______________.Phone_______________.Name_______________________.Title______________.Phone_______________.Nameofresponsiblephysician:_____________________________________________Nameofclinic/hospital/institution:_____________________________________________


TREATMENTCONSENTStatementfromthepatient:

IhavereadtheprovidedMedicationGuide,orithasbeenreadtome.Ihavehadtheopportunityto ask questions about it and any questions that I have asked have been answered to mysatisfaction.Iconsenttoreceivedelamanidfortreatingthedrug-resistanttuberculosisdiseasethatIamsufferingfrom.PrintNameofPatient:_____________________________________________________SignatureofPatient:_______________________________________________________Date:_________________________________(Day/month/year)If illiterate, a literate witness must sign. (If possible, this person should be selected by theparticipant and should haveno connection to the care providers). Patientswho are illiterateshouldincludetheirthumbprint.Statementfromthewitness:

I have witnessed the accurate reading of the consent form to the potential recipient ofdelamanid, and the individual has had the opportunity to ask questions. I confirm that theindividualhasgivenconsentfreely.Printnameofwitness:_________________________ANDThumbprintofpatientSignatureofwitness:__________________________Date:_________________________________(Day/month/year) Statementfromthepersontakingconsent:I confirmthattheparticipantwasgivenanopportunity toaskquestionsaboutthe treatment,andallthequestionsaskedbytheparticipanthavebeenansweredcorrectlyandtothebestofmy ability. I confirm that the individual has not been coerced into giving consent, and theconsenthasbeengivenfreelyandvoluntarily.Acopyofthisinformedconsentformhasbeenprovidedtotheparticipant.Printnameofpersontakingtheconsent:_____________________________________Signatureofpersontakingtheconsent:______________________________________ Date:_________________________________(Day/month/year)


6 Monitoring schedule

6.1 Monitoring schedule for patient follow-up

Patientshouldundergoappropriatefollow-upatbaseline,duringandaftertreatment, includingclinicalevaluation,bacteriologicalandlaboratorytesting asdescribed in the following table.Thebaseline visit refers to thebeginningof the treatmentwithnewTBdrugs: this canoccur at anymomentduringthetreatmentcourseofdrug-resistantTB.ThemonitoringscheduleshouldbeappliedtopatientsreceivinganytreatmentregimencontainingnewTBdrugs,regardlessofthecompositionoftheregimen.Additionalremarks:

• The laboratory and ECG follow-up should be continued at monthly intervals for all the duration of treatment with bedaquiline and/ordelamanid(i.e.forlongerthan6monthsincaseoftreatmentprolongationbeyond24weeks)

• Morefrequentmonitoringmaybeadvisableinspecificcategoriesofpatients,includingelderlypeople,patientsinfectedwithHIV,affectedbyHBV- or HCV-related hepatitis, diabetes mellitus, with moderate to severe hepatic or renal impairment, or receiving specific drugcombinations(i.e.bedaquilineanddelamanid)

• In caseof electrolytedisturbancesorECGabnormalities,more frequentmonitoring shouldbeperformedasdescribed in the chapteronclinicalmanagementofadverseeventsofinterest(Section7.3.7)

• Morefrequentalbumindosing(i.e.monthly)maybeindicatedduringtreatmentwithdelamanidinspecificcases,i.e.inpatientswithGrade2orworseHypoalbuminemia(<30g/L)atbaseline,orinpatientsexperiencingQTintervalprolongationasdescribedinSection7.3.3.

• If sputum culture positive at Month 4 of treatment, baseline and Month 4 respiratory specimens should be sent to the SupranationalReferenceLaboratorytoperformcomprehensivefirst-andsecond-lineDST(ifpossible).

Table13Monitoringschedule

Baseline Visit

Week 2

Month 1

Month 2

Month 3

Month 4

Month 5

Month 6

While on injectable*

Until end of

treatment

End of treatment

Post-treatmentmonth 6

Clinical evaluation

Vital signs X X X X X X X Monthly

Performance status X X X

Brief peripheral neuropathy screen X X X X X X X Monthly X X

Audiometry X X X X X X X Monthly X


Baseline Visit

Week 2

Month 1

Month 2

Month 3

Month 4

Month 5

Month 6


Until end of

treatment

End of treatment


Visual acuity and colorblindness screen X X X X X X X Monthly X X

Outcome consultation X X

Assessment and follow-up of adverse events(Section6) X X X X X X X X At each scheduled

/unscheduled visit X X

Weight X X X X X X X X Monthly X

Bacteriological testing

Smear X X X X X X X Monthly X X

Culture X X X X X X X Monthly X X

Xpert MTB/RIF X

Hain GenoType MTBDRsl (some sites) X If smear- or culture-positive

Culture-based first-line DST X If smear- or culture-positive

Culture-based second-line DST (some sites) X If smear- or culture-positive

Laboratory testing

ECG X X X X X X X X X X

Full Blood Count X X X X X X X X Monthly X

Urea, creatinine X X X X X X X Monthly X

Serum electrolytes (potassium) X X X X X X X Monthly X

Liver function tests (AST, ALT) X X X X X X X Monthly X

TSH X X every 3 months

Hepatitis Bs Antigen X

Hepatitis C Antibody X

HbA1c (repeated every 3 months if elevated) X

Pregnancy test X


Baseline Visit

Week 2

Month 1

Month 2

Month 3

Month 4

Month 5

Month 6


Until end of

treatment

End of treatment


HIV serostatus X

CD4 (repeated every 6 months if HIV+) X

HIV VL (repeated every 6 months if HIV+) X

Chest X-Ray X X X

*Injectable=kanamycin,amikacin,capreomycin.


7 Drug safety

7.1 Scope of safety data collection and definitions

Pharmacovigilance is in place to ensure timely detection and proper transmission ofinformationrelatingtodrugsafety,especiallyadverseevents.

Anadverseevent(AE)isdefinedasanyuntowardmedicaloccurrenceinapatientadministereda pharmaceutical product and that does not necessarily have a causal relationshipwith thistreatment.AnAEcanthereforebeanyunfavorableandunintendedsign(includinganabnormallaboratory finding), symptom, or disease temporally associated with the use of a medicinalproduct,whetherornotrelatedtothismedicinalproduct.

Allpatients,irrespectivelyfromtreatmentallocation,aremonitoredandassessedclinicallyforAEs(includinglababnormalities)atallvisitsduringtreatment(seealsovisitscheduleinsection6). Systematic symptomatic screening and referral for potential AEs is a mandatory part ofscheduled and unscheduled visits. In addition, the evolution and outcome of the previouslyrecordedAEsshouldbesystematicallyassessed.

LaboratoryscreeningforhematologicandbiochemicalabnormalitiesandECGformonitoringoftheQTlengthareconductedatspecificvisitsduringtreatment(seealsovisitscheduleinsection6)andmorefrequentlyasneeded.

SafetydatacollectionstartsattimeoffirstMDRTBtreatmentadministrationintheframeoftheendTBprogram.EachAEisfollowed-upuntilresolutionorstabilization.24

SafetydatacollectionintheframeofendTBislimitedtothefollowingelements:

• AEsofclinicalsignificance,including:

o SeriousAdverse Events (SAEs)definedasanyuntowardmedicaloccurrence that,atanydose:

§ Resultsindeath,

§ Requireshospitalizationorprolongationofhospitalization,

§ Resultsinpersistentorsignificantdisability/incapacity,

§ Is life-threatening; life-threateninginthiscontextrefers toareaction inwhich thepatientwasatriskofdeathatthetimeofthereaction;itdoesnotrefertoareactionthathypotheticallymighthavecauseddeathifmoresevere,

§ Isacongenitalanomalyorabirthdefect,

§ Is otherwise medically significant; Medical and scientific judgment should beexercised in deciding whether other situations should be considered seriousreactions, such as important medical events that might not be immediately lifethreateningorresultindeathorhospitalizationbutmightjeopardisethepatientormight require intervention to prevent one of the other outcomes listed above.Suspected transmissionof an infectious agent (e.g. pathogenic ornon-pathogenic)viadrugisalwaysconsideredanSAE.

o AEs of interest, defined as all AEs regardless of their seriousness, severity or causalrelationshiptotheMDRTBtreatment,pertainingtothefollowingmedicalconditions:

24Resolution,returntopre-treatmentstatus;stabilization,nofurtherdeteriorationorimprovementexpected.


§ Peripheralneuropathy,

§ Myelosuppression(anemia,thrombocytopenia,orneutropenia),

§ ProlongedQTinterval,

§ Opticnervedisorder(opticneuritis),

§ Hepatitis,

§ Hearingimpaired,

§ Acutekidneyinjury,

§ Hypokalemia,and

§ Hypothyroidism.

• Adverse events leading to treatment discontinuation or change in drug dosage,definedasallAEsregardlessoftheirseriousness,severity,orcausalrelationshiptotheMDRTBtreatment, leadingtoadiscontinuationofMDRTBtreatment, includingpermanentandtemporary treatment interruption, or changes in drug(s) dosage(s) or drug regimen, asdecidedbytheclinician.

• Adverseevents judgedasotherwiseclinicallysignificant,definedasallAEsregardlessoftheirseriousness,severity,orcausalrelationshiptotheMDRTBtreatment,notpertainingto one of the above-mentioned category but considered of clinical significance by thetreatingphysician.

• Pregnancy must be avoided during MDR-TB treatment and effective contraception isrecommended. If despite all precautions, a patient is found to be pregnant, the pregnantpatientshouldbereferredtoreceivethelocal,standardofMDR-TBtreatmentforpregnantwomen. All pregnancies (including pregnancies of partners of male patients) should befollowed-upuntilanoutcome isknown. Infantsborn fromexposedpregnanciesshouldbefollowed-upuntiltheyreach12monthsofage.

• Medication errors defined as unintended mistakes in the prescribing, dispensing andadministrationofamedicinethatcouldcauseharmtoapatient(e.g.wrongdrugprescribed,overdose)mustbemanagedonacasebycasebasis.Hospitalizationshouldbeconsideredasappropriate.

The clinician is responsible for appropriately managing AEs, drug-exposed pregnancies, andpotentialmedicationerrorsinaccordancewiththelocalstandardsofcareandforreferringthepatienttotheappropriatespecialistifneeded.He/sheshouldadditionallyassessthebenefitofthecontinuationofthecurrentTBtreatmentinthelightofthewholeclinicalpicture:weighingtreatmentcontinuationbenefitsvs.therisks(includingAEs,pregnancyexposure,abnormallabresults, etc.). Specific clinicalmanagement suggestions are available in section7.3 for AEs ofinterest.

7.2 Recording, medical assessment and notification of adverse events

Recordingandnotificationofadverseeventsoccursasfollows:

• Immediate transmission (within24 hours of awareness) of Serious Adverse Events (asdefinedinsection7.1),drug-exposedpregnanciesandmedicationerrors(withorwithoutassociatedAEs/SAEs)tothepharmacovigilance(PV)unit([email protected])asrecordedusingtheSAEorPregnancyReportForm.

• RoutinerecordingofallotherAEs(non-serious)usingtheAEForm/AELog.


Upon recording, all SAEs and AEs should begraded for severity according to the providedSeverityGradingScale(grades1-425).ForthoseAEsnotdescribedintheSeverityGradingScale,thegeneraldefinitionofclinicalseverityshouldapply.

Table14Generaldefinitionofseverity

Grade1Mild Grade2Moderate Grade3Severe Grade4Life-threatening

Transientormilddiscomfort(<48hours);nomedicalintervention/therapyrequired.

Mildtomoderatelimitationinactivity*-someassistancemaybeneeded;noorminimalmedicalintervention/therapyrequired.

Markedlimitationinactivity*,someassistanceusuallyrequired;medicalintervention/therapyrequired,hospitalizationspossible.

Extremelimitationinactivity*,significantassistancerequired;significantmedicalintervention/therapyrequired,hospitalizationorhospicecareprobable.

*The term ‘activity’ covers basic self-care functions such as bathing, dressing, toileting, transfer/movement,continenceandfeeding;butalsousualsocialandfunctionalactivitiesoradaptivetasksanddesirableactivities,suchasgoingtowork,shopping,cooking,useoftransportation,pursuingahobby,etc.

AllAEsshouldadditionallybeevaluatedtodeterminetheircausalrelationshipwithMDRTBtreatment(includingMDRTBdrugsandotherdrugsasappropriate),usingthestandardtermsas displayed in the table below. This evaluation should take into account all other possiblecausal factors (e.g. medical history, risk factors, past drug use, concomitant procedures, TBprogression).

Table15Causalitycategoriesdefinition

Causalitycategory Description

Related

ThereisareasonablepossibilitythattheAEmayberelatedtothedrug(s).Elementsinfavourofareasonablecausalrelationshipinclude:

• Afavourabletemporalrelationship,• Apositivedechallengeand/orrechallenge,• Aplausiblepharmacological/biologicalmechanismofaction(whetherproven

orpotential),• Previousknowledgeofsimilarreactionwiththedrug(s),or• Nootherevidentcause(e.g.previousdisease,otherdrugs).

ThereisinsufficientinformationtoevaluatethecausalrelationshipbetweentheAEandtheexposure.Conservatively,theAEshouldbeconsideredrelatedtothedrug(s)untilaproperassessmentisfeasible(i.e.uponfollow-up).

NotrelatedThereisnoreasonablepossibilitythattheAEisrelatedtothedrug(s).ThisimpliesthatthereisaplausiblealternativecausefortheAEthatbetterexplainstheoccurrenceoftheAEorthathighlyconfoundsthecausalrelationshipbetweenthedrug(s)andtheAE.

25ThescaleincludesalltermsfromtheNationalInstituteofAllergyandinfectiousDiseases(NIAID)DivisionofMicrobiologyandInfectiousDiseases(DMID)gradingsystemandaselectionofrelevanttermsfromtheNationalCancerInstitute(NCI)CommonTerminologyCriteriaforAdverseEvents(CTCAE)orotherscales.


A dedicated pharmacovigilance guideline for endTB details all processes relating topharmacovigilance describing how SAE/Pregnancy Report Forms should be completed andproviding further guidance on severity and causality assessment. A Data Management plandetailstherecordingofclinicalinformation(non-seriousAEs,labvalues)intheclinicalpracticedatabase. In case of severity grading questions, please also refer to the "Frequently AskedQuestionsontheseveritygradingscale".

7.3 Clinical management of adverse events of interest

7.3.1 Peripheral neuropathy

Possibleanti-TBdrugcauses:Lzd,Cs/Trd,H,S,Km,Cm,H,FQ,Pto/Eto,E.

Possibleothercauses:d4T,ddI.

• PeripheralneuropathyisacommonsideeffectofMDR-TBtreatmentcausedbydrugtoxicitytothenervesoftheperipheralnervoussystem.

• All patients taking isoniazid should receive 50mg of pyridoxine daily; all patients takingCs/Trdshouldreceive50mgofpyridoxinedailyforevery250mgofCs/Trd.

• Peripheralneuropathyisextremelycommoninpatientstakinglinezolid.Inoneclinicaltrialoflinezolid,55%ofthepatientsexperiencedclinicallysignificantperipheralneuropathy.

• Skin punch biopsies, nerve conduction studies or other specialized tests are the goldstandardbutarenotnecessaryforadiagnosis.

• According to the ACTG Brief Peripheral Neuropathy Screen (BPNS), a patient can bediagnosed with peripheral neuropathy if he/she reports typical symptoms (numbness,tingling, burning, pain)plusdecreasedvibration sense in thebig toesordecreasedankletendonreflexes.

• Whenassessingthepatient'ssymptomswiththeBPNS(SeeStep1oftheBPNSdescription),assess whether his/her symptom is suggestive of neuropathic pain. Although difficult todefine and variable for each individual, neuropathic pain is often described as "burning","electric", "tingling", and "shooting" in nature. It can vary from a constant pain tointermittent sharp shooting pains. As described, the pain is most often present withoutassociatedstimulation,butcanbeexacerbatedbystimuli.

• Afteradiagnosis of peripheralneuropathy, the subjective sensoryneuropathy score fromtheBPNS(SeeStep1oftheBPNSdescription)shouldbeusedforgrading(Table16).

Table16Clinicalmanagementofperipheralneuropathyaccordingtoseveritygrading

Severitygrade*


Paresthesia(Burning,Tingling,etc.)

Milddiscomfort;notreatmentrequired;and/orBPNSsubjectivesensoryneuropathyscore1-3onanyside.

Moderatediscomfort;non-narcoticanalgesiarequired;and/orBPNSsubjectivesensoryneuropathyscore4-6onanyside.

Severediscomfort;ornarcoticanalgesiarequiredwithsymptomaticimprovement;and/orBPNSsubjectivesensoryneuropathyscore7-10onanyside.

Incapacitating;ornotresponsivetonarcoticanalgesia

Action StopCs/Trd,high-doseH,andLzd.If

StopCs/Trd,high-doseH,andLzd.If

SameasGrade2. SameasGrade2.


Severitygrade*


symptomsimprove,considerrestartingthesedrugs.ConsiderrestartingLzdatalowerdose(300mgdailyor600mgthriceweekly).IfCs/Trdorhigh-doseHarenotessentialtotheregimen,considersuspendingthesedrugs.

symptomsimprove,andifthedrugsareessentialtotheregimen,considerrestartingCs/Trdorhigh-doseH.DonotreintroduceLzd.Providesymptomaticreliefasdescribedbelow.

*Reference:NIAIDDivisionofMicrobiologyandInfectiousDiseases,severityscale,Nov-2007.

Suggestedmanagementstrategy:

• Manypatientsexperienceimprovementwhenoffendingdrugsaresuspended,especiallyifthesymptomsaremild.

• The neuropathy associated with linezolid is common after prolonged use and oftenextremelypainfulandirreversible.Forthisreason,linezolidshouldbeimmediatelystoppedandnotreintroducedwhensymptomaticneuropathydevelops(grade2orabove).Consideradditionalanti-TBdrugstoreinforcetheregimen.

• In HIV coinfected patients, avoid use of d4T or ddI in combination withcycloserine/terizidoneorlinezolidbecauseofanincreasedriskofperipheralneuropathy.

• Symptomaticrelief:

o Non-steroidalanti-inflammatorydrugsoracetaminophenmayhelpalleviatesymptoms.

o Tricyclicantidepressantshavealsobeenusedsuccessfully.Startamitriptyline25mgatbedtime. The dose may be increased to a maximum of 150 mg daily for refractorysymptoms.Ifpossible,theco-administrationofamitriptylineandLzdshouldbeavoidedduetopotentialriskofserotonergicsyndrome.

o Carbamazepinemayalsobeeffectiveinrelievingpainandothersymptomsofperipheralneuropathy.CarbamazepineisastronginducerofCYP3A4andshouldnotbeusedwithbedaquilineordelamanid.

ACTGBriefPeripheralNeuropathyScreen(BPNS):

Step1.GradeSubjectiveSymptoms

Ask the subject to rate the severity of each symptom on a scale from 01 (mild) to 10 (mostsevere)forrightandleftfeetandlegs.EnterthescoreforeachsymptominthecolumnsmarkedR(rightlowerlimb)andL(leftlowerlimb).

Normal Mild------------------------------------------------------------------------------------------Severe00 01 02 03 04 05 06 07 08 09 10

Symptoms R L


a.Pain,aching,orburninginfeet,legs

b."Pinsandneedles"infeet,legs

c.Numbness(lackoffeeling)infeet,legs

Usethesinglehighestseverityscoreabovetoobtainasubjectivesensoryneuropathyscore.SubjectiveSensoryNeuropathyScore Severitygrade00 001–03 104–06 207–10 3

Step2.EvaluatePerceptionofVibration

Compress the ends of a 128-Hz tuning fork just hard enough that the sides touch. Place thevibrating tuning fork on a bony prominence on the subject's wrist or hand to be sure thathe/shecanrecognizethevibrationor"buzzing"qualityofthetuningfork.Again,compresstheendsofthetuningforkjusthardenoughthatthesidestouch.Immediatelyplacethevibratingtuningforkgentlybutfirmlyonthetopofthedistalinterphalangeal(DIP)jointofonegreattoeand begin counting the seconds. Instruct the subject to tell you when the "buzzing" stops.Repeat for theother great toe. Thediagrambelow illustrateswhere toplace the tuning fork(adapted from InternationalWorking Group on theDiabetic Foot, Practical guidelines on themanagementandpreventionofthediabetic,2007).

Vibrationperception Result ScoreFelt>10seconds Normal 0Felt6-10seconds Mildloss 1Felt<5seconds Moderateloss 2Notfelt Severeloss 3

Step3.EvaluateDeepTendonReflexes

With the subject seated, the examinerusesonehandtopressupwardon theball of the foot,dorsiflexingthesubject'sankleto90degrees.Usingareflexhammer,theexaminerthenstrikestheAchillestendon.Thetendonreflexisfeltbytheexaminer'shandasaplantarflexionofthefoot, appearing after a slight delay from the time the Achilles tendon is struck. Usereinforcement by having the subject clenching his/her fist before classifying the reflex asabsent.


Anklereflexes ScoreAbsent 0Hypoactive 1Normaldeeptendonreflexes 2Hyperactive 3Clonus 4

A diagnosis of peripheral neuropathy can be made with the combination of a subjectiveneuropathygradegreaterthan0andatleastonebilateralobjectivefinding(abnormalvibratorysenseorabnormaldeeptendonanklereflex).However,onlythesubjectivesensoryneuropathyscore–BPNSstep1)isusedforgrading.

7.3.2 Myelosuppression (anemia, thrombocytopenia, or neutropenia)

Possibleanti-TBdrugcauses:Lzd.

Possibleothercauses:AZT,cotrimoxazole.

• The mean corpuscular volume (MCV) may be helpful to assess whether anemia isnormocyticversusmicrocyticversusmacrocytic.MacrocyticanemiaismorelikelytobeduetoAZT,butAZTcanalsoinduceanormocyticanemia.

• Ifthepatienthasthrombocytopeniaorneutropenia,thisismorelikelytobeduetolinezolid.AZTcandothis,butitisrarer.

• Myelosuppression is very common in patients receiving linezolid. In one clinical trial oflinezolid, approximately18%ofpatients taking linezolid experienced clinically significantmyelosuppression.

• Acutebloodloss(occultGIbleedingfromapepticulcer)cancauseanemia.

• Othercausesofanemia(TB,iron-deficiency,etc.)arepossible,butlesslikelytooccurinthemiddleoftreatment,especiallyifthepatientisclinicallyimproving.

Table17Clinicalmanagementofmyelosuppressionaccordingtoseveritygrading

Severitygrade* Grade1Mild Grade2Moderate Grade3Severe Grade4Life-threatening

Anemia 10.5-9.5g/dL 9.4-8.0g/dL 7.9-6.5g/dL <6.5g/dL

Plateletsdecreased

99,999-75,000/mm³

74,999-50,000/mm³

49,999-20,000/mm³ <20,000/mm³

Whitebloodcellsdecreased

<LLN-3,000/mm3

<3,000-2,000/mm3 <2,000-1,000/mm3 <1,000/mm3

Absoluteneutrophilcountlow

1500-1000/mm3

999-750/mm3 749-500/mm3 <500/mm3

Action Monitorcarefully,andconsiderreductionofdoseofLzd(300mgdailyor600mgthrice

Monitorcarefully,andconsiderreductionofdoseofLzd(300mgdailyor600mgthriceweekly);incaseofGrade2neutropenia,stopLzdimmediately.

StopLzdimmediately.IncaseofGrade3anemia,considerEPO.RestartatreduceddoseoncetoxicityhasdecreasedtoGrade1.

StopLzdimmediately.ConsiderhemotransfusionorEPO.Restartatreduceddoseoncetoxicityhas



weekly).

IncaseofGrade2anemia,considerEPO.RestartatreduceddoseoncetoxicityhasdecreasedtoGrade1.

decreasedtoGrade1.

Reference:NIAIDDivisionofMicrobiologyandInfectiousDiseases,severityscale,Nov-2007.


1. Stopthecausativedrugimmediately.

2. Monitorfullbloodcountsregularly.3. ConsidererythropoietinforanemiaGrade2or3.

4. Hospitalizethepatientandconsidertransfusionorerythropoietinifthemyelosuppressionissevere.

5. Consideradditionalanti-TBdrugstoreinforcetheregimen.

Erythropoietin(EPO)

Treatmentwitherythropoietinisnotintendedforpatientswhorequireimmediatecorrectionofanemia (Grade 4). In this case, blood transfusions should be considered.Whole blood countshould be repeated weekly to assess the response to treatment. Blood pressure should beadequatelycontrolledbeforeinitiationandmonitoredduringtherapy.ErythropoietintreatmentshouldinanycasebediscontinuedatHemoglobinlevelsover12g/dL.

Contraindications

Erythropoietintreatmentshouldbeadministeredwithcautioninthepresenceof:

• Untreated,inadequatelytreatedorpoorlycontrolledhypertension• Epilepsy• Thrombocytosis• Chronicliverfailure• Hyperkalemia

Presentation

Epoetinalfaprefilledsyringesof10000UIor40000IU/mltobestoredincoldchain(2°Cto8°C).

Dosing

Epoetin alfa: 150 IU/Kg three times a week or 450 IU/Kg once a week subcutaneously orintravenously.

7.3.3 Prolonged QT interval

Possibleanti-TBdrugcauses:Cfz,Bdq,Mfx,Dlm,Lfx.

Possible other causes: Many other drugs can cause QT prolongation (e.g. erythromycin,clarithromycin, quinidine, ketoconazole, fluconazole, antipsychotics (all have some riskincluding haloperidol, chlorpromazine and risperidone), many anti-nausea drugs


(ondansetron/granisetron, domperidone), methadone, and some antiretrovirals); geneticcausessuchaslongQTsyndrome;hypothyroidism.

• Check an ECG if the patient has clinical symptoms (tachycardia, syncope, palpitations, orweaknessordizziness)ofcardiotoxicity.ChecktheQTintervalandruleoutanarrhythmia.

• TheQTcwillbecalculatedusing theFridericia's formulawhichcorrects for theheartrateand has been shown to be more accurate at slower or faster heart rates than othercorrectionformulae:

QTcF = '(√**+

Where:

QTcF=thecorrectedQTinterval

QT=thetimebetweenthestartoftheQRScomplexandtheendoftheTwave

RR=thetimebetweenthestartofoneQRScomplexandthestartofthenextQRScomplex

• The ECG machine should be calibrated to ensure that the following voltage and speeds

apply:


ProcedureformeasuringRRandQTinterval

• Obtainthe12-leadECG:

o Ensurethatthe12-leadECGisperformedinarelaxedpatienttoavoidartifacts.Usetheappropriateelectrodesandcleanthepatient’sskinifnecessary.

o Ensurethesweepspeedissetto25mm/sec.ThiswillallowforstandardcalibrationandmeasurementoftheQTinterval.

• MeasuretheRRandQTintervalsmanually(Figure1illustratestheintervals):

o TheQTintervalshouldbemeasuredmanually,preferablybyusingoneofthelimbleadsthatbestshowstheendoftheTwaveona12-leadECG.

§ Often, leads IIorV5maybestshowtheendoftheTwave.Try tomeasuretheQTintervalintheseleadsfirst.

§ IftheendoftheTwaveisnotwellseeninleadsIIorV5,thentheclinicianshouldusetheirbestjudgmenttoassesswhichleadbestshowstheendoftheTwave.

o TheQTintervalshouldbemeasuredfromthebeginningoftheQRScomplextotheendoftheTwave.

§ Iftherhythmisirregular(i.e.atrialfibrillation),theQTintervalshouldbeaveragedover3to5beats.CalculatetheQTcFforeachofthe3to5beats,andthencalculatethearithmeticaverageQTcFofthebeats.

§ U waves possibly corresponding to the late repolarization of cells in the midmyocardiumshouldbeincludedinthemeasurementonlyiftheyarelargeenoughtoseemtomergewiththeTwave.ThefigurebelowillustrateshowtodeterminethestartoftheQwaveandendoftheTwavebydrawingabaselineandatangentlineonthebacksideoftheTwave.

§ Each1 mm (small) horizontal box corresponds to 0.04 second (40 msec), withheavierlinesforminglargerboxesthatincludefivesmallboxesandhencerepresent0.20 sec (200msec) intervals. Count the number of boxes thatmake up theQTinterval and thenmultiply the number of boxes by 40msec. if the start of the Q


waveortheendoftheTwavefallinthemiddleofthebox,estimateittothenearest¼ofabox.

• CorrecttheQTintervalfortheheartrate:

o Forstandardization,wewillbeusingtheFridericiaformulatocorrectforheartrate.TheFridericiaformulaperformsbetteratlowerandhigherheartratesthanothercorrectionmethods.

o TheQTcFcanalsobedeterminedbyusingacalculatorandusingtheformulainSection6.3.3;however, it is recommended forclinicians touse theothermethodsas it is lesspronetoerror.OnewayistousetheQTcFnomogrambelow.

o Even simpler and quicker than the nomogram are several applications available onmobile phones (e.g. Android, iPhone) that are designed to calculate the QTcFwith aminimumof effort, for example, theQTcCalculator forAndroidphones (GooglePlay).Theseapplicationsrequire theuser toenter theQT intervaland theRR interval,afterwhichtheQTcwillbecalculatedaccordingtoseveralformulas.Thecorrectunitsshouldbeselected(e.g.mmormsec),aswellasthecorrectformula.

o ComparethecorrectedvaluemeasuredmanuallywithwhattheECGmachineproduces(if the ECG machine has the function of automatically calculating the corrected QTinterval). If there is a difference of more than 20 ms repeat the manualmeasurement.Themanualmeasurementservesasthe"goldstandard".

• RecordRRinterval,heartrate,andtheQTcFintervalinthepatient’schart:

o TheRRintervalismeasuredinseconds.

o Record the heart rate from the ECG machine if it produces it automatically ordetermineditbymeasuringtheRRintervalanddividinginto60.(HR=60/RRintervalinsecond).

o RecordtheQTcFintervalascalculatedbytheinstructionsabove.

HowtousetheQTcFNomogram

Identifythepatient’sHRorRRintervalonthetopofthetable.

IdentifythemeasuredQT(uncorrected)intervalontheleftofthetable. FindthecorrespondingcalculatedQTcFinthecellbelowtheHR(orRR)andtotherightoftheQTinterval.RecordthecalculatedQTcFintheendTBECGform.

Heart rate 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150


(beats per minute)

R-R interval

(sec) 1.33 1.20 1.09 1.00 0.92 0.86 0.80 0.75 0.71 0.67 0.63 0.60 0.57 0.55 0.52 0.50 0.48 0.46 0.44 0.43 0.41 0.40

QT

inte

rval

(mse

c)

300 273 282 291 300 308 316 323 330 337 343 350 356 362 367 373 378 383 388 393 398 403 407 310 282 292 301 310 318 326 334 341 348 355 361 368 374 379 385 391 396 401 406 411 416 421 320 291 301 311 320 329 337 345 352 359 366 373 379 386 392 397 403 409 414 419 424 429 434 330 300 311 321 330 339 347 355 363 371 378 385 391 398 404 410 416 421 427 432 438 443 448 340 309 320 330 340 349 358 366 374 382 389 396 403 410 416 422 428 434 440 446 451 456 461 350 318 329 340 350 359 368 377 385 393 401 408 415 422 428 435 441 447 453 459 464 470 475 360 327 339 350 360 370 379 388 396 404 412 420 427 434 441 447 454 460 466 472 477 483 489 370 336 348 359 370 380 390 399 407 416 424 431 439 446 453 460 466 473 479 485 491 497 502 380 345 358 369 380 390 400 409 418 427 435 443 451 458 465 472 479 485 492 498 504 510 516 390 354 367 379 390 401 411 420 429 438 446 455 462 470 477 484 491 498 505 511 517 523 529 400 363 376 389 400 411 421 431 440 449 458 466 474 482 490 497 504 511 518 524 531 537 543 410 373 386 398 410 421 432 442 451 460 469 478 486 494 502 509 517 524 531 537 544 550 556 420 382 395 408 420 431 442 452 462 472 481 490 498 506 514 522 529 536 543 550 557 564 570 430 391 405 418 430 442 453 463 473 483 492 501 510 518 526 534 542 549 556 563 570 577 584 440 400 414 427 440 452 463 474 484 494 504 513 522 530 539 547 554 562 569 577 584 590 597 450 409 423 437 450 462 474 485 495 505 515 524 534 542 551 559 567 575 582 590 597 604 611 460 418 433 447 460 472 484 496 506 517 527 536 545 554 563 571 580 588 595 603 610 617 624 470 427 442 457 470 483 495 506 517 528 538 548 557 566 575 584 592 600 608 616 623 631 638 480 436 452 466 480 493 505 517 528 539 549 559 569 578 587 596 605 613 621 629 637 644 651 490 445 461 476 490 503 516 528 539 550 561 571 581 590 600 609 617 626 634 642 650 658 665 500 454 471 486 500 514 526 539 550 562 572 583 593 603 612 621 630 639 647 655 663 671 679 510 463 480 495 510 524 537 549 561 573 584 594 605 615 624 634 643 651 660 668 676 684 692 520 472 489 505 520 534 547 560 572 584 595 606 617 627 636 646 655 664 673 681 690 698 706 530 482 499 515 530 544 558 571 583 595 607 618 628 639 649 658 668 677 686 694 703 711 719 540 491 508 525 540 555 568 582 594 606 618 629 640 651 661 671 680 690 699 708 716 725 733 550 500 518 534 550 565 579 592 605 618 630 641 652 663 673 683 693 702 712 721 729 738 746 560 509 527 544 560 575 590 603 616 629 641 653 664 675 685 696 706 715 725 734 743 751 760 570 518 536 554 570 585 600 614 627 640 652 664 676 687 698 708 718 728 738 747 756 765 774 580 527 546 563 580 596 611 625 638 651 664 676 688 699 710 720 731 741 751 760 769 778 787 590 536 555 573 590 606 621 636 649 663 675 688 700 711 722 733 743 754 763 773 783 792 801 600 545 565 583 600 616 632 646 660 674 687 699 711 723 734 745 756 766 776 786 796 805 814

Table18ClinicalmanagementofprolongedQTintervalaccordingtoseveritygrading

Severitygrade* Grade1Mild Grade2Moderate

Grade3Severe Grade4Life-threatening

ElectrocardiogramQTCorrectedIntervalProlonged

QTcF450–480ms#

QTcF481–500ms#

QTcF>=501mswithoutsigns/symptomsofseriousarrhythmia#

QTcF>=501or>60mschangefrombaselineandoneofthefollowing:Torsadedepointesorpolymorphicventriculartachycardiaorsigns/symptomsofseriousarrhythmia#

Action Monitormoreclosely;atleastweeklyECGuntilQTcFhasreturnedtolessthangrade1.Repleteelectrolytesasnecessary.

Monitormoreclosely;atleastweeklyECGuntilQTcFhasreturnedtolessthangrade1.Repleteelectrolytesas

Stopthesuspectedcausativedrug(s).Hospitalizeandrepleteelectrolytesasnecessary.

Stopthesuspectedcausativedrug(s).Hospitalizeandrepleteelectrolytesasnecessary.


Severitygrade* Grade1Mild Grade2Moderate

Grade3Severe Grade4Life-threatening

necessary.

*NCICommonTerminologyCriteriaforAdverseEvent,v.4.0314-Jun-2010.#WhenmultipleECGsarerecordedonasameday,averageoftheQTcFmeasuresshouldbeusedtodeterminethegrade.

Checkingandrepletingserumelectrolytes:

• Serum potassium (K+), ionized calcium (ionized Ca++), and magnesium (Mg++) should beobtainedintheeventaprolongedQTintervalisdetected.

• Abnormalelectrolytesaremostcommonlyduetotheinjectableandshouldbecorrected.

• Whenever a low potassium is detected it should trigger urgent management withreplacementandfrequentrepeatpotassiumtesting(oftendailyormultipletimesaday)todocumentthepotassiumismovinginthecorrectdirection.

• Ifpotassiumisfoundlow,alwayscheckmagnesiumandionizedcalciumandcompensateasneeded. (If unable to check, consider oral empiric replacement doses of magnesium andcalcium).

• Inpatientsreceivingdelamanid,serumalbuminshouldbeobtainedandrepeatedmonthlyintheeventaprolongedQTintervalisdetected.


StopallQTprolongingdrugsimmediately.ARTisusuallynotstoppedunlessthepatientisseverelyunstable.

HospitalizeandconsidercontinuouselectrocardiacmonitoringforGrade3.HospitalizationshouldoccurinafacilitycapableinthemanagementofTorsadesdePointesarrhythmia.

Checkelectrolytesandmanageasdescribedabove.

CheckTSHandtreatanyhypothyroidismfound. Oncestable(QTCFintervalbelow450andnormalelectrolytes),criticalQTprolonginganti-TBdrugscanbeaddedback:

• If the patient is on any non-TB drugs that are prolong the QT interval considersuspendingthem.

• Ifthepatientwasonmoxifloxacinconsiderusinglevofloxacininstead.

• Ifthepatientwasonclofazimineconsidersuspendingitpermanentlyifnotcriticaltotheregimen.

• If the patient is on bedaquiline and it is considered critical to the regimen, consideraddingthedrugbacktothepatient’sregimenwhilesuspendingallotherQTprolongingdrugs(withtheexceptionofstoppingART,whichshouldnotnormallybesuspendedinthemanagementofQTprolongation).

• If the patient is on delamanid and it is considered critical to the regimen, consideraddingthedrugbacktothepatient’sregimenwhilesuspendingallotherQTprolongingdrugs(withtheexceptionofstoppingART,whichshouldnotnormallybesuspendedinthemanagementofQTprolongation).

7.3.4 Optic nerve disorder (optic neuritis)

Possibleanti-TBdrugcauses:Lzd,E,Eto/Pto,rifabutin,H,S.


Possibleothercauses:ddI.

• Opticneuritis is inflammationof theopticnerve eventually resulting inpermanent visionloss.Thefirstsignofopticneuritisisusuallythelossofred-greencolordistinction.ThisisbesttestedusingtheIshiharatest.Othersymptomsincludecentralscotomas.

• LinezolidisbyfarthemostcommoncauseofopticneuritisamongstalloftheTBdrugs.Inaclinical trialof linezolid,18%ofpatientseventuallydevelopedopticneuritis,mostlyafterfourmonthsoftreatment.

• Patientswithdiabetesareatincreasedriskforopticneuritis.Theyshouldbemanagedwithtightglucosecontrolasameansofprevention.Patientswithadvancedkidneydiseasearealsoatincreasedriskforopticneuritis.

Table19Clinicalmanagementofopticnervedisorderaccordingtoseveritygrading

Severitygrade*


Opticnervedisorder

Asymptomatic;clinicalordiagnosticobservationsonly

Limitingvisionoftheaffectedeye(20/40[6/12]orbetter)

Limitingvisionintheaffectedeye(worsethan20/40[6/12]butbetterthan20/200[6/60])

Blindness(20/200[6/60]orworse)intheaffectedeye

Action StopLzdimmediatelyifthereareanysuspicionsofopticneuritis.Donotrestartit.

StopLzdimmediatelyifthereareanysuspicionsofopticneuritis.Donotrestartit.



*NCICommonTerminologyCriteriaforAdverseEvent,v.4.0314-Jun-2010.


• Donotrestartthesuspectedcausativedrug(linezolidorethambutol).

• Referpatienttoanophthalmologistforimmediateevaluationandmanagement.

• Opticneuritisgenerallyimprovesfollowingcessationofoffendingdrug,ifitcanbestoppedearlyenough.

• Consideradditionalanti-TBdrugstoreinforcetheregimen.

7.3.5 Elevated liver enzymes (hepatotoxicity)

Possibleanti-TBdrugcauses:Z,H,Cfz,PAS,Eto/Pto,Bdq,FQ,Amx/Clv.

Possibleothercauses:viralhepatitis(A,B,C),NVP,manyotherdrugs.

Hepatitisischaracterizedbynausea,vomiting, jaundice,scleralicterus,tea-coloredurine,palestool,anddiminishedappetiteinthesettingofelevatedliverfunctiontests.

• Mildelevationofliverenzymes,especiallyatbaseline,mayberelatedtoTBratherthananadverseeffectoftreatment.

• Generally hepatotoxicity due to medications resolves upon discontinuation of suspecteddrug.

• InHIVcoinfection,cotrimoxazolecanbeacauseofhepatotoxicity.


• NVP hepatotoxicity usually occurs shortly after exposure, accompanied by flu-likesymptomswith or without rash. It can also happen late as an isolated hepatitis withoutconstitutional symptoms. Patients who experience NVP hepatotoxicity should not berechallenged.

Table20Clinicalmanagementofelevatedliverenzymesaccordingtoseveritygrading


ALT(SGPT) >ULN–3.0xULN >3.0–5.0xULN >5.0–20.0xULN >20.0xULN

AST(SGOT) >ULN–3.0xULN >3.0–5.0xULN >5.0–20.0xULN >20.0xULN

Action Continuetreatmentregimen.Patientsshouldbefolloweduntilresolution(returntobaseline)orstabilizationofAST/ALTelevation.

Continuetreatmentregimen.Patientsshouldbefolloweduntilresolution(returntobaseline)orstabilizationofAST/ALTelevation.

Stopalldrugs,includinganti-TBdrugs;measureLFTsweekly.Treatmentmaybereintroducedaftertoxicityisresolved.

Stopalldrugs,includinganti-TBdrugs;measureLFTsweekly.Treatmentmaybereintroducedaftertoxicityisresolved.


Reintroductionofanti-TBdrugs:

• Reintroduceanti-TBdrugsonceliverenzymesreturntobaseline.Anti-TBdrugsshouldbereintroducedinserialfashionbyaddinganewmedicineeverythreetofourdays.Theleasthepatotoxic drugs should be added first, whilemonitoring liver function tests after eachnewexposure.

• Considersuspendingthemostlikelyoffendingdrugpermanentlyifitisnotessentialtotheregimen.Thisisoftenthecaseforpyrazinamideifitislesslikelytobeeffectivebyclinicalhistory.Consideradditionalanti-TBdrugstoreinforcetheregimen.

7.3.6 Hearing impaired

Possibleanti-TBdrugcauses:S,Km,Am,Cm,Clr.

Possibleothercauses:none.

• Hearing impaired is adisorder characterized by partial or complete loss of the ability todetectorunderstandsoundsresultingfromdamagetoearstructures.

• The injectablescancausedamageof thehearingapparatusof the innerear, including thecochlea, vestibule, semicircular canals, and cranial nerve VIII. Symptoms include hearingloss and tinnitus, as well as vestibular symptoms such as disequilibrium and visionproblems.

• Hearing loss is commonly observed in patients receiving large cumulative doses ofinjectables.Capreomycinmaybemildlylessototoxicthantheaminoglycosides.

• Hearinglossandvestibulardysfunctionaregenerallynotreversibleupondiscontinuationoftherapy.

• Some degree of hearing loss occurs with most patients taking an injectable, but high-frequencylossmaynotsignificantlyaffectthepatient'squalityoflife.

• Somepatientsmaychoosetotoleratesignificanthearinglosstoachieveahigherchanceofcure. This should be discussed between the patient and a physician trained in MDR-TB.


Continuingtheinjectableinsuchsituationsalmostalwaysresultsinpermanenthearinglossandsometimescompletedeafness.

• Patientswithpreviousexposuretoaminoglycosidesmayhavealreadysustainedadegreeofhearingloss.Thesepatientsareatthehighestriskofincurringfurtherototoxicity.Insuchpatients,audiometrymaybehelpfulinguidingtherapytopreventfurtherdamage.

• Concomitant use of furosemide, particularly in the setting of renal insufficiency, mayexacerbateototoxiceffectsoftheinjectables.


Table21Clinicalmanagementofhearingimpairmentaccordingtoseveritygrading

Severitygrade*


HearingImpaired

AdultsEnrolledonaMonitoringProgram(ona1,2,4,3,6and8kHzaudiogram):thresholdshiftof15-25dBaveragedat2contiguoustestfrequenciesinatleastoneearorsubjectivechangeintheabsenceofaGrade1Thresholdshift.Pediatric(ona1,2,4,3,6and8kHzaudiogram):thresholdshift>20dBat8kHzinatleastoneear.

Adultenrolledinmonitoringprogram(ona1,2,3,4,6and8kHzaudiogram):thresholdshiftof>25dBaveragedat2contiguoustestfrequenciesinatleastoneear.Adultnotenrolledinmonitoringprogram:hearinglossbuthearingaidorinterventionnotindicated;limitinginstrumentalADL.Pediatric(ona1,2,3,4,6and8kHzaudiogram):thresholdshift>20dBat4kHzandaboveinatleastoneear.

Adultenrolledinmonitoringprogram(ona1,2,3,4,6and8kHzaudiogram):thresholdshiftof>25dBaveragedat3contiguoustestfrequenciesinatleastoneear;therapeuticinterventionindicated.AdultNotenrolledinmonitoringprogram:hearinglosswithhearingaidorinterventionindicated;limitingselfcareADL.Pediatric(ona1,2,3,4,6and8kHzaudiogram):hearinglosssufficienttoindicatetherapeuticintervention,includinghearingaids):Thresholdshift>20dBat3kHzandaboveinatleastoneear;additionalspeech-languagerelatedservicesindicated.

Adults:profoundbilateralhearingloss(Threshold>80dBHLat2kHzandabove);nonservicablehearingPediatric:audiologicindicationforcochlearimplantandadditionalspeech-languagerelatedservicesindicated.

Action Considerdecreasinginjectablefrequency(e.g.MWF).Considerreplacingtheinjectablewithanon-ototoxicdrug.

Considerreplacinginjectablewithanon-ototoxicTBdrug.Decreaseinjectablefrequency(e.g.MWF)ifinjectableisessential.

Replaceinjectablewithanon-ototoxicTBdrug.Decreaseinjectablefrequency(e.g.MWF)ifinjectableisessential.

Incasesofcompletehearingloss,someclinicianswillcontinuetheinjectableasthehearinglossisirreversible.Considersuspensionoftheinjectableifsomehearingmightbestillpreservedorifitiscausingotherreversiblesymptomssuchastinnitusorvestibulardisturbances.




• Perform a monthly assessment of hearing loss and balance. Audiometry is helpful indetectingearlyhigh-frequencyhearinglossthatthepatientmaynotevenbeawareof.

• If the patient is experiencing hearing loss, stop the injectable and replace itwith a non-ototoxic drug. If there is no other non-ototoxic drug available or effective, considerdecreasingthedosingfrequencyoftheinjectabletotwotothreetimesaweek.Evenwhennon-ototoxicdrugsarenotavailable,stoppingtheinjectablecanbeconsideredbasedonthepatient'sdesiretomaintainhearing.

• Ifmoderateorseverevertigo,tinnitus(ringingintheears)orvestibulardisturbancesarise,with or without significant hearing loss, consider decreasing frequency or stopping theinjectableagent.

Source:AuditoryNeuroscience:MakingsenseofSound.AccessedJune2013,http://auditoryneuroscience.com/acoustics/clinical_audiograms

Notesonaudiogram:

• This audiogram represents high-frequency hearing loss, which is often the first sign ofauditorytoxicityduetoinjectables.

• Thepatientwith thisaudiogramcouldstillhearconversations.Frequenciesaround2,000Hzarethemostimportantforunderstandingconversations;thepatienthasonlymoderatehearinglossinthisarea.

• Oftenpatientsdonotnoticehearinglossabove4,000Hz.

• Anaudiogram thatdemonstrateshearing loss as illustratedabove is agoodexampleof asituationwheresuspending(orsubstituting)adifferentanti-TBdrugisindicated;thiscanpreventfurtherlossofhearing.


7.3.7 Acute kidney injury Possibleanti-TBdrugcauses:S,Km,Am,Cm.

PossibleARTcauses:TDF(rare).

• Acutekidneyinjuryischaracterizedbytheacutelossofrenalfunctionandistraditionallyclassifiedaspre-renal(lowbloodflowintokidney),renal(kidneydamage)andpost-renalcauses(ureteralorbladderoutflowobstruction).

• The injectables (aminoglycosides and capreomycin) are themost common cause of acuterenal failure in MDR-TB patients. Capreomycin may be less nephrotoxic than theaminoglycosides.

• Injectable nephrotoxicity is often asymptomatic in the early stages and can only bediagnosed with routine laboratory monitoring. End-stage renal failure may present witholiguria/anuriaor signsof volumeoverload includingperipheral edemaand shortnessofbreath. Mental status changes due to uremia or electrolyte abnormalities are a latesymptom.

• Othercommoncausesofacuterenalfailure:

o Prerenaletiologiesincludehypovolemiaduetodehydrationfromvomitingordiarrheaasaside effect ofanti-TB therapy.Hypotensive shock in critically illpatients canalsocauseprerenalphysiology.

o Etiologiesintrinsictothekidneyincludeacutetubularnecrosisduetoaminoglycosidesandcapreomycinoracuteinterstitialnephritisfromotherantibioticslikebeta-lactamsandsulfadrugs.

• TDF may cause renal injury with the characteristic features of Fanconi syndrome:Hypophosphatemia, hypouricemia, proteinuria, normoglycemic glycosuria and, in somecases,acuterenalfailure.

o Evenwithout theconcurrentuseof tenofovir,HIV-infectedpatientshaveanincreasedrisk of renal toxicity secondary to aminoglycosides and capreomycin. Frequentcreatinineandelectrolytemonitoringisrecommended.

o AvoidTDF inpatients receiving aminoglycosidesor capreomycin. IfTDF is absolutelynecessary,serumcreatinineandelectrolytesshouldbemonitoredfrequently(weeklyatthestartoftreatment).

Table22Clinicalmanagementofacutekidneyinjuryaccordingtoseveritygrading

Severitygrade*


AcuteKidneyInjury

Creatininelevelincreaseof>0.3mg/dL;creatinine1.5-2.0xabovebaseline

Creatinine2-3xabovebaseline

Creatinine>3xbaselineor>4.0mg/dL;hospitalizationindicated

Life-threateningconsequences;dialysisindicated

Action Considerstoppinginjectableuntilcreatininehasreturnedtobaseline.Considerrestartingtheinjectableatlowerfrequency(e.g.MWF).

Stopinjectableuntilcreatininehasreturnedtobaseline.Considerrestartingtheinjectableatlowerfrequency(e.g.MWF)orsubstitutewithanon-

Stopinjectableuntilcreatininehasreturnedtobaseline.Considerrestartingtheinjectableatlowerfrequency(e.g.MWF)orsubstitutewithanon-nephrotoxicdrug.

Stopinjectableuntilcreatininehasreturnedtobaseline.Considerrestartingtheinjectableatlowerfrequency(e.g.MWF)orsubstitutewithanon-


nephrotoxicdrug. nephrotoxicdrug.



Monitor serum creatinine and electrolytes frequently in patients receiving injectables.Patients with pre-existing kidney disease, diabetes, or HIV are at high risk of injectablenephrotoxicityandmaybemonitoredmorefrequently.

o Anyincreaseofserumcreatinineabovenormallimitsshouldbeconsideredacuterenalinsufficiency.

o Adoublingofserumcreatinineabovebaseline,evenifwithinnormallimits,shouldbeconsideredworrisomeforacuterenalinsufficiencyandmonitoredcarefully.

Repeatelectrolytesifnecessary.o Injectablenephrotoxicitymaybeassociatedwithinjectable-inducedelectrolytewasting.

For example, it is possible to see elevated creatinine and severehypokalemia/hypomagnesemiaatthesametime.

o The etiology of this phenomenon is unclear, but it may occur more often in HIVcoinfectedpatients.

Discontinuethesuspecteddrug(usuallytheinjectable).Iftheacuterenalfailureissevere,thenstopalldrugs.

o Nephrotoxicity due to the injectable is frequently reversible after the injectable isstopped,butpermanentdamagecanresultifitisnotdetectedearly.

o If the acute renal insufficiency is severeor resolving slowly, thedoseof other renallyexcreteddrugsshouldbeadjusted.

Considerothercontributingetiologies(prerenal,intrinsicrenal,andpostrenal).

Follow serum creatinine and electrolytes closely until the creatinine has returned tobaselineorhasstabilized.

Consider reintroducing the injectablewith an intermittentdosing schedule (two or threetimesaweek)ifthedrugisessentialtotheregimen.

o Consider using capreomycin if an aminoglycoside had been the prior injectable inregimen.

o Considerstrictweight-baseddosingoftheinjectableifthepatient'sweightis lessthan50kg.

o Suspend the injectable permanently if the nephrotoxicity recurs despite intermittentdosing,andaddadditionalanti-TBdrugstoreinforcetheregimen.

7.3.8 Hypokalemia Possibleanti-TBdrugcauses:Cm,Km,Am,S.

PossibleARTcauses:TDF(rare).

• Hypokalemiaandhypomagnesemiaareoftenasymptomatic.

o Moderatecasesmaypresentwithfatigue,myalgia,cramps,paresthesia,lowerextremityweakness,behaviorormoodchanges,somnolence,andconfusion.

o Severe disturbances can lead to tetany, paralysis, and life-threatening cardiacarrhythmias.


• Hypokalemiaandhypomagnesemiaare common inpatients receivingMDR-TBtreatment.CommoncausesinMDR-TBpatientsare:

o Vomitinganddiarrhea.

o Renaltubulartoxicityfromtheinjectable(probablymorecommonincapreomycinthantheaminoglycosides).

o The injectables can cause a syndrome of electrolyte wasting, including potassium,magnesium,calcium,andbicarbonate.

o Thissyndrome ismorecommonandsevere inHIVcoinfectedpatients;hospitalizationandaggressiveserumelectrolytemonitoringandcorrectionmaybenecessary.

• Formulations of oral potassium chloride vary bymanufacturer and country. Slow-releaseversions are common in resource-limited settings. The amount of potassium is oftendifferentthanthetabletsize.Forexample,one200-mgtabletofSlow-Kcontains8mEqofpotassium.

o Oralpotassiumandmagnesiumshouldbeadministeredeithertwohoursbeforeorfourto six hours after fluoroquinolones as they can interfere with fluoroquinoloneabsorption.

o Oralpotassiumcancausenauseaandvomiting.Oralmagnesiumcancausediarrhea.

• Dietary intake of potassium should be encouraged. Bananas, oranges, tomatoes are goodsourcesofsupplementation.

• Amiloride5 to10mgPOdailyorspironolactone25mgPOdailymaydecreasepotassiumandmagnesiumwastingdue to the injectable andmaybe useful in severe cases that arerefractorytoreplacementtherapy.

Table23Clinicalmanagementofhypokalemiaaccordingtoseveritygrading

Severitygrade*


Hypokalemia 3.4-3.0mmol/L 2.9-2.5mmol/L 2.4-2.0mmol/Lorintensivereplacementtherapyorhospitalizationrequired

<2.0mmol/Lorabnormalpotassiumwithparesis,ileusorlife-threateningarrhythmia

Action Continueinjectable.Startoralpotassiumreplacementtherapy.Checkserummagnesiumandreplaceifnecessary.

Continueinjectable.Startaggressiveoralpotassiumreplacementtherapy.Replacemagnesiumasnecessary.

Considerstoppingtheinjectabletemporarily.StartIVpotassiumreplacementtherapyinadditiontooral.Replacemagnesiumandotherelectrolytesasnecessary.

Stopinjectabletemporarily.StartIVpotassiumreplacementtherapyinadditiontooral.Replacemagnesiumandotherelectrolytesasnecessary.


Table24Clinicalmanagementofhypomagnesemiaaccordingtoseveritygrading



Hypomagnesemia 0.70-0.60mmol/L 0.59-0.45mmol/L 0.44-0.30mmol/L <0.30mmol/L

Action Startoralmagnesiumreplacementtherapy.

Startaggressiveoralmagnesiumreplacementtherapy.

Startintravenousmagnesiumreplacementtherapyinadditiontooral.Replaceotherelectrolytesasnecessary.

Startintravenousmagnesiumreplacementtherapyinadditiontooral.Replaceotherelectrolytesasnecessary.



Monitor serum potassium, magnesium, and calcium frequently in patients withvomiting/diarrheaandpatientsreceivinginjectables.

Check for signs of dehydration in patients with vomiting and diarrhea. Start oral orintravenousrehydrationtherapyimmediatelyuntilvolumestatusisnormal.

Repletepotassiumandmagnesium.o Hypokalemiamayberefractoryifconcurrenthypomagnesemiaisnotalsocorrected.

o Ifunabletocheckserummagnesium,giveempiricoralreplacementtherapyinallcasesofhypokalemiawithmagnesiumgluconate1000mgtwicedaily.

In all cases of detected serum electrolyte disturbances (Grade 1-4) obtain anelectrocardiogram as soon as possible and then weekly until potassium and otherelectrolytesreturntonormal.

DrugsthatprolongtheQTintervalshouldbediscontinuedinpatientswithevidenceofQTintervalprolongation.

Electrolyte abnormalities are reversibleupondiscontinuationof the injectable. Evenaftersuspendingtheinjectable,itmaytakeweeksormonthsforthissyndrometodisappear,soelectrolytereplacementtherapyshouldcontinueforseveralmonthsaftercompletionoftheinjectablephaseofMDR-TBtreatment.

Table25Potassiumreplacementtherapy

Potassiumlevel(mmol/L)

Dosing Monitoringfrequency

>3.4 None Monthly

3.3-3.4 40mmolPOin2-3divideddosesdaily Monthly

2.9-3.2 60-80mmolPOin3divideddosesdaily Weekly

2.7-2.8 60mmolPOeveryeighthours Onetotwodays

2.5-2.6 80mmolPOeveryeighthours Daily

<2.5 10mmol/hourIVand80mmolPOeverysixtoeighthours

Onehourafterinfusion,everysixhourswithIVreplacement


Note:Thenormalpreparationofapotassiumchlorideinfusionis40mmol(3ampoules)in1LofNaCl0.9%infusedover4hours.Donotexceedaninfusionrateof10mmol/hour(250mL/hour).Potassiumchloride10%(100mg/ml)ampoules=1gperampoule=13.4mmol.Potassiumchloridecontrolledreleasetabletsof600mg=8mmol/tablet.

Table26Magnesiumreplacementtherapy

Magnesiumlevel(mmol/L) Totaldailydose Monitoringfrequency

>0.7.0ormore None Monthly

0.60-0.70 1,000mg-1,200mg Monthly

0.45-0.59 2,000mg Onetosevendays

<0.45 3,000mg-6,000mg Daily

Note:Quantitiesgreaterthan2,000mgareusuallygivenIVorIM.Thenormalpreparationismagnesiumsulfate2gin100mLor4gin250mLofnormalsaline.Donotexceedaninfusionrateof150mg/min(2gin100mLadministeredoveronetotwohours,4gin250mLadministeredovertwotofourhours).

7.3.9 Hypothyroidism Possibleanti-TBdrugcauses:Eto/Pto,PAS.

PossibleARTcauses:d4T.

• Ethionamide (or prothionamide) and PAS have a direct toxic effect on the thyroid thatinterferes with thyroid hormone synthesis. The exact incidence of hypothyroidism isunknown,butitisprobablymorecommonthantraditionallythought.

• Patients may develop symptoms as soon as a few weeks after exposure to offendingmedications.

• Symptomsofhypothyroidismincludefatigue,somnolence,coldintolerance,dryskin,coarsehair,andconstipation,aswellasdepressionandinabilitytoconcentrate.Thyromegalyanddelayeddeeptendonreflexesmaybeencounteredonexam.

• Inprimaryhypothyroidism,thediagnosisisconfirmedbyaserumlevelofTSHgreaterthan10.0mU/L,indicatingsuppressionofthethyroidhormoneproductionbythethyroidgland.Nootherthyroidtests(e.g.,freeT4,T3)arenecessaryfordiagnosisortreatmentmonitoring.

• InHIVcoinfectedpatients there issomeevidence thatsubclinicalhypothyroidismmaybeassociatedwithsomeARVs,particularlystavudine(d4T).

• Hypothyroidism can result in QT interval prolongation. Check an ECG wheneverhypothyroidismisfoundandifQTintervalprolongationoranarrhythmiaisfoundreferforhospitalizationandappropriatemanagement.

Table27Clinicalmanagementofhypothyroidismaccordingtoseveritygrading

Severitygrade*


Hypothyroidism Asymptomatic;clinicalordiagnosticobservationsonly;

Symptomatic;thyroidreplacementindicated;limiting

Severesymptoms;limitingselfcareADLhospitalizationindicated

Life-threateningconsequences;urgentinterventionindicated


interventionnotindicated

instrumentalADL

Action Continueanti-TBdrugs.

Continueanti-TBdrugs.Startthyroxine.

Continueanti-TBdrugs.Startthyroxine.

Stopallanti-TBdrugs.Startthyroxine.



Inpatientswithhypothyroidism,mostadultswillrequire100to150mcgoflevothyroxinedaily.

o Younghealthyadultscanbestartedon75to100mcgdaily.

o Olderpatientsshouldbegintreatmentwith50mcgdaily.

o Patientswithsignificantcardiovasculardiseaseshouldstartat25mcgdaily.

Childrenclearthyroxinefasterthanadults,sodailyreplacementdosesmaybehigher.

o Children(4-15years):4mcg/kg/day(maximumdoseis200mcg).

o Infants(1-3years):10-15mcg/kg/day(maximumdoseis200mcg).

MonitorTSHeveryone to twomonthsand increasedoseby25 to50mcguntilTSH is innormalrange.Adjustdosemoreslowlyintheelderlyandpatientswithcardiacconditions.

Hypothyroidismisreversibleupondiscontinuationofethionamide/prothionamideorPAS.Asaresult,thyroidhormonereplacementmaybestoppedseveralmonthsaftercompletionofMDR-TBtreatment.


7.4 Frequent adverse events

ThistableisextractedfromthefullSeverityGradingScale,whichisavailableathttp://endtb.org/resources/pharmacovigilance.Thefollowingtabledoesnotincludetheadverseeventsofinterest;forthosegradingscales,refertotherelevantsection.

Table23.Listofmostfrequentadverseevents

Adverseevent Definition Grade1 Grade2 Grade3 Grade4

Cardiovasculardisorders

Cardiacrhythm AbnormalityincardiacrhythmotherthanQTIntervalProlongation.

N/A Asymptomatic,transientsigns,notreatmentrequired

Recurrent/persistent;symptomatictreatmentrequired

Unstabledysrhythmia;hospitalizationandtreatmentrequired

Chemistry

Lactateincreased(lacticacidosis)

Increaseinbloodlactateaccompaniedornotwithbloodacidification.

ULNto<2.0xULNwithoutacidosis

≥2.0xULNwithoutacidosis

IncreasedlactatewithpH<7.3withoutlifethreateningconsequences

IncreasedlactatewithpH<7.3withlifethreateningconsequences

EarDisorders

Tinnitus Adisordercharacterizedbynoiseintheears,suchasringing,buzzing,roaringorclicking

Mildsymptoms;interventionnotindicated

Moderatesymptoms;limitinginstrumentalADL

Severesymptoms;limitingselfcareADL

N/A

VestibularDisorder Adisordercharacterizedbydizziness,imbalance,nausea,andvisionproblems.

N/A Symptomatic;limitingiADL

Severesymptoms;limitingselfcareADL

N/A

GastrointestinalDisorders

Diarrhea Adisordercharacterizedbyfrequentandwaterybowelmovements.

Mildortransient;3-4loosestools/dayormilddiarrhealast<1week

Moderateorpersistent;5-7loosestools/dayordiarrhealasting>1week

>7loosestools/dayorbloodydiarrhea;ororthostatichypotensionorelectrolyteimbalanceor>2LIVfluidsrequired

Hypotensiveshockorphysiologicconsequencesrequiringhospitalization

Dyspepsia Adisordercharacterizedbyanuncomfortable,oftenpainfulfeelingin

Mildsymptoms;interventionnot

Moderatesymptoms;medicalintervention

Severesymptoms;surgicalinterventionindicated

N/A


thestomach,resultingfromimpaireddigestion.Symptomsincludeburningstomach,bloating,heartburn,nauseaandvomiting.

indicated indicated

Nausea Adisordercharacterizedbyaqueasysensationand/ortheurgetovomit.

Mildortransient;maintainsreasonableintake

Moderatediscomfort;intakedecreasedsignificantly;someactivitylimited

Nosignificantintake;requiresIVfluids

Hospitalizationrequired

OralDiscomfort/Dysphagia

Adisordercharacterizedbydifficultyinswallowing.

Milddiscomfort;nodifficultyswallowing

Somelimitsoneating/drinking

Eating/talkingverylimited;unabletoswallowsolidfoods

Unabletodrinkfluids;requiresIVfluids

Pancreatitis Adisordercharacterizedbyinflammationofthepancreas.

N/A Enzymeelevationorradiologicfindingsonly

Severepain;vomiting;medicalinterventionindicated(e.g.analgesia,nutritionalsupport)

Life-threateningconsequences;urgentinterventionindicated

Vomiting Adisordercharacterizedbythereflexiveactofejectingthecontentsofthestomachthroughthemouth.

1episodein24hours

2-5episodesin24hours

>6episodesin24hoursorneedingIVfluids

Physiologicconsequencesrequiringhospitalizationorrequiringparenteralnutrition

GeneralDisorders

Headache Adisordercharacterizedbyasensationofmarkeddiscomfortinvariouspartsofthehead,notconfinedtotheareaofdistributionofanynerve.

Mild,notreatmentrequired

Transient,moderate;treatmentrequired

Severe;respondstoinitialnarcotictherapy

Intractable;requiresrepeatednarcotictherapy

ImmuneDisorders

AllergicReaction Adisordercharacterizedbyanadverselocalorgeneralresponsefromexposuretoanallergen.Worststage'anaphylaxis'ischaracterizedbyanacuteinflammatoryreactionresultingfromthereleaseof

Prurituswithoutrash

Localizedurticaria Generalizedurticaria;angioedema

Anaphylaxis


histamineandhistamine-likesubstancesfrommastcells,causingahypersensitivityimmuneresponse.Clinically,itpresentswithbreathingdifficulty,dizziness,hypotension,cyanosisandlossofconsciousnessandmayleadtodeath.

MusculoskeletalDisorders

Arthralgia(jointpain) Adisordercharacterizedbyasensationofmarkeddiscomfortinajoint.

Mildpainnotinterferingwithfunction

Moderatepain,analgesicsand/orpaininterferingwithfunctionbutnotwithADL

Severepain;painand/oranalgesicsinterferingwithADL

Disablingpain

Arthritis Adisordercharacterizedbyinflammationinvolvingajoint.

Mildpainwithinflammation,erythemaorjointswelling,butnotinterferingwithfunction

Moderatepainwithinflammation,erythemaorjointswelling;interferingwithfunction,butnotwithADL

Severepainwithinflammation,erythemaorjointswellingandinterferingwithADL

Permanentand/ordisablingjointdestruction

Myalgia Adisordercharacterizedbymarkeddiscomfortsensationoriginatingfromamuscleorgroupofmuscles.

Myalgiawithnolimitationofactivity

Muscletenderness(atotherthaninjectionsite)orwithmoderateimpairmentofactivity

Severemuscletendernesswithmarkedimpairmentofactivity

Frankmyonecrosis

Tendinopathy Tendoninjuriesfrommildinflammation,partialteartorupture.

Stretchedtendonfibers(notear).Tendernessandswelling.Jointstable.

Partialtendontear.Moderatetendernessandswelling.Jointunstableorgivesawayduringactivity,decreasedrangeofmotion.

Completetendontear/rupture,Significanttendernessandswelling.Jointunstable.Nojointmovementonmusclecontraction.Surgeryrequired.

Life-threateningcomplicationfromsurgery.

NeurologicalDisorders

Dysgeusia Adisordercharacterizedbyabnormalsensualexperiencewiththetasteof

Alteredtastebutnochangeindiet

Alteredtastewithchangeindiet(e.g.

N/A N/A


foodstuffs;itcanberelatedtoadecreaseinthesenseofsmell.

oralsupplements);noxiousorunpleasanttaste;lossoftaste

Seizure Adisordercharacterizedbyasudden,involuntaryskeletalmuscularcontractionsofcerebralorbrainstemorigin.

Briefpartialseizure;nolossofconsciousness

Briefgeneralizedseizure

Multipleseizuresdespitemedicalintervention

Life-threatening;prolongedrepetitiveseizures

PsychiatricDisorders

Anxiety Adisordercharacterizedbyapprehensionofdangeranddreadaccompaniedbyrestlessness,tension,tachycardia,anddyspneaunattachedtoaclearlyidentifiablestimulus.

Mildsymptoms;interventionnotindicated;and/orHamiltonAnxietyRatingScalescore1-17.

Moderatesymptoms;limitinginstrumentalADL;and/orHamiltonAnxietyRatingScalescore18-24.

Severesymptoms;limitingselfcareADL;hospitalizationnotindicated;and/orHamiltonAnxietyRatingScalescore25-30.

Life-threatening;HamiltonAnxietyRatingScalescore>30;and/orhospitalizationindicated

Depression Adisordercharacterizedbymelancholicfeelingsofgrieforunhappiness.

Milddepressivesymptoms;and/orPHQ9depressionscore1-9.

Moderatedepressivesymptoms;limitinginstrumentalADL;and/orPHQ9depressionscore10-14.

Severedepressivesymptoms;limitingselfcareADL;hospitalizationnotindicated;and/orPHQ9depressionscore15-19.

Life-threateningconsequences,threatsofharmtoselforothers;PHQ9depressionscore20-27;and/orhospitalizationindicated

Psychosis Adisordercharacterizedbypersonalitychange,impairedfunctioning,andlossoftouchwithreality.

Mildpsychoticsymptoms

Moderatepsychoticsymptoms(e.g.,disorganizedspeech;impairedrealitytesting)

Severepsychoticsymptoms(e.g.,paranoid;extremedisorganization);hospitalizationnotindicated

Life-threateningconsequences,threatsofharmtoselforothers;hospitalizationindicated

Suicidalideation Adisordercharacterizedbythoughtsoftakingone'sownlife.

Increasedthoughtsofdeathbutnowishtokilloneself

Suicidalideationwithnospecificplanorintent

Specificplantocommitsuicidewithoutseriousintenttodiewhichmaynotrequirehospitalization

Specificplantocommitsuicidewithseriousintenttodiewhichrequireshospitalization

Reproductivesystemandbreastdisorders

Gynecomastia Adisordercharacterizedbyexcessive Asymptomatic Symptomatic(e.g.pain Severesymptoms;elective N/A


developmentofthebreastsinmales. breastenlargement orpsychosocialimpact)

operativeinterventionindicated

SkinDisorders

MucocutaneousSymptoms

Generalscaleforskindisordersfromsignsandsymptoms(e.g.itching)tolife-threateningskinconditions(e.g.StevenJohnsonsyndrome).

Erythema;pruritus Diffuse,maculopapularrash,drydesquamation

Vesiculationormoistdesquamationorulceration

Exfoliativedermatitis,mucousmembraneinvolvementorerythema,multiformeorsuspectedStevens-Johnsonornecrosisrequiringsurgery

Pruritus Adisordercharacterizedbyanintenseitchingsensation.

Slightitchingatinjectionsite

Moderateitchingatinjectionextremity

Itchingoverentirebody N/A

SkinHypo-orHyper-Pigmentation

Adisordercharacterizedbylossofskinpigmentoradarkeningoftheskinduetoexcessivemelanindeposition.

Hypo-/Hyper-pigmentationordepigmentationcovering<10%BSA;nopsychosocialimpact

Hypo-/Hyper-pigmentationordepigmentationcovering>10%BSA;associatedpsychosocialimpact

N/A N/A

8 References

Relevantreferencestoproducethisguideinclude:

• Companion handbook to the WHO 2011 guidelines for the programmatic management ofdrug-resistanttuberculosis,2ndedition(WHO/HTM/TB/2014.11).WHO,Geneva.2015.

• PIHGuide to theMedicalManagement ofMDR-TB, 2ndEdition. Partners InHealth, Boston,USA.USAIDTBCAREII.2013.

• ReportoftheGuidelineDevelopmentGroupMeetingontheuseofbedaquilineinthetreatmentof multidrug-resistant tuberculosis: A review of available evidence (2016)(WHO/HTM/TB/2017.01).WHO,Geneva.2017.

• Tuberculosis: practical guide for clinicians, nurses, laboratory technicians and medicalauxiliares.2014Edition.MédecinsSansFrontièresandPartnersInHealth.

• The use of bedaquiline in the treatment of MDR-TB: interim policy guidance(WHO/HTMTB/2013.6).WHO,Geneva.2013.

• The use of delamanid in the treatment of MDR-TB: interim policy guidance(WHO/HTM/TB2014.23).WHO,Geneva.2014.

• The use of delamanid in the treatment of multidrug-resistant tuberculosis in children andadolescents:interimpolicyguidance(WHO/HTM/TB/2016.14).WHO,Geneva.2016.

• WHO treatment guidelines for drug-resistant tuberculosis, 2016 update(WHO/HTM/TB/2016.04).WHO,Geneva.2016.

• WHO best-practice statement on the off-label use of bedaquiline and delamanid for thetreatment of multidrug-resistant tuberculosis (WHO/HTM/TB/2017.20). WHO, Geneva.2017.

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Clinical and Programmatic Guide for Patient Management ... guide for New … · 1 Introduction Two new anti-TB drugs have been granted conditional medical approval by stringent regulatory